toremifene and Breast-Neoplasms

Adjuvant endocrine therapy is a vital portion of postoperative comprehensive treatment for breast cancer patients. In recent years, studies have shown that endocrine therapy has a certain impact on the serum lipids of breast cancer patients, and the changes of lipid profiles may bring a series of problems. However, very few studies focus on this issue to date. The results of these studies are inconsistent, and the influence of different adjuvant endocrine modalities on lipid profiles still remains controversial. In order to better explore this issue, we conduct this network meta-analysis.. The protocol followed preferred reporting items for systematic reviews and meta-analyses protocols. Three main databases (PubMed, Embase, and the Cochrane Library) will be searched systematically for eligible randomized controlled trials without language restriction. In addition, a manual search of the references of relevant published studies will also be considered. Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is the variation of biochemical parameters - the serum lipid profiles (cholesterol, triglyceride, high-density lipoprotein, low low-density lipoprotein).. The results will provide useful information about the side effects of different adjuvant endocrine drugs on lipid profiles in postoperative breast cancer patients (estrogen receptor-positive and/or progesterone receptor-positive).. The findings of this study will be published in a peer-reviewed journal.. CRD42019129850.

Topics: Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Humans; Letrozole; Lipids; Network Meta-Analysis; Research Design; Tamoxifen; Toremifene

Traditional menopausal hormone therapy containing estrogens/progestin has been associated with an increased risk of breast cancer, and estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective estrogen receptor modulators, antiestrogens, and the first tissue selective estrogen complex combining conjugated estrogens with the selective estrogen receptor modulator bazedoxifene in postmenopausal women. Selective estrogen receptor modulators and antiestrogens act as estrogen receptor antagonists in the breast. Tamoxifen, toremifene, and the selective estrogen receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective estrogen receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective estrogen receptor modulators and selective estrogen receptor modulator combinations capable of achieving the ideal balance of estrogen receptor agonist and antagonist effects.

Topics: Animals; Breast; Breast Neoplasms; Drug Therapy, Combination; Estradiol; Estrogen Antagonists; Estrogens; Estrogens, Conjugated (USP); Female; Fulvestrant; Humans; Indoles; Osteoporosis; Postmenopause; Protective Factors; Raloxifene Hydrochloride; Risk Assessment; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have varying estrogen agonist and antagonist activities in different tissues, most likely due to the receptor conformation changes associated with that SERM's binding and the subsequent effect on transcription. Clinical trials aim to differentiate amongst SERMs on selected target tissues for use in postmenopausal women including effects on breast, bone, cardiovascular venous thrombosis risk, endometrium, vagina, vasomotor symptoms, and brain. This paper describes differences in clinical effects on selected target tissues of SERMs that are approved, discontinued or in development. FDA approved SERMs include tamoxifen and toremifene used for prevention and treatment of breast cancer, raloxifene approved for prevention and treatment of osteoporosis and prevention of invasive breast cancer, and ospemifene approved for treatment of dyspareunia from menopausal vaginal atrophy. The FDA approved first tissue selective estrogen complex (TSEC) a pairing of conjugated equine estrogens with the SERM, bazedoxifene. This pairing reduces the risk of endometrial hyperplasia that can occur with the estrogenic component of the TSEC without the need for a progestogen in women with a uterus. It also allows for the estrogenic benefits on relief of hot flashes and prevention of bone loss without stimulating the breast or the endometrium. In clinical practice, the tissue-selective actions of SERMs, alone or paired with estrogens, allow for individualization in meeting the treatment needs of postmenopausal women by providing targeted tissue effects. This article is part of a Special Issue entitled 'Menopause'.

Topics: Breast Neoplasms; Clinical Trials as Topic; Dyspareunia; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Osteoporosis; Osteoporosis, Postmenopausal; Postmenopause; Pyrrolidines; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Toremifene

A meta-analysis of randomized trials was performed to compare the efficacy of toremifene (TOR) with tamoxifen (TAM) in patients with breast cancer. A total of 4,768 intention-to-treat patients from nine randomized trials were identified, with 2,587 patients in TOR group and 2,181 patients in TAM group. The primary outcomes were objective response rate (ORR), time to progression (TTP), and overall survival (OS). The ORR for TOR group was 26.2 % (303/1,156), whereas the ORR for TAM group was 25.2 % (284/1,128). The pooled RR suggested that the ORR were not statistically different between the two therapeutic groups (RR 1.04, 95 % CI 0.91-1.20, P = 0.57). The median TTP was 6.7 months for the TOR group and 9.7 months for the TAM group. The median OS was 30.1 months for the TOR group and 31.7 months for the TAM group. There were no significant difference in TTP and OS between two therapeutic groups (for TTP: HR 0.91, 95 % CI 0.82-1.00; for OS: HR 1.02, 95 % CI 0.91-1.15). Adverse events were generally similar in two therapeutic groups, but TOR may cause fewer vaginal bleeding (4.0 vs. 6.7 %, P < 0.01), headache (0.2 vs. 3.1 %, P = 0.02) and thromboembolic events (4.7 vs. 7.0 %, P = 0.04). Sensitivity analyses were performed by deleting a single study each time; all the results were not materially altered. In summary, the results of this meta-analysis suggest that TOR and TAM have similar efficacy in the treatment of patients with breast cancer.

Topics: Breast Neoplasms; Female; Humans; Randomized Controlled Trials as Topic; Tamoxifen; Toremifene; Treatment Outcome

Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) > 40 years ago represented a revolutionary advance in the treatment of breast cancer. As a therapeutic class, SERMs have either estrogenic or antiestrogenic activity, depending on the target tissue and the hormonal environment. In breast tissue, SERMs are antiestrogenic, making them a major treatment option for women with hormone-sensitive breast cancer. Toremifene citrate was developed > 20 years ago with the goal of achieving efficacy similar to that of tamoxifen and with an improved safety profile. Although studies to date have not confirmed a clear safety advantage or disadvantage for toremifene, clinical data support the efficacy and safety of toremifene for the treatment of breast cancer in postmenopausal patients. Toremifene also has a pharmacokinetic profile and metabolic pathway different from that of tamoxifen, which may provide a therapeutic advantage in certain patients. In addition, because of the selective estrogenic effects of SERMs in bone and on lipid levels along with a different side effect profile compared with the aromatase inhibitors (AIs), toremifene is a viable option to the AIs for some patients. Despite a number of clinical trials and over 500,000 patient years of use, many oncologists have limited familiarity with toremifene data. This article will examine the rationale for the use of toremifene in the treatment of women with breast cancer and review data from 20 years of clinical experience with this agent.

Topics: Adult; Aged; Aged, 80 and over; Aromatase Inhibitors; Bone Density; Breast Neoplasms; Cytochrome P-450 CYP2D6; Drug Resistance, Neoplasm; Female; Humans; Lipids; Middle Aged; Postmenopause; Selective Estrogen Receptor Modulators; Toremifene

Toremifene and tamoxifen are both selective estrogen receptor modulators used in the treatment of breast cancer patients. Therefore, we carried out a meta-analysis to achieve a more precise evaluation of the effects of toremifene versus tamoxifen on breast cancer patients, including the efficacy and safety, and the effects on the uterus, lipids, and bone. Comprehensive literature searches were conducted using the electronic databases and reference lists to include randomized controlled trials (RCTs) that compared toremifene with tamoxifen for breast cancer patients. Two reviewers independently selected studies and abstracted data. Data were analyzed by Review Manager, version 5.0. Twenty-three trials (7242 patients) were included. For early stage breast cancer, toremifene was associated with higher 5-year survival rates (OR 1.25, 95 % CI 1.04, 1.50), more vaginal discharge (OR 1. 32, 95 % CI 1.01, 1.73), a greater decrease in serum triglyceride levels (SMD -1.01, 95 % CI -1.89, -0.14), a smaller decrease in LDL cholesterol levels (SMD 0.45, 95 % CI 0.07, 0.84) and in bone mineral density in Ward's triangle (SMD -0.36, 95 % CI -0.71, -0.01), and a greater increase in HDL cholesterol levels (SMD 0.43, 95 % CI 0.08, 0.77) than tamoxifen. For advanced breast cancer patients, toremifene was associated with more vaginal bleeding (OR 0.45, 95 % CI 0.26, 0.80) and a greater decrease in serum triglyceride levels (SMD -1.15, 95 % CI -1.90, -0.39) than tamoxifen. Available evidence showed that toremifene could be an alternative option to tamoxifen for both early and advanced breast cancer patients. However, the methodological quality of the included studies was low. More rigorous RCTs are needed to confirm the results of this meta-analysis in the future.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Meta-Analysis as Topic; Prognosis; Tamoxifen; Toremifene

Toremifene is a triphenylethylene selective estrogen receptor modulator (SERM) that differs from tamoxifen in a single chloride ion addition on a side chain, resulting in a potentially more favorable toxicity profile.. This article reviews the pharmacokinetics of toremifene and its potential use for the treatment of osteoporosis. This article was based on articles found through a literature search containing the terms 'toremifene' and 'SERMs.'. Toremifene can be administered orally with an excellent bioavailability. The overall pharmacokinetic profile is remarkably similar to tamoxifen. Toremifene is highly metabolized in the liver and is eliminated primarily in the feces following enterohepatic circulation. Some of its metabolites retain biological activity. This SERM was approved by the FDA for the treatment of estrogen receptor-positive metastatic breast cancer and is under investigation for its potential skeletal benefits in men on androgen deprivation therapy. Despite the positive preclinical and clinical evidences for the prevention of bone loss and fractures, the chemopreventive effect on prostate cancer remains to be confirmed and an increased risk of venous thromboembolism was evidenced in a large Phase III trial. Thus, additional data are required to establish the full clinical profile of this compound and its potential advantages over antiresorptive agents commonly in use for the treatment of osteoporosis.

Topics: Breast Neoplasms; Clinical Trials, Phase III as Topic; Female; Humans; Liver; Male; Osteoporosis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Thromboembolism; Toremifene

Toremifene (TOR) and tamoxifen (TAM) can both be used as treatments for advanced breast cancer.. To compare the efficacy and safety of TOR with TAM in patients with advanced breast cancer.. The Cochrane Breast Cancer Group's Specialised Register was searched (1 July 2011) using the codes for "toremifene", "fareston", "tamoxifen, "nolvadex, and "breast cancer". We also searched MEDLINE (via PubMed) (from inception to 1 July 2011), EMBASE (via Ovid) (from inception to 1 July 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2011), and the WHO International Clinical Trials Registry Platform search portal (1 July 2011). In addition, we screened the reference lists of relevant trials or reviews.. Randomised controlled trials (RCTs) that compared the efficacy and safety, or both of TOR with TAM in women with advanced breast cancer. Trials that provided sufficient data on one of the following items: objective response rate (ORR), time to progression (TTP), overall survival (OS), and adverse events, were considered eligible for inclusion.. Studies were assessed for eligibility and quality. Two review authors independently extracted the following details: first author, publication year, country, years of follow-up, treatment arms, intention-to-treat (ITT) population size, menopausal status of patients, hormone receptor status, response criteria, efficacy and safety outcomes of TOR and TAM arms. Hazard ratios (HR) were derived for time-to-event outcomes, where possible, and response and adverse events were analysed as dichotomous variables. We used a fixed-effect model for meta-analysis unless there was significant between-study heterogeneity.. A total of 2061 patients from seven RCTs were included for final analysis, with 1226 patients in the TOR group and 835 patients in the TAM group. The ORR for the TOR group was 25.8% (316/1226) whereas, the ORR for the TAM group was 26.9% (225/835). The pooled risk ratio (RR) suggested that the ORRs were not statistically different between the two groups (RR 1.02, 95% confidence interval (CI) 0.88 to 1.18, P = 0.83). The median TTP was 6.1 months for the TOR group and 5.8 months for the TAM group. The median OS was 27.8 months for the TOR group and 27.6 months for the TAM group. There were no significant differences in TTP and OS between the two therapeutic groups (for TTP: HR 1.08, 95% CI 0.94 to 1.24; for OS: HR 1.02, 95% CI 0.86 to 1.20). The frequencies of most adverse events were also similar in the two groups, while headache seemed to occur less in the TOR group than in the TAM group (RR 0.14, 95% CI 0.03 to 0.74, P = 0.02). There was no significant heterogeneity between studies in most of the above meta-analyses. Sensitivity analysis did not alter the results.. TOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Randomized Controlled Trials as Topic; Tamoxifen; Toremifene

Compared to tamoxifen, the efficacy and side effects of toremifene in adjuvant endocrine therapy for breast cancer were not very clear. This meta-analysis was conducted to give a more precise estimation of the efficacy and severe side effects of toremifene given in the adjuvant setting in comparison to tamoxifen. The electronic database PubMed was searched for randomized trials comparing toremifene with tamoxifen as adjuvant therapies. Four randomized trials published in three articles were eligible, including 1,890 pooled cases treated with toremifene and 1,857 cases treated with tamoxifen. Compared to patients in tamoxifen group, patients in toremifene group did not have a significantly different overall survival rate (risk ratio (RR): 1.07, 95% confidence interval (CI): 0.97-1.19, P = 0.994 for heterogeneity) or a disease-free survival (DFS) rate (RR: 1.05, 95% CI: 0.95-1.17, P = 0.431 for heterogeneity) at the end of the follow-up time. The rates of thromboembolic events in toremifene group, including deep vein thrombosis (odds ratio (OR): 0.68, 95% CI: 0.40-1.17, P = 0.926 for heterogeneity), cerebrovascular accident (OR: 0.59, 95% CI: 0.32-1.09, P = 0.438 for heterogeneity), and pulmonary embolism (OR: 0.91, 95% CI: 0.42-2.01, P = 0.618 for heterogeneity), were not significantly different from those in tamoxifen group. The rates of endometrial polyps and endometrial cancer between the two groups were almost the same. This meta-analysis suggested that toremifene was as effective as tamoxifen in the adjuvant setting for both perimenopausal and postmenopausal breast cancer patients with similar severe adverse effects to tamoxifen. Toremifene was a convincing and safe change for tamoxifen in adjuvant endocrine therapy.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Tamoxifen; Toremifene; Treatment Outcome

Selective estrogen receptor modulators (SERMs), known previously as "antiestrogens", are a new category of therapeutic agents used for the prevention and treatment of diseases such as osteoporosis and breast cancer. SERMs act as ER-agonist in some tissues while acting as ER-antagonist in others based on conformational change of the receptors, particularly at the helix 12. Currently, there are two classes of clinically approved SERMs; triphenylethylene derivatives (e.g., tamoxifen) and benzothiophene derivatives (e.g., raloxifene). Tamoxifen, raloxifene and toremifene are the most widely used SERMs. Tamoxifen, an antagonist of the breast tissue, is the first clinically identified compound with noticeable SERM activity. Although tamoxifen has been very successful in breast cancer treatment, its agonistic effect on the uterus is said to be associated with increase risk of developing endometrial cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagonist in the breast and uterus. Therefore, the therapeutic goal of SERMs is the prevention of estrogen deficiency diseases without promoting estrogen-associated tumor growth. Therefore, the objective of this review is to summarize various effects that have been applied in improving the tissue-selectivity of SERMs, highlighting the emerging understanding of their mechanism of actions in selected target tissues and the development of the SERMs. The significance in recent discovery of selective estrogen receptor alpha modulators, SERAMs will also be reviewed.

Topics: Breast Neoplasms; Drug Design; Estrogen Receptor alpha; Female; Humans; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Stilbenes; Structure-Activity Relationship; Tamoxifen; Thiophenes; Toremifene

Toremifene has been in clinical use for 8 years for the treatment of advanced hormone-sensitive breast cancer and the adjuvant treatment of early breast cancer. More than 350,000 patient treatment years have accumulated, sufficient to allow evaluation of its longer-term safety profile in comparison with tamoxifen and, where possible, with raloxifene and aromatase inhibitors. We reviewed all preclinical and clinical safety data from 1978 to 2004 and comparative clinical safety data between October 1995 and the end of 2004. Secondary endometrial cancer incidence was lower with toremifene than with tamoxifen and was similar to that with raloxifene. It is speculated that toremifene may unmask existing endometrial tumors rather than induce new events. The risk of stroke, pulmonary embolism, and cataract may be lower with toremifene than with tamoxifen and the risk of pulmonary embolism and deep vein thrombosis lower than with raloxifene. Beneficial estrogen agonistic effects were equivalent to those of tamoxifen regarding bone mineral density and superior regarding lipid profiles.

Topics: Breast Neoplasms; Cardiovascular Diseases; Case-Control Studies; Clinical Trials as Topic; Endometrial Neoplasms; Female; Humans; Neoplasms, Hormone-Dependent; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Hormonal agents have a confirmed role in the management of postmenopausal women with receptor-positive advanced breast cancer. Until recently, tamoxifen has been the accepted agent for treating these patients. However, accumulating evidence suggests that the new antiaromatase agents will replace the antiestrogens as the preferable option in hormone-naive patients. Comparative trials indicate that the aromatase inhibitors, anastrozole and letrozole, and the aromatase inactivator, exemestane, have at least equivalent efficacy to tamoxifen with similar or superior tolerability. These agents are also more effective than the progestin, megestrol acetate, when studied in patients progressing on tamoxifen. The improved aromatase selectivity and high potency of these antiaromatase agents when compared with earlier agents have resulted in improved efficacy and tolerability. Additionally, no cross-resistance has been reported between the antiaromatase agents and tamoxifen or, in some instances, among the antiaromatase agents themselves. The role of antiaromatase agents will certainly expand in the near future to include not only treatment of metastatic breast cancer, but use in the adjuvant and neoadjuvant settings as well, and, ultimately, breast cancer prevention. The results of ongoing investigations are awaited with interest.

Topics: Aminoglutethimide; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Estrogen Antagonists; Humans; Neoplasms, Hormone-Dependent; Tamoxifen; Toremifene

The role of estrogens, including its sources, tissue distribution, metabolism, and mechanism of action, is discussed in this review. The ER alpha and beta are functioning separately, and there is a physiological balance between their activity. Whenever this balance is over thrown due to endogenous or exogenous carcinogenic factors, malignancy develops. Risk factors of breast cancer are listed and evaluated individually. It should be stressed however, that their carcinogenic effect sums up. The knowledge of established risk factors rises the possibility of chemoprevention, which might be highly desirable in case of gene carriers. Special emphasis is attached to the SERM molecules which act as antiestrogens. Their antitumour effect is largely used in the treatment of hormone sensitive advanced breast cancer patients, and their efficacy has been proved in adjuvant therapy as well. Their preventive use might also be justified, especially in gene carriers. Aromatase inhibitors form a special class among the SERM molecules. In Hungary, anastrozole, letrozole and exemestane are widely applied for the therapy of breast cancer patients, while raloxifene has only been introduced recently, mainly in order to prevent osteoporosis. The therapeutic value of fulvestrant is unknown yet and its antitumour effect has to be explored. The therapeutic significance of these molecules lies in the fact that they might be effective after the development of tamoxifen resistance. There are several explanations for this phenomenon offering new targets for the further development of a succesful antitumour chemotherapy.

Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Breast Neoplasms; Enzyme Inhibitors; Estradiol; Estrogen Receptor Modulators; Female; Fulvestrant; Humans; Letrozole; Nitriles; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Toremifene; Triazoles

During the past decade, a number of new hormonal therapies (HTs) have been developed, including the selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and estrogen receptor (ER) antagonists. Their uses in breast cancer are continually evolving as new clinical trial results become available. Although tamoxifen, the most widely used HT for breast cancer, was originally approved for and used in the treatment of metastatic breast cancer (MBC), its effectiveness as MBC therapy led to its subsequent assessment and use as adjuvant and risk-reduction therapy for breast cancer. However, tamoxifen is not universally effective in these settings and is associated with infrequent known toxicities such as increased risk of thromboembolism and endometrial cancer; therefore, a search for more effective and more tolerable HTs has evolved.. This article reviews the data supporting the use of newer HTs as initial treatment of MBC and their potential use as adjuvant, neoadjuvant, and chemopreventive therapies.. Articles for inclusion in this manuscript were identified through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997-2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, breast cancer guidelines, hormonal therapies, tamoxifen, toremifine, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780.. Recent studies have focused on newer agents as initial and subsequent treatment of MBC, adjuvant or neoadjuvant treatments of breast cancer, and chemopreventive agents in both healthy women and women with a history of ductal carcinoma in situ (DCIS). Results of clinical trials comparing AIs with tamoxifen as first-line MBC treatment show that AIs are as effective as, or more effective than, tamoxifen and are associated with fewer serious adverse events. Tamoxifen remains the gold standard for adjuvant therapy. However, preliminary results of ongoing clinical trials comparing tamoxifen with anastrozole suggest that anastrozole may be the superior agent. Both tamoxifen and the AIs have been shown to be active in the neoadjuvant treatment of breast cancer. Trial results have shown that tamoxifen is effective for breast cancer prevention in patients at high risk of developing breast cancer but who are otherwise healthy, patients with a history of DCIS, and patients with lobular carcinoma in situ.. Although tamoxifen has been the gold standard of HT for breast cancer, results of ongoing trials assessing the newer HTs as initial, neoadjuvant, adjuvant, and chemopreventive therapies may substantially change our current clinical practice patterns.

Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Chemotherapy, Adjuvant; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Nitriles; Tamoxifen; Toremifene; Triazoles

Selective estrogen receptor modulators (SERMs) represent a growing class of compounds that act as either estrogen receptor gonists or ntagonists in tissue-selective manner. SERMs with the appropriate selectivity profile offer the opportunity to dissociate the favorable bone and cardio-vascular effects of estrogen from its unfavorable stimulatory effects on the breast and uterus. The triphenylethylene drug tamoxifen proved to be invaluable to treat and protect against breast cancer and bone loss, probably reduces cardiovascular risk, but had side effects on uterus similar to natural estrogens. The tamoxifen derivate toremifene is also used to treat breast cancer, but has less effect on bone. The non-steroidal benzothiophene derivate, raloxifene, is the best SERM available thus far. It has the potential to prevent breast cancer (like tamoxifen), but has better profile in its actions on bone and cardiovascular system (produces a rapid reduction of serum cholesterol, decreases fibrinogen and lipoprotein, improves the vascular epithelial function, attenuates vascular intimal thickening, etc.). It does not increase the incidence of endometrial cancer. Compounds of this class are the first step in developing the perfect hormone replacement and other multitargeted therapy. This review summarizes the recent important knowledge about SERMs.

Topics: Breast Neoplasms; Coronary Disease; Estrogen Antagonists; Estrogens; Female; Humans; Osteoporosis, Postmenopausal; Raloxifene Hydrochloride; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

This article provides an overview of the historical development, current research, clinical benefits, and potential future applications of the selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene. The understanding of the mechanism of action of SERMs led not only to the development of tamoxifen, the first widely used antiestrogen for breast cancer treatment, but also to its application as a chemopreventive agent. The SERM principle of antiestrogenic actions in the breast but estrogenlike actions in bone is reviewed in clinical practice through analysis of the current applications and the potential for expanding the role of SERMs. The current view of the molecular mechanism of SERM action is summarized to identify potential target sites for future research. The clinical success of tamoxifen and raloxifene for the prevention and treatment of breast cancer and osteoporosis, respectively, has encouraged the development of a range of new agents that target breast cancer, osteoporosis, coronary heart disease, and endometrial safety.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cinnamates; Drug Design; Forecasting; Humans; Molecular Biology; Piperidines; Pyrrolidines; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Stilbenes; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Toremifene; Treatment Outcome

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Topics: Adult; Anastrozole; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Enzyme Inhibitors; Estrogen Antagonists; Female; Forecasting; Humans; Indoles; Letrozole; Middle Aged; Neoplasm Metastasis; Nitriles; Osteoporosis; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

Endocrine therapy of advanced or recurrent breast cancer was described. The presence of ER or PgR in primary breast tumors is the best-established marker for response to endocrine therapy. However, ER-positive breast tumors overexpressing EGF-R and/or HER-2 (Erb B2) are resistant to endocrine therapy. Recently it was suggested that an elevated level of the circulating extracellular domain of HER-2 could be a predictor for poor response to endocrine therapy. LH-RH agonist is used as a first-line therapy for premenopausal patients. And LH-RH agonist plus tamoxifen (TAM) has shown a higher response rate and more prolonged survival than LH-RH agonist or TAM alone. As two new aromatase inhibitors, anastrozole (ANA) and letrozole, have shown an equal or higher response rate and a prolonged time to progression than TAM as a first-line therapy, these could be used as a first-line therapy instead of TAM. In a cross-over trial of ANA and TAM, the response rate of ANA after TAM failure was equal to that of TAM after ANA failure. As these drugs showed an equal or higher response rate and longer survival than progestin in TAM resistant cases, these drugs could also used as a second-line therapy. In addition, the trend of recent studies regarding the mechanisms of hormone resistance is also described.

Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Estrogen Antagonists; Fadrozole; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Neoplasm Recurrence, Local; Tamoxifen; Toremifene

In general, the selective estrogen receptor modulators (SERMs) currently indicated for the treatment and prevention of breast cancer, i.e. tamoxifen and toremifene, are fairly well tolerated. However, tamoxifen has been shown to induce hepatocellular carcinomas in rats, but not in humans, and can increase the risk of endometrial cancer in humans by two to three times. Other potentially serious adverse effects which have been associated with tamoxifen and toremifene therapy include vasomotor symptoms, an increased risk of venous thromboembolic events, and an increased incidence of cataracts and ocular toxicity, fatty liver, and nonmalignant hepatic and uterine changes. In addition, long term tamoxifen use almost always results in resistance to the drug and, indeed, has actually been shown to promote tumour proliferation in human breast cancer cells. Both tamoxifen and toremifene display drug interactions with a variety of drug classes. The adverse events associated with these compounds have raised significant concerns regarding their widespread use for the treatment and prevention of breast cancer. In addition, because of the weakness and scarcity of the data on toremifene, any conclusions about its tolerability remain tentative until outcomes of ongoing clinical trials in the adjuvant setting are known. A third SERM, raloxifene, is the focus of several large randomised trials examining its efficacy in the prevention of breast cancer. At present, each potential adverse event needs to be weighed against potential benefits in the decision to undergo SERM treatment. An array of therapies is currently available for patients with breast cancer and women at increased risk of disease; the risk-to-benefit ratio for each agent should be carefully examined in determining the most advantageous regimen.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Estrogen Receptor Modulators; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Treatment Outcome

Oral anti-cancer drugs play an important role in the treatment of breast cancer. Because these hormonal agents are related to mammary carcinogenesis and tumor growth, they are used not only for therapy but also to prevent the onset of the disease. Tamoxifen, toremifene, fadrozole and other aromatase inhibitors, goserelin, leuprolin and MPA are used widely in Japan as hormonal anti-cancer drugs. In addition oral anti-cancer chemotherapeutic agents, such as cyclophosphamide, 5-FU, 5'-DFUR, FT and UFT are used for breast cancer. The combination of these hormonal and chemotherapeutic agents produces good clinical results in curing the disease. Oral drugs are superior to injected drugs with regard to the QOL of patients.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase II as Topic; Cyclophosphamide; Drug Administration Schedule; Fadrozole; Female; Floxuridine; Fluorouracil; Gonadotropin-Releasing Hormone; Humans; Medroxyprogesterone Acetate; Survival Rate; Tamoxifen; Toremifene

Meta-analysis of all clinical data was conducted to compare toremifene 40-60 mg/day (TOR) with tamoxifen 20-40 mg/day (TAM) in postmenopausal women with estrogen receptor (ER) positive or ER unknown advanced breast cancer and assess factors predicting treatment outcome. Data from five randomized parallel group studies (all studies) were combined. Efficacy variables were the response rate in all studies and also the time to treatment failure and survival in the three major studies (pivotal studies). Of the 1421 patients, 725 received TOR and 696 TAM. Response rates were 24.0% and 25.3%, respectively (p = 0.675) with 95% confidence interval (95% CI) for the difference -5.3 to 3.4. Of the 1157 patients in the pivotal studies, 75% had progressed and 50% expired. Median treatment times were 4.9 months in TOR and 5.3 months in TAM groups (p = 0.762, hazard ratio 0.98 with 95% CI 0.87-1.11). Median survival times were 31.0 (TOR) and 33.1 (TAM) months (p = 0.758, hazard ratio 0.98 with 95% CI 0.83-1.15). All results are consistent with the criteria of statistical equivalence between TOR and TAM. More patients in TAM (20%) than in TOR (14%, p = 0.007) discontinued the treatment prematurely but overall the treatments were well tolerated. As the treatments were equally effective all data were analyzed together for predictive factors. High tumor ER concentration, long disease free time, soft tissue metastases, few metastatic sites, and good performance status all independently predicted longer survival (p<0.001). Previous adjuvant tamoxifen predicted shorter survival (p = 0.008). Objective response to treatment or disease stabilization for at least 12 months both predicted prolonged survival (p = 0.001). TOR 60 mg/day and TAM are equally effective and well tolerated in the treatment of advanced breast cancer in postmenopausal women. Probability of survival may be predicted based on patient characteristics and on the initial response to the treatment.

Topics: Aged; Analysis of Variance; Antineoplastic Agents, Hormonal; Breast Neoplasms; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Postmenopause; Prognosis; Randomized Controlled Trials as Topic; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Survival Analysis; Tamoxifen; Toremifene; Treatment Failure

Tamoxifen is currently the standard hormonal treatment of breast cancer, both for metastatic disease and in the adjuvant setting. A new antiestrogen, toremifene, was approved recently for use in managing metastatic breast cancer in postmenopausal women.. Toremifene is structurally similar to tamoxifen, differing only by a single chlorine atom, and has a similar pharmacologic profile. The major difference between the two compounds is in the preclinical activity; chronic, high-dose tamoxifen is hepatocarcinogenic in the rat, whereas toremifene is not. Neither agent is hepatocarcinogenic in mice, hamsters, or humans; therefore, clinical relevance of the rat data may not be significant.. In a worldwide phase III trial, the two agents demonstrated comparable efficacy and safety against metastatic breast cancer. Both agents have shown a significant hypocholesterolemic effect after long-term administration.. Due to the paucity of long-term clinical data on toremifene, important unresolved questions remain, which include its effects on bone mineral density, the frequency of cardiac events, and the risk for endometrial cancer. Tamoxifen has been associated with maintenance of bone mineral density, a reduction in cardiac events, and a slightly increased risk of endometrial cancer. Toremifene is not likely to be used as second-line therapy after tamoxifen failure due to cross-resistance, and its ultimate place in therapy of advanced breast cancer remains to be determined.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cricetinae; DNA Adducts; Drug Resistance, Neoplasm; Female; Humans; Lipids; Mammary Neoplasms, Experimental; Mice; Rats; Tamoxifen; Toremifene

Tamoxifen is by far the most clinically tested antiestrogenic drug currently used as adjuvant therapy for breast cancer and it continues to provide considerable benefit in this setting. The balance from clinical trials indicates a strong association between the use of tamoxifen and an increase in uterine tumors (three to sixfold). In rats, tamoxifen is a mutagenic, genotoxic hepatocarcinogen. These actions are not related to its estrogen antagonist activity but have been shown to be as a result of metabolic activation of this drug by cytochrome P450 enzymes, resulting in irreversible binding to cellular DNA. The mechanism of endometrial cancer associated with tamoxifen treatment is unclear, although there are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in uterine cells or (2), it promotes the development of endometrial tumors through its estrogen agonist activity. The evidence for a genotoxic effect of tamoxifen in the uterus is highly contentious and, on balance, we have concluded that it is more likely that the estrogenic effects of tamoxifen promote tumor development.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinogens; Chemotherapy, Adjuvant; Cytochrome P-450 Enzyme System; DNA Damage; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Rats; Risk; Tamoxifen; Toremifene

Toremifene (Fareston) received FDA approval in 1997 for the first-line treatment of postmenopausal women with estrogen receptor (ER)-positive or -unknown metastatic breast cancer. Phase II and III trials have demonstrated that first-line therapy with toremifene, 60 mg/d, is as effective and as well tolerated as tamoxifen (Nolvadex), 20 or 40 mg/d, in such patients. To date, phase III trials have failed to show a statistically significant advantage of higher toremifene doses over standard doses of tamoxifen in these women. Studies appeared to indicate minimal efficacy of high toremifene doses in women with ER-negative tumors, but the number of patients studied was small. Although results of some trials of high-dose (240 mg/d) toremifene in tamoxifen-"refractory" patients were negative, other trials that included prolonged (> or = 6 months) stable disease as an indication of clinical benefit yielded positive results.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Estrogen Antagonists; Female; Humans; Neoplasms, Hormone-Dependent; Randomized Controlled Trials as Topic; Receptors, Estrogen; Survival Analysis; Tamoxifen; Toremifene; Treatment Outcome

When results from the phase II trials of toremifene (Fareston) and tamoxifen (Nolvadex) in metastatic breast cancer were published, the Finnish Breast Cancer Group began to plan the first trial of toremifene in an adjuvant setting. This multicenter, randomized trial is comparing toremifene (40 mg/d) to tamoxifen (20 mg/d) in postmenopausal lymph node-positive breast cancer patients. Treatment duration is 3 years. About 1,150 of a planned 1,460 patients have been enrolled to date. The International Breast Cancer Study Group is also conducting two adjuvant trials evaluating 5 years of toremifene (60 mg/d) vs tamoxifen (20 mg/d). More than 1,000 patients have been enrolled in these studies to date. The efficacy of toremifene is being explored in all of these trials. In the Finnish trial, additional protocols are evaluating treatment side effects, including the formation of DNA adducts in the endometrium and leukocytes, certain ocular problems, thromboembolic events, and subjective side effects. The effects of toremifene on lipid levels and bone density are also being studied. An interim safety analysis, performed in the Finnish study after 500 patients were enrolled (mean follow-up, 18 months), showed no significant differences between toremifene and tamoxifen in terms of efficacy or side effects. Toremifene seems to be well tolerated and may have additional positive effects. Ongoing trials will soon reveal how beneficial toremifene is in the adjuvant setting and whether it is devoid of the adverse effects observed with tamoxifen.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Estrogen Antagonists; Europe; Female; Humans; Multicenter Studies as Topic; Neoplasms, Hormone-Dependent; Randomized Controlled Trials as Topic; Receptors, Estrogen; Tamoxifen; Toremifene

Various ongoing double-blind clinical trials are evaluating the use of tamoxifen (Nolvadex) as chemoprevention for breast cancer. A total of over 24,000 healthy women have been randomized to these trials, and it should be possible, by the year 2000, to detect any preventive effect of tamoxifen in healthy women. Furthermore, with the large numbers of women involved, it should be possible to evaluate prevention in subgroups of participants according to risk of the disease, particularly those women carrying high-risk genes, such as BRCA1 and BRCA2. Adverse effects of tamoxifen have been identified, including a transient bone loss in premenopausal women and uterine effects, including polyps, cysts, and endometrial cancer, in postmenopausal women. Although the potential benefit of tamoxifen in preventing breast cancer in healthy women is likely to outweight any potential long-term risks, the use of other tamoxifen-like drugs, such as raloxifene (Evista) and toremifene (Fareston) is now being investigated.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Endometrial Neoplasms; Estrogen Antagonists; Female; Genes, BRCA1; Humans; Italy; Neoplasms, Hormone-Dependent; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Tamoxifen; Toremifene; United Kingdom; United States

In postmenopausal women, about 65% to 80% of breast cancers contain estrogen receptors (ERs) and 50% to 65%, progesterone receptors (PRs). Receptor-positive breast cancer is somewhat less common in premenopausal patients. Recently, the biochemical dextran-coated charcoal (DCC) assay for ERs has been replaced in many laboratories by immunohistochemical and immunocytochemical methods, which are not disturbed by endogenous estrogen or antiestrogen treatment. Receptors now can also be assayed from fine-needle biopsy and paraffin-embedded tissue specimens. The ER has been shown to be a prognostic factor for overall and disease-free survival in newly diagnosed and relapsed breast cancer. The value of the ER in predicting response to both surgical and medical endocrine treatment of breast cancer has been demonstrated. Ample evidence supports the predictive value of the ER in the treatment of breast cancer with the antiestrogen tamoxifen (Nolvadex). The first studies of a new antiestrogen, toremifene (Fareston), support the value of the ER in predicting breast cancer treatment results.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Predictive Value of Tests; Receptors, Estrogen; Tamoxifen; Toremifene

Toremifene (Fareston) is a triphenylethylene derivative structurally similar to tamoxifen (Nolvadex) that was selected for development based on its in vitro activity against breast cancer and its lesser uterotrophic effect than tamoxifen in rat models. In phase I and II studies conducted in several countries, toremifene was well tolerated over a wide range of doses (10 to 680 mg/d). The major side effects were hot flashes, nausea, and vomiting. Toremifene's excretion half-life is 5 days. It produces a modest decline in serum levels of luteinizing hormone, follicle-stimulating hormone, and antithrombin III, as well as an increase in sex hormone-binding globulin levels. In studies in which toremifene was used as first-line therapy in patients with estrogen receptor (ER)-positive or ER-unknown tumors, response rates to doses of 40 to 60 mg/day ranged from 30% to 54%. In two larger studies of patients who had proved refractory to tamoxifen therapy, toremifene produced an objective response rate of 4% to 5%. When patients with stable disease were added to those with objective responses, 27% to 28% of patients were considered to derive clinical benefit from toremifene. The dose range chosen for further study was 40 to 60 mg/d.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Humans; Rats; Toremifene

To compare the efficacy and safety of high doses (200 or 240 mg/d) of toremifene (Fareston) to standard doses (20 or 40 mg/d) of tamoxifen (Nolvadex) in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown advanced breast cancer, we pooled data from two randomized, three-arm clinical trials. Of the 733 patients included in the overview, 369 were randomized to high-dose toremifene and 364, to tamoxifen. At median follow-up of 19 months, disease had progressed in over 70% of the patients. Response rates were 25.2% in the high-dose toremifene arm and 19.8% in the tamoxifen arm (P = .087). The two treatments appeared to be statistically equivalent with respect to risk for disease progression and survival. Reversible SGOT elevation was observed in 26 tamoxifen-treated patients vs 64 high-dose toremifene recipients (P < .001) and nausea in 33 vs 50 patients (P = .085). Reversible corneal keratopathy was diagnosed in two patients on tamoxifen and eight on high-dose toremifene (P = .061). Treatment had to be discontinued in 17.3% of patients in the high-dose toremifene arm and 20.1% in the tamoxifen arm. Discontinuation due to toxicity was rare, and toxicity did not differ significantly between the treatments. Toremifene, in doses up to 240 mg/d, is an effective, safe treatment for postmenopausal women with ER-positive/unknown advanced breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Middle Aged; Postmenopause; Survival; Tamoxifen; Time Factors; Toremifene; Treatment Outcome

Three pivotal phase III trials conducted in North America and Europe served as the basis for the application for approval of toremifene (Fareston) by the FDA. These trials demonstrated that 60 mg/d of toremifene is safe and effective in the treatment of advanced breast cancer in postmenopausal women. The studies also indicated that, on the basis of antitumor efficacy, as well as safety, toremifene is at least equivalent to tamoxifen and may have some long-term advantages.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Quality of Life; Tamoxifen; Toremifene; Treatment Outcome

The triphenylethylene antiestrogen toremifene is a chlorinated derivative of the antiestrogen tamoxifen, an agent which has been widely and successfully used in the treatment of breast cancer. Clinical trials investigating the efficacy of toremifene as first-line endocrine therapy in postmenopausal women with advanced breast cancer (estrogen receptor status positive or unknown) have shown this drug to have similar antitumour activity to that of tamoxifen. In multicentre comparative trials, objective responses (complete and partial) occurred in 20 to 29% of patients treated with toremifene (60 to 240 mg/day) and in 19 to 37.5% of tamoxifen (20 or 40 mg/day) recipients. The duration of response, time to disease progression and median overall survival time were generally similar in both treatment groups. Toremifene is well tolerated. Most drug-related adverse effects are mild or moderate in severity and rarely necessitate discontinuation of therapy. The tolerability profile of toremifene is similar to that reported for tamoxifen, the most common adverse effects being hot flushes, sweating, nausea and/or vomiting, dizziness, oedema, and vaginal discharge and/or bleeding. Thus, toremifene provides an equally effective and well tolerated alternative to tamoxifen for the first-line endocrine therapy of postmenopausal advanced breast cancer. Preclinical studies showing toremifene to have a lower carcinogenic potential than tamoxifen indicate that toremifene may be a preferable agent for long term treatment regimens; however, these findings require confirmation in the clinical setting.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Mammary Neoplasms, Experimental; Toremifene

Toremifene is a chlorinated tamoxifen analogue that is indicated for the treatment of postmenopausal hormone-dependent breast cancer. It competes with estradiol for estrogen receptors and has growth-inhibitory effects on MCF-7 breast cancer cells. At concentrations < 10(-6) mol/L, this growth inhibition can be reversed by estradiol, but at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene (DMBA)-induced mammary cancer in rats, toremifene has been shown to decrease the number of new tumours and to inhibit the growth of existing tumours. Toremifene causes growth inhibition by suppressing mitosis and inducing apoptosis. The mechanism by which these events occur may involve the induction of transforming growth factor-beta 1 and inhibition of insulin-like growth factor-1 (mecasermin). Toremifene is primarily an antiestrogen, but it has some estrogen agonist properties in postmenopausal women. The latter are reflected by the fall in luteinising hormone and follicle-stimulating hormone levels and the rise in sex hormone-binding globulin levels that are associated with its use in most women. After estrogen priming, toremifene 68mg administered orally has been found to exert a similar antiestrogenic effect on the vaginal epithelium in postmenopausal women as tamoxifen 60mg. The half-life of toremifene in plasma is 5 days, and the drug is > 99% bound to plasma proteins. The main metabolites of toremifene are N-demethyl-toremifene and deaminohydroxy-toremifene. Altered liver, but not kidney, function affects the pharmacokinetics of toremifene. Toremifene 60mg daily is as effective as tamoxifen 20mg daily in the treatment of postmenopausal hormone-dependent breast cancer, producing a response in about 50% of patients. Soft tissue and visceral metastases respond better to toremifene than bone metastases. Most of the adverse effects of toremifene are related to its activity at estrogen receptors and include hot flashes, vaginal discharge and nausea. Although toremifene decreases antithrombin III levels slightly, the incidence of thromboembolic complications is low. Thus far, no carcinogenic effects have been noted in humans, and preclinical data are mostly reassuring. Toremifene has favourable effects on serum lipids, and thus has potential in preventing coronary heart disease. Although toremifene is somewhat more expensive to use than tamoxifen, toremifene is an effective and well tolerated alternative to tamoxifen in the treatment of postmenopa

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Humans; Neoplasms, Hormone-Dependent; Postmenopause; Tamoxifen; Toremifene

As reported by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in Lancet (1992), the 10-year relapse-free survival or overall survival was significantly better in the tamoxifen (TAM) treatment group than in the control group in both node-positive and -negative groups. Adjuvant TAM treatment works better on patients over 50 years of age. Adjuvant TAM treatment for over 2 years is more effective than less than that time. Some reports demonstrated that long-term TAM treatment caused an increase in the circulating estrogen levels of premenopausal patients. This increase blocked the antitumor effect of TAM in a dose dependent fashion in our animal models. Similar results were obtained in toremifene or TAT-59 in our animal models. These results show that antiestrogens are more effective for postmenopausal than premenopausal women. LH-RH agonist or aromatase inhibitor may be a promising adjuvant endocrine agent of breast cancer. Combination therapy of TAM and LH-RH agonist, or LH-RH agonist and aromatase inhibitor will be an effective new adjuvant endocrine therapy for breast cancer. The combination of endocrine therapy and biological response modifiers, or of endocrine therapy with vitamin D3 will be clinically used in the future.

Topics: Animals; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Gonadotropin-Releasing Hormone; Humans; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Middle Aged; Survival Rate; Tamoxifen; Toremifene

The biological rationale and extensive clinical experience with the breast cancer drug tamoxifen make it the agent of choice for testing as a breast cancer preventive. However, concerns (Jordan and Morrow, Eur J Cancer, in press) about development of endometrial cancer in patients and liver tumors in rats with tamoxifen has encouraged the investigation of other antiestrogens. At present no compounds are available to replace tamoxifen, but two triphenylethylenes, toremifene and droloxifene, have been tested in postmenopausal women to treat advanced breast cancer. The response rates are similar to those observed with tamoxifen (i.e., approximately 35% [CR+PR] in unselected patients), although dosage regimens of the new antiestrogens are higher than the 20 mg tamoxifen required daily. Doses of up to 200 mg toremifene daily are being tested and studies use up to 100 mg droloxifene daily. Side effects appear comparable, but neither droloxifene nor toremifene produce liver tumors in rats. Tamoxifen produces DNA adducts, whereas toremifene and droloxifene appear to be only weakly active. A new tamoxifen analogue, idoxifene, is entering clinical trial. The drug is designed to be metabolically stable so that there will be low carcinogenic potential. In contrast, a novel strategy may be considered to be of value to protect women from developing breast cancer. It is known from laboratory and clinical studies that antiestrogens protect bone and prevent rat mammary cancer. One compound, raloxifene, is being tested as an agent to treat osteoporosis. If the drug becomes generally available to prevent osteoporosis in postmenopausal women, a beneficial side effect may be a reduction in breast cancer risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Breast Neoplasms; Clinical Trials as Topic; Drug Design; Estrogen Antagonists; Female; Humans; Liver Neoplasms, Experimental; Piperidines; Raloxifene Hydrochloride; Rats; Tamoxifen; Toremifene

Tamoxifen (20-40 mg/day) has been widely used for the treatment of breast cancer and is recognized as a useful antiestrogen. A 40 mg/day dose of toremifene showed comparable efficacy, safety and usefulness to a 20 mg/day dose of tamoxifen in the double-blind comparative study with tamoxifen. Furthermore, high-dose toremifene (120 mg/day) was effective on the tamoxifen-failed breast cancer patients. Although droloxifene (3-hydroxytamoxifen) showed efficacy and safety in phase I and phase II studies, this trial has regretably been ineffective in Japan. In phase I and early phase II trials in Japan, the safety and efficacy of TAT-59 was demonstrated and a 20 mg/day dose was moderate. Tamoxifen analogues including their metabolites are expected to act effectively on tamoxifen-resistant, low estrogen receptor levels or estrogen receptor-negative tumors by mechanisms of action different from tamoxifen.

Topics: Binding, Competitive; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Receptors, Estrogen; Tamoxifen; Toremifene

Antiestrogens block by definition specifically the actions of estrogens. In the classical uterotropic assay in immature rodents, where estrogens cause fluid retention and cell proliferation, triphenylethylenes have also species-specific estrogen-like (agonistic) effects. 4-hydroxylated triphenylethylenes have in general less estrogenic properties than unhydroxylated ones, and ICI 164,384 has no estrogenic activity in this model. Uterus responds to estrogens by stimulation of cell proliferation. Some other tissues, like breast, liver, and bone respond by regulation of specific protein synthesis. Some of the proteins act as growth factors, and some have unknown functions. The regulation of gene expression is a complex phenomenon: estrogens may turn the responsive gene on or off. Similarly antiestrogens may participate in the gene regulation by mimicking or antagonising estrogen-like actions. This paper summarizes the estrogenic and antiestrogenic effects of classical and new antiestrogens in different tissues.

Topics: Animals; Bone and Bones; Breast Neoplasms; Estradiol; Female; Gene Expression Regulation, Neoplastic; Liver; Mice; Polyunsaturated Alkamides; Rats; Receptors, Estrogen; Tamoxifen; Toremifene; Uterus

In a combined phase I-II study the hormonal effects of Toremifene were investigated in 15-15 patients at two dose levels: 60 mg and 300 mg per os, daily. Serum estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone were monitored by radioimmunoassay and sexual hormone binding globulin by immunoradiometric assay prior to treatment and at the 2nd, 8th and 12th weeks. The influence of Toremifene upon the hypothalamo-hypophyseal axis was also controlled by a tirotropin releasing hormone functional test using 400 micrograms tirotropin releasing hormone injection iv. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and prolactin decreased proving the antiestrogenic activity of the drug. Sexual hormone binding globulin significantly (p less than 0.002) increased by week 12 at both doses, probably due to a direct effect of Toremifene upon the liver. The increase in sexual hormone binding globulin suggests the partial estrogenic effect of the drug. The tirotropin releasing hormone induced prolactin release was also suppressed. On the basis of hormonal changes and the clinical response of patients 60 mg of Toremifene proved to be as effective as 300 mg.

Topics: Breast Neoplasms; Estrogen Antagonists; Estrogens; Female; Humans; Tamoxifen; Toremifene

The predictive value of estrogen receptor (ER) concentrations was evaluated in a group of 113 postmenopausal patients with estrogen-receptor-positive (ER greater than 7 fmol/mg protein) advanced breast cancer. In 103 patients, tumors were also sampled for progesterone receptor (PgR) determination. All patients were treated with toremifene, a novel antiestrogen, 60 mg daily. The median ER in 51 responders was 78 fmol/mg protein, and in 62 nonresponders, 51 fmol/mg protein; the median PgR levels were 40 and 37 fmol/mg protein, respectively. The response rate in patients with ER less than 50 fmol/mg protein was 38%, and 51% in the group with ER greater than 50 fmol/mg protein (not significant [NS]). The response rate in patients with PgR less than 10 fmol/mg protein was 42%, and in patients with greater than 10 fmol/mg protein, 44%. The duration of response in patients with ER greater than 50 fmol/mg protein was significantly longer than with lower ER levels (P = 0.002). PgR was not associated with the duration of response. In Cox's multiple regression analysis, ER was an independent prognostic factor (P = 0.005) for response duration. Thus, the ER concentration of tumor tissue predicts the duration of response but not the response rate to toremifene in patients with advanced breast cancer. The PgR status does not predict the response rate or the duration of response.

Topics: Aged; Bone Neoplasms; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Menopause; Middle Aged; Predictive Value of Tests; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Remission Induction; Tamoxifen; Toremifene

Toremifene, a triphenylethylene antiestrogen first synthesized in 1981, binds to the estrogen receptor with an affinity about 5% that of estradiol. Its antiestrogenicity/estrogenicity ratio in animal models is about 5 times that of tamoxifen, though it requires somewhat higher doses for full effectiveness, and it is active against breast cancer in animal and cell culture models. It has a long elimination half-life and there are several metabolites, but the principal antitumor activity appears to be due to the unchanged drug. In Phase I and Phase II clinical trials, toremifene has shown good response rates in ER-positive or ER-unknown tumors, and significant responses after failure of tamoxifen or other hormonal or chemotherapeutic regimens, with rare and mild side effects.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Rats; Tamoxifen; Toremifene

The antitumor activity of the new triphenylethylene drug toremifene has been studied in advanced breast cancer of postmenopausal women as first line treatment at dose levels of 20, 60, and 240 mg, and as second line or later treatment at high dose levels of 200-240 mg. The response rates (complete + partial response) have been 21% with 20 mg (14 patients), 52% with 60 mg (93 patients in three separate trials), and 68% with 240 mg (38 patients) as first line treatment. After failure on previous therapy (hormonal or chemotherapy) the response rates have been about 10% with 200 mg of toremifene (71 patients in two different trials). In patients whose disease had previously responded to tamoxifen with at least stabilization, the response rate with toremifene has been 23%; but among unselected patients, including patients progressing during adjuvant tamoxifen, the response rate (CR + PR) with toremifene in tamoxifen failures has been 3%. If long lasting (more than 5 months) stabilization of the disease is also considered, a further 20% of previously treated patients have benefitted from toremifene. The treatment has been well tolerated at all dose levels. The most reported side effects have been hot flushes (8-19%) and nausea (8%). 0-6% of patients in different trials have interrupted the treatment because of side effects.

Topics: Antineoplastic Agents; Breast Neoplasms; Climacteric; Drug Evaluation; Estrogen Antagonists; Female; Humans; Menopause; Nausea; Remission Induction; Tamoxifen; Toremifene

Toremifene is a nonsteroidal antiestrogen currently being evaluated for the treatment of breast cancer. Toremifene (10(-10)-10(-6) M) inhibited the growth of MCF-7 breast cancer cells in vitro but was ineffective against hormone-independent MDA-MB-231 cells. This activity was reproduced in vivo using the athymic mouse model. Maximal MCF-7 tumor growth was produced in athymic mice by circulating estradiol levels of approximately 200 pg/ml (from a 0.5 cm silastic capsule implanted sc). Toremifene (77 +/- 44 micrograms/day from a 2 cm silastic capsule) inhibited estradiol (0.5 cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist and potent antagonist on the mouse uterus. The growth of MDA-MB-231 tumors was not influenced by either estradiol or toremifene. Toremifene (200 micrograms/day) was effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given po from day 28 after carcinogen administration. The antitumor activity was reversed if the toremifene was stopped. These findings indicate toremifene is a tumoristatic agent rather than a tumoricidal agent. Clinical trials with toremifene should employ an indefinite treatment strategy to control tumor recurrence in adjuvant studies.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Screening Assays, Antitumor; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Organ Size; Rats; Tamoxifen; Toremifene; Tumor Cells, Cultured; Uterus

The antiestrogen tamoxifen has had an enormous impact upon the therapy of breast cancer. It is the most widely used antihormonal therapy. The success of tamoxifen has stimulated broader applications of the drug (long-term adjuvant therapy and chemosuppression) and has spurred the development of toremifene, droloxifene, and zindoxifene. However, the clinical evaluation of tamoxifen as a chemosuppressive agent is not sufficiently advanced to be able to provide any conclusion about the success of this strategy. It may be a decade before a randomized clinical study can be analyzed and the value of chemosuppression assessed. In the near future, the clinical evaluation of new antiestrogens will provide additional information about the potential value of these drugs and will perhaps challenge our ideas about the mode of action of antiestrogens as antitumor agents.

Topics: Breast Neoplasms; Estrogen Antagonists; Female; Humans; Indoles; Tamoxifen; Toremifene

In this study, the characteristics of hemodynamic changes with use of toremifene before and after neoadjuvant chemotherapy in breast cancer treatment were analyzed using resting-state functional magnetic resonance imaging. Also, the effect of toremifene on the quality of life of patients with advanced breast cancer was analyzed. The study population comprised 100 patients who received endocrine therapy after breast cancer surgery in our hospital from January 2016 to January 2019. Patients were randomly divided into an observation group and a control group, with 50 cases in each group. The observation group was treated with tamoxifen combined with toremifene treatment; the control group was treated with toremifene. Before and after chemotherapy, the same scheme was used to perform dynamic contrast-enhanced imaging of the breast using a 1.5T superconducting scanner with 3 mL/second bolus injection of adiphenine meglumine 0.2 mmol/kg. Semiquantitative blood flow measurement was completed on the workstation and before and after chemotherapy to compare results. The patient's quality of life, progesterone and estrogen levels, social function, physical function, mental function, and material function were analyzed. The mean values of the early enhancement parameters Efirst, Vfirst, Ee, and Ve before chemotherapy were greater than in the residual lesions after chemotherapy (P < 0.5). The semiquantitative study of resting brain function before and after breast cancer neoadjuvant chemotherapy showed that the hemodynamics of the residual lesions were significantly reduced, and the blood flow rate was significantly reduced. Compared with the clinical effect of tamoxifen in the treatment of breast cancer after surgery, tamoxifen combined with toremifene has more advantages in improving quality of life, improving progesterone levels, and reducing estrogen levels, and it has no detrimental effects on the endometrium.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Brain; Breast Neoplasms; Cognition; Endometrium; Estrogens; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Mastectomy; Middle Aged; Neoadjuvant Therapy; Organ Size; Progesterone; Quality of Life; Tamoxifen; Toremifene

Toremifene (TOR) is a selective oestrogen receptor modulator (SERM) and has comparable efficacy to that of tamoxifen (TAM) in breast cancer patients. Herein, we compared the safety of TOR to that of TAM in the adjuvant treatment of premenopausal breast cancer.. This was a prospective randomized and open-label clinical study. Premenopausal patients with hormonal receptor (HR)-positive early breast cancer were randomly assigned (1:1) to receive TOR) or TAM treatment. The follow-up period was 1 year. The primary end point was the incidence of ovarian cysts, and secondary end points were the incidence of endometrial thickening, changes in female hormones, the incidence of fatty liver, changes in the modified Kupperman index (mKMI) and changes in quality of life.. There were 92 patients in the final analysis. The incidences of ovarian cysts were 42.6% in the TOR group and 51.1% in the TAM group (p = 0.441). Forty-one patients (87.2%) in the TOR group and 36 patients (80.0%) in the TAM group experienced endometrial thickening (p = 0.348). The proportions of patients with fatty liver were 31.9% in the TOR group and 26.7% in the TAM group (p = 0.581). No significant differences in the mKMI or quality of life were observed between the two groups.. TOR and TAM have similar side effects on the female genital system and quality of life in premenopausal early breast cancer patients.. ClinicalTrials.gov NCT02344940. Registered 26 January 2015 (retrospectively registered).

Topics: Adult; Antineoplastic Agents, Hormonal; Breast; Breast Neoplasms; Endometrium; Fatty Liver; Female; Follow-Up Studies; Humans; Incidence; Middle Aged; Ovarian Cysts; Premenopause; Prospective Studies; Quality of Life; Receptors, Estrogen; Receptors, Progesterone; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

Topics: Aged; Alkaline Phosphatase; Antineoplastic Agents, Hormonal; Bone and Bones; Breast Neoplasms; Chemotherapy, Adjuvant; Cholesterol; Cholesterol, LDL; Collagen Type I; Female; Humans; Letrozole; Lipids; Middle Aged; Postmenopause; Prospective Studies; Toremifene

We compared characteristics and outcomes of palpable versus nonpalpable, hormone-sensitive, early-stage breast cancers.. Patients from the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial were divided into palpable (n = 513) and nonpalpable (n = 1063) tumor groups. Differences in pathological features, loco-regional therapy, disease-free survival (DFS) and overall survival (OS) were analyzed.. Patients with palpable tumors were older, had larger tumors, and higher rates of lymph-node involvement. The tumors were more likely to be poorly differentiated, of high nuclear grade, and display lymphovascular invasion. After mean followup of 59 months, DFS and OS were significantly lower for palpable than nonpalpable tumors (DFS 93.5% vs. 98.4%, p < 0.001, OS 88.5% vs. 95.6%, p < 0.001). Controlling for age, size and nodal status, palpability was an independent factor for DFS (OR = 2.56; 95%CI, 1.37-4.79, p = 0.003) and OS (OR = 2.12; 95%CI, 1.38-3.28, p < 0.001).. In a group of hormone-sensitive, mostly postmenopausal early-stage breast cancer patients, palpable tumors were more likely to have more aggressive features and metastatic potential, which translated in to a higher incidence of breast cancer-related events and worse overall survival.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Early Detection of Cancer; Female; Follow-Up Studies; Humans; Palpation; Prospective Studies; Receptors, Estrogen; Survival Rate; Tamoxifen; Toremifene; United States

The purpose of the present research work was to study the CYP2D6 gene polymorphism survival outcome after breast cancer patient received the toremifene and tamoxifen treatment. Seventy-eight patients who received radical mastectomy and toremifene and tamoxifen treatment after operation were divided into three groups: CYP2D6*1/*1 group (13 cases), CYP2D6*1/*10 group (28cases) and CYP2D6*10/*10 group (35 cases), according to the gene polymorphism of blood serum CYP2D6. The results of treatment of three groups were compared. After operation the content of blood serum CA125, CA153, VEGF, IGF-1 were all lower than before. The content of CYP2D6*10/*10 group was higher than those of CYP2D6*1/*1 group and CYP2D6*1/*10 group. The content of CYP2D6*1/*1 group had no difference with that of CYP2D6*1/*10 group. All patients were followed up for a median duration of 30.5 months. Progression-free survival (PFS) of CYP2D6*10/*10 was shortened. The recurrence rate increased and the survival rate reduced. There were no obvious differences between CYP2D6*1/*1group and CYP2D6*1/*10 group. In summary, CYP2D6 gene polymorphism relates with the effect of toremifene and tamoxifen treatment in patient with ER positive breast cancer and null allele homozygote CYP2D6*10/*10 can lead to a poor prognosis.

Topics: Antigens, Neoplasm; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; CA-125 Antigen; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Insulin-Like Growth Factor I; Mastectomy; Membrane Proteins; Middle Aged; Polymorphism, Genetic; Pregnancy; Progression-Free Survival; Recurrence; Survival Rate; Tamoxifen; Toremifene; Vascular Endothelial Growth Factor A

Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen.. The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events.. A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated.. Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Asian People; Breast Neoplasms; Female; Humans; Middle Aged; Postmenopause; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Treatment Outcome

After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity.. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM.. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating.. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE.. UMIN000001841.

Topics: Aged; Aged, 80 and over; Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Hormone-Dependent; Prognosis; Receptors, Estrogen; Survival Rate; Toremifene

Third-generation aromatase inhibitors(AIs)are now common in adjuvant hormone therapy for breast cancer in postmenopausal women. However, a suitable treatment has yet to be established for patients who develop cancer recurrence during or after adjuvant AI therapy.. This prospective study evaluated the efficacy and safety of 120mg/day toremifene citrate(TOR-120)administered orally to 23 patients with recurrent breast cancer who were receiving or had received adjuvant AI therapy. Primary therapy for recurrence was TOR-120 monotherapy.. The response rate was 13. 0%(partial response: three patients), the clinical benefit rate was 78. 3%(partial response: three patients; long-term stable disease: 15 patients), and median time to progression was 8. 1 months. Grade 1 adverse events such as loss of appetite, sweating, flushing and edema face were observed.. TOR-120 monotherapy was effective and safe as a primary hormone therapy for recurrent breast cancer unresponsive to AIs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Toremifene

The degree of adherence to oral anticancer agents may influence treatment efficacy. Tamoxifen and toremifene usage data from two International Breast Cancer Study Group (IBCSG) studies were used to evaluate the impact of treatment adherence on the efficacy of these two selective estrogen receptor modulators (SERMs). Between 1993 and 1999, IBCSG Trial 13-93 randomized premenopausal women with node-positive disease to tamoxifen or no endocrine therapy and IBCSG Trial 14-93 compared tamoxifen and toremifene in postmenopausal women with node-positive disease. 690 women with estrogen-receptor positive enrolled in these two trials were alive and disease-free 4 years after the start of SERM. The median follow up for this analysis was 9.0 years. Using a Kaplan-Meier landmark analysis at 4 years, the 609 women completing at least 4 years of SERM had improved 10-year disease-free survival (DFS) (71 %) compared with the 81 women taking less than 4 years (64 %), but these differences did not reach statistical significance [DFS hazard ratio (<4 year/4+ year) 1.31, 95 % CI 0.86-1.98), p value = 0.20]. Women who completed less than 4 years of SERM treatment (12 %) appeared not to have achieved the full benefit from their therapy. These results suggest that more effort should be made to educate women regarding the benefits of a full course of treatment. This is especially important in light of the results of the recently reported ATLAS and aTTom trials which suggest a benefit of 10 years of tamoxifen.

Topics: Breast Neoplasms; Disease-Free Survival; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Patient Compliance; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

The potential long-term adverse effects on quality of life have to be considered when selecting agents for adjuvant hormonal treatment for postmenopausal patients with estrogen receptor-positive breast cancer. We performed a 2-year multicenter randomized study to assess the differences in the time course effects between toremifene (TOR) and anastrozole (ANA) on serum lipid profiles and bone metabolism. This study assessed the serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A1), and apolipoprotein B (Apo B) as lipid profiles and bone-specific alkaline phosphatase (BAP) and the N-telopeptide of type-I collagen (NTX) as bone turnover markers in patients who received daily doses of 40 mg and 1 mg for TOR and ANA, respectively. A decreased serum level of TC, LDL-C, and Apo B was, respectively, observed at 6 months in 6.2, 12.9, and 13.8% of the patients who received TOR compared with the baseline. These decreases were maintained for at least 24 months. These lipid levels were not changed in those who received ANA. In the TOR patients, there was an increase in the serum level of HDL-C and Apo A1 at 6 months in 17.1 and 16.3%, respectively, which was maintained for at least 24 months, whereas these levels were almost stable in the patients who received ANA. Serum BAP decreased by 12.1% at 12 months and further decreased at 24 months and the serum NTX decreased by 22.0% at 6 months, which was maintained for at least 24 months in the patients who received TOR. In contrast, the serum BAP was increased by 26.0% at 6 months and by 29.2% at 12 months and the serum NTX increased by 21.3% at 24 months compared with baseline in those received ANA. However, the serum BAP increase was not significant at 24 months. TOR provides better effects than ANA in terms of lipid profiles and bone metabolism in postmenopausal females with early breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Agents, Hormonal; Bone and Bones; Breast Neoplasms; Female; Humans; Lipid Metabolism; Lipids; Middle Aged; Nitriles; Postmenopause; Receptors, Estrogen; Toremifene; Triazoles

Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized that toremifene as compared with tamoxifen given as adjuvant therapy for early stage breast cancer would result in equivalent survival with an improved side effect profile, therefore, providing superior therapeutic efficacy.. The North American Fareston versus Tamoxifen Adjuvant trial assigned 1813 perimenopausal or postmenopausal women with hormone receptor (HR)-positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS) and overall survival (OS).. Median follow-up was 59 months. The baseline characteristics of the 2 treatment groups were well-balanced. On the basis of intent-to-treat, 5-year actuarial DFS was not significantly different between tamoxifen and toremifene (91.2% [standard error of the mean [SE] 1.2%] vs 91.2% [SE 1.1%], respectively). Similarly, 5-year actuarial OS was not significantly different between tamoxifen and toremifene (92.7% [SE 1.1%] vs 93.7% [SE 1.0%], respectively). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene versus tamoxifen in terms of OS (OR = 0.951; 95% confidence interval [CI], 0.623-1.451, P = .951) or DFS (OR = 1.037; 95% CI, 0.721-1.491, P = .846). Adverse events were similar in the 2 groups.. Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of HR-positive patients with either tamoxifen or toremifene is appropriate.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Toremifene and tamoxifen have been used for adjuvant therapy in post-menopausal patients with breast cancer in Japan. Dyslipidemias are common in post-menopausal women. However, limited data are available on the effects of these agents on lipid profiles in Japanese patients. The Japan Toremifene Cooperative Study Group has been conducting a Phase III randomized trial of post-menopausal patients with breast cancer. One of its secondary endpoints is to confirm the effects of these agents on serum lipid profiles.. The subjects were post-menopausal Japanese patients who had undergone surgery for early breast cancer. Toremifene or tamoxifen was administered for 2 years. Lipid levels were measured before and up to 24 months after initiation.. Compared with baseline, at 24 months, the toremifene group (n = 123) showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001), and significantly increased high-density lipoprotein cholesterol levels (P < 0.001). Their triglyceride levels were not affected (P = 0.677). The tamoxifen group (n = 120) also showed significantly decreased total cholesterol (P < 0.001) and low-density lipoprotein cholesterol levels (P < 0.001); no significant changes occurred in high-density lipoprotein cholesterol (P = 0.297) or triglyceride levels (P = 0.120).. Distinct differences between two selective estrogen receptor modulators on lipids were observed. Toremifene improved lipid profiles, particularly as an enhancer of high-density lipoprotein cholesterol. To a large extent, tamoxifen improved low-density lipoprotein cholesterol levels. The impact of these improved lipid profiles on the risk of cardiovascular diseases needs further confirmation.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Japan; Lipids; Middle Aged; Postmenopause; Tamoxifen; Toremifene

The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of the first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for 5 years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of 8 years and endocrine therapy (toremifene or tamoxifen) versus chemo-endocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular, the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemo-endocrine therapy compared with endocrine therapy.

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cohort Studies; Cyclophosphamide; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasms, Second Primary; Survival Analysis; Tamoxifen; Toremifene

The main purpose of this research was to study the impact of hormonotherapy on changes of the lipid metabolism in patients with breast cancer. 451 breast cancer patients were under investigation. Depending on the treatment method, all patients were divided into four groups. The first group was composed of 117 patients who received hormonotherapy consisting of tamoxifen 20 mg/day; the second group was composed of 115 patients who received Toremifen 60 mg/day; The third group was composed of 106 patients who received Toremifen 240 mg/day; The fourth group consisted of 113 patients who received Letrozol 2,5 mg/day. To determine of lipid metabolism disorders, we estimated cholesterol fractions, triglycerides and high and low density lipoproteins both prior to the beginning of hormonotherapy, and in 3, 6, 12 months. After 12 month of hormonotherapy with Tamoxifen 20 mg/day all fractions of very low density lipoproteins were increased. Patients treated with Toremifen 240 mg/day demonstrated increase of total cholesterol and triglycerides in blood and decrease of concentration of high density lipoproteins. In the groups of patients who were treated with Toremifen 60 mg/day and Letrazol 2,5 mg/day any considerable disorders of lipid metabolism was not observed. It is concluded that hormonotherapy of the breast cancer may lead to the disorders of lipid metabolism, which may also lead to disorders of heart-vascular system.

Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Cholesterol, LDL; Dyslipidemias; Estrogen Antagonists; Female; Humans; Letrozole; Lipid Metabolism Disorders; Nitriles; Tamoxifen; Time Factors; Toremifene; Triazoles; Triglycerides

To compare time to progression (TTP) with a steroidal aromatase inhibitor (AI) atamestane (ATA) combined with toremifene (TOR; complete estrogen blockade) versus letrozole (LET) in receptor-positive advanced breast cancer (ABC).. Eligibility included postmenopausal receptor-positive ABC and adjuvant hormonal therapy completed more than 12 months prior to study entry. Participants received daily ATA 500 mg with TOR 60 mg (ATA + TOR), or letrozole 2.5 mg (LET). The primary end point was TTP, whereas secondary objectives included objective response (OR), overall survival (OS), and time to treatment failure (TTF). The study had 80% power to detect a 25% increase in TTP assuming a TTP of 9.4 months in the LET population.. A total of 865 patients were randomly assigned (434 to ATA + TOR and 431 to LET) in 60 centers in the United States, Canada, Russia, and Ukraine. Baseline characteristics were balanced. Median TTP was identical in the two arms at 11.2 months (P < .92). Median TTF was similar at 9.24 months (ATA + TOR) versus 10.44 months (LET). The hazard ratios (LET/ATA + TOR) were 1.00 (95% CI, 0.92 to 1.08) for TTP, 0.99 (95% CI, 0.92 to 1.06) for TTF, and 0.98 (95% CI, 0.87 to 1.11) for OS. OR occurred in 30% of patients receiving ATA + TOR and in 36% of patients receiving LET (P < .1). Adverse events (AEs) were similar for patients receiving ATA + TOR versus LET, and serious AEs were 10% v 11%, respectively.. TTP for patients receiving ATA + TOR was identical to that for patients receiving LET, representing the first endocrine therapy comparable to LET in ABC. Unlike in the Anastrozole, Tamoxifen, and Combined trial, addition of an antiestrogen did not decrease efficacy of the AI. Future studies of AIs in combination with more effective selective estrogen receptor modulators or selective receptor downregulators is warranted.

Topics: Aged; Androstenedione; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Double-Blind Method; Female; Humans; Letrozole; Middle Aged; Nitriles; Postmenopause; Receptors, Steroid; Toremifene; Triazoles

The prognostic and predictive relevance of p53 immunoreactivity is used here as a tentative approach for defining more accurately the benefit of adjuvant hormonal therapy in postmenopausal node-positive breast cancer patients. Ninety-seven postmenopausal patients with axillary lymph node metastasis were treated with an antiestrogen for a period of 3 years after primary surgery and radiotherapy. The p53 status of the primary tumor was assessed by immunohistochemistry and 24% of the samples showed positive expression of p53. Within the average follow-up time of 59 months, disease recurrence was diagnosed in 34 patients (35%). Multivariate analysis showed high clinical stage, negative estrogen receptor status and p53 positivity to be independent prognostic factors predicting both shortened disease-free survival and worse overall survival. p53 immunoreactivity was associated with worse clinical outcome irrespective of hormone receptor status. The data suggest that adjuvant therapy with antiestrogens is insufficient in this patient population with p53-positive tumors.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estrogen Antagonists; Female; Gene Expression Profiling; Genes, p53; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Postmenopause; Prognosis; Receptors, Estrogen; Tamoxifen; Toremifene; Treatment Outcome; Tumor Suppressor Protein p53

Distant metastases from breast cancer are incurable. In endocrine-responsive patients antiestrogens are commonly administered as first and second line therapy. Regrettably, tumor growth becomes resistant to this relatively innocuous therapy. Beta-interferon was unsuccessfully added to tamoxifen to induce estrogen receptor enhancement. In mice, interleukin-2 added to tamoxifen increased their mutual anti-tumor activities. Nevertheless, no effective clinical application has been developed. We started an exploratory clinical trial based on the association of these immunostimulating cytokines with antiestrogens for first line salvage therapy of hormone dependent breast cancer with distant metastases. Twenty-six consecutive breast cancer patients with distant metastases, 23 of which had metastases at multiple sites, were studied for responsiveness to treatment with first line salvage antiestrogen therapy, combined with beta-interferon and interleukin-2 immuno-therapy. Clinical response and survival were compared with that of 30 consecutive historical control patients treated with antiestrogen therapy alone. Controls showed, as expected, a median duration of response, a median survival time after treatment, and after diagnosis of distant metastases, of 16, 31 and 34 months, respectively. After a mean follow-up of 62+/-36 months (range 17-155), the interval times in the non-control patients were 61 (P<0.001), 101 (P<0.000001) and 106 (P<0.000001) months. Two long-term survivors appeared to be cured after 155 and 94 months from the time of diagnosis with multiple bone metastases. Nineteen of the patients treated with beta-interferon and interleukin-2 have survived. Hormone immuno-therapy was given in an outpatient setting and was very well tolerated. These data suggest that immuno-therapy plays an important role in endocrine-dependent metastatic breast cancer.

Topics: Breast Neoplasms; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunotherapy; Interferon-beta; Interleukin-2; Letrozole; Multivariate Analysis; Neoplasm Metastasis; Nitriles; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triazoles

A double-blind, randomised, placebo-controlled pilot study was initiated to evaluate the feasibility of chemoprevention with toremifene 60 mg/day in healthy women at high risk for breast cancer. Enrolment in the study was terminated earlier than planned because of slow patient accrual, although 13% of patients continued for 5 years. The revised efficacy outcomes were change in bone mineral density (BMD) from baseline at four skeletal sites, plus effects on serum lipids. In premenopausal women there was a trend for sustained increase in BMD during toremifene therapy after year 1 in lumbar spine. In postmenopausal women, toremifene had little or no effect on BMD trends. Levels of total and low-density lipoprotein (LDL) cholesterol were largely unchanged from baseline in premenopausal women treated with toremifene but were often slightly lower than in the placebo group during follow-up. Total and LDL cholesterol levels declined slightly from baseline in the postmenopausal women and were, at several points during the first 3 years, significantly lower than in the corresponding placebo group (p < 0.01). We conclude that: (a) assessment of toremifene 60 mg/day in chemoprevention will require further clinical trials; (b) toremifene 60 mg/day has no substantive negative effects on BMD in pre- or postmenopausal women and may exert a minor favourable influence (in particular, the effects of toremifene 60 mg/day on BMD in premenopausal women may make the drug an attractive alternative to tamoxifen 20 mg/day for that patient subset); (c) lipid effects of toremifene 60 mg/day are, at minimum, neutral and may be modestly favourable for reducing cardiovascular risk.

Topics: Adult; Analysis of Variance; Bone Density; Breast Neoplasms; Cholesterol; Dose-Response Relationship, Drug; Double-Blind Method; Female; Finland; Humans; Middle Aged; Pilot Projects; Postmenopause; Premenopause; Selective Estrogen Receptor Modulators; Toremifene; Triglycerides; United Kingdom

Among patients with breast cancer who consulted the Department of Radiology, Kochi Medical School to undergo breast-conservation treatment, toremifene (TOR) alone was administered to 7 postmenopausal women as initial treatment for reasons such as the patient's desire, advanced age, and concomitant disease. In 6 patients, breast-conserving surgery was performed 1-12 months after the start of the administration of TOR alone. A 90-year-old patient has been treated with TOR alone for 56 months, and is being followed up. Six of 7 patients showed 50% or greater reduction of tumors, including 1 in whom the administration of TOR alone for 5 months reduced the tumor from a clinical diagnosis of skin invasion (T4b) to T1c, allowing lumpectomy under local anesthesia. In one patient, there were no changes (reduction ratio: 14%). No progressive disease was detected in any patient. In this study, the administration of TOR alone markedly reduced tumors in patients with estrogen receptor (ER)-positive breast cancer, facilitating down-staging. Treatment with TOR alone may be a useful neoadjuvant therapy or single therapy in elderly patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; History, 18th Century; Humans; Middle Aged; Postmenopause; Receptors, Estrogen; Toremifene

To study the effects of tamoxifen and toremifene on bone mineral density (BMD) in postmenopausal women with breast cancer.. Seventy patients with stage II-III breast cancer were randomized to start either tamoxifen (n = 36; 20 mg per day) or toremifene (n = 34; 40 mg per day) for 3 years. BMD in the lumbar spine and in the proximal femur was measured by dual-energy X-ray absorptiometry both before and during the treatment and 1 year after the discontinuation of the anti-estrogens.. The baseline BMD measurements were comparable between the groups. In 3 years, lumbar BMD decreased by 1.7% in tamoxifen (P = 0.048) and 3.0% in toremifene (P = 0.001) users (ns between the groups), and femoral neck BMD by 0.9% (P = 0.040) and 1.3% (P = ns), respectively. The use of hormone replacement therapy (HRT) until the diagnosis of breast cancer was associated with decreases in lumbar BMD during anti-estrogen regimen (4% at 3 years) in contrast to unchanged lumbar BMD in women with no previous use of HRT. During the 1st year after the cessation of anti-estrogen, lumbar BMD did not change at all in either group whereas femoral BMD decreased in both the groups at the rate of 1.5-3.2%, as expected.. We conclude that tamoxifen (20 mg) and toremifene (40 mg) have similar bone-sparing efficacy that in lumbar spine extends up to 1 year after the cessation of these regimens. This effect is not seen in lumbar spine BMD in those postmenopausal women who discontinue HRT at the time of breast cancer diagnosis.

Topics: Absorptiometry, Photon; Analysis of Variance; Antineoplastic Agents, Hormonal; Bone Density; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Femur Neck; Follow-Up Studies; Humans; Lumbar Vertebrae; Middle Aged; Radiotherapy, Adjuvant; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher (p < 0.01) and TG was significantly lower (p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cardiovascular Diseases; Chemotherapy, Adjuvant; Female; Humans; Lipid Metabolism; Lipids; Middle Aged; Postmenopause; Tamoxifen; Toremifene

The objective of this study was to evaluate the different profiles of serum lipids resulting from the administration of selective estrogen receptor modulators (SERMs). Postmenopausal primary breast cancer patients (n = 197) with node-negative, hormone receptor-positive who were treated at our department or in other related medical institutions from April 1997 through March 2001 were given adjuvant therapy. The adjuvant therapy included 1 year's administration of tamoxifen (TAM) 20 mg or toremifene (TOR) 40 mg. The profiles of serum lipids such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) were observed. After 1 year administration TC had significantly decreased (p < 0.001) both in the TAM group and the TOR group, but no significant difference was found between these groups (p = 0.249). HDL had significantly decreased in the TAM group (p < 0.001), while it had significantly increased in the TOR group (p < 0.001), and a significant difference was found between the groups (p < 0.001). TG had significantly increased in the TAM group (p < 0.001) but significantly decreased in the TOR group (p < 0.001). The medication was switched in those who still had abnormal lipid metabolism and given to them for another year. After 1 year from the crossover TC and HDL had increased to the levels of before administration (p < 0.001) and TG had decreased in those (n = 57) whose medication was switched from TAM to TOR. While TC had decreased and TG had increased in those (n = 23) whose medication was switched from TOR to TAM (p < 0.001). The above findings have suggested that TOR provides better profiles of lipid metabolism than TAM.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cardiovascular Diseases; Chemotherapy, Adjuvant; Cross-Over Studies; Female; Humans; Lipids; Middle Aged; Postmenopause; Receptors, Estrogen; Receptors, Progesterone; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years.. 1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy.. Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three).. Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Quality of Life; Receptors, Estrogen; Tamoxifen; Toremifene; Treatment Outcome

It has been proposed that knowledge of estrogen receptor beta (ER-beta) expression may refine estrogen receptor alpha (ER-alpha) predictivity of response to endocrine therapy. We challenged this hypothesis in ER-alpha-positive breast cancers subjected to preoperative antiestrogen treatment. Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months). ER-alpha and ER-beta (ERs) mRNA was determined by semiquantitative RT-PCR, before (on core needle biopsy) and after (on surgical specimens) neoadjuvant treatment. Study end points included: (1) relation between treatment response and ER mRNA expression; and (2) changes in ER expression after treatment. The response was clinically assessed as tumor size change at the end of the preoperative treatment. ER mRNA expression was assessable before and after treatment in 38 and 20 cases respectively. ER-beta was co-expressed with ER-alpha at variable levels and significantly correlated only with progesterone receptor (P = 0.0285). Objective clinical response, including patients with minor change (> or =25-<50% tumor shrinkage after treatment), was documented in 68.4% of cases and was independent of ER-beta levels or changes. ER-alpha levels were higher in tumors from patients in complete remission than in those from women achieving partial response or minor change compared with non-responsive patients (median expression values: 801 versus 516 versus 320 arbitrary units) and were consistently down-regulated by preoperative treatment. We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Humans; Neoadjuvant Therapy; RNA, Messenger; Selective Estrogen Receptor Modulators; Toremifene; Treatment Outcome; Tumor Burden

Bexarotene is a retinoid X receptor-selective retinoid that has preclinical antitumor activity in breast cancer. We evaluated the efficacy and safety of oral bexarotene in the treatment of patients with metastatic breast cancer.. The following three groups of patients were treated: hormone-refractory, chemotherapy-refractory, and tamoxifen-resistant patients. Patients in the first two groups were treated with bexarotene alone, whereas the tamoxifen-resistant patients received both tamoxifen and bexarotene. Patients in all groups were randomly assigned to receive bexarotene at either 200 or 500 mg/m(2)/d.. One hundred forty-eight patients were randomized; 145 patients were treated. Of 48 hormone-refractory patients, there were two partial responses (6%) and 10 patients with stable disease lasting more than 6 months; of 47 chemotherapy-refractory patients, there were two partial responses (6%) and five patients with stable disease; and of 51 tamoxifen-resistant patients, there was one partial response (3%) and 11 patients with stable disease. All partial responses occurred at the 200-mg/m(2)/d dose. The projected median time to progression across all of the arms was 8 to 10 weeks. There were no drug-related deaths, and only two patients had drug-related serious adverse events. The most common drug-related adverse events were hypertriglyceridemia (84%), dry skin (34%), asthenia (30%), and headache (27%). There were no cases of pancreatitis.. The efficacy of bexarotene in patients with refractory metastatic breast cancer is limited. However, it is an oral agent with minimal toxicity and a unique mechanism of action, which produced clinical benefit in approximately 20% of patients. Future efforts should define populations likely to benefit from this agent.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Breast Neoplasms; Disease Progression; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Survival Analysis; Tamoxifen; Tetrahydronaphthalenes; Thyroid Hormones; Toremifene; Treatment Outcome

3Tamoxifen and toremifene are non-steroidal anti-oestrogens widely used in the treatment of advanced breast cancer and as adjuvant therapy following surgery in early stage disease. Tamoxifene has also been approved for use in reducing the incidence of breast cancer amongst high risk women. However, certain well documented adverse effects, mainly involving the reproductive organs, have been reported amongst users of both drugs. The aim of this study was to monitor the ocular side-effects of both of these commonly used anti-oestrogens.. Sixty postmenopausal (age range 50-79 years) breast cancer patients were randomized into adjuvant tamoxifen or toremifene therapy groups for 3 years. Prior to commencement of medication, a thorough ocular examination was undertaken. The first follow-up visit took place after 6 months and the remaining three at 12-month intervals thereafter.. Sixteen patients had cataract at the first visit (seven in the tamoxifen group and nine in the toremifene group). Ten patients developed cataract during the study period (five in each group), giving annual cataract rates of 6.8% and 6.2% in the tamoxifen and toremifene groups, respectively. Three patients had macular crystals at the first visit (one in the tamoxifen group and two in the toremifene group). The crystals remained stable throughout the follow-up. Macular drusen were diagnosed in five patients at the first ophthalmological check-up (two in the tamoxifen and three in the toremifene group). Two patients in the toremifene group developed drusen maculopathy during follow-up visits. Yellowish spots in the macular area were found in one tamoxifen-treated patient at the second visit. At the final visit after 3.5 years' follow-up the spots had disappeared. No abnormal corneal findings or keratopathy were documented during the follow-up.. We observed no serious ocular side-effects among the 60 breast cancer patients treated with tamoxifen or toremifene over a 3.5-year period.

Topics: Aged; Breast Neoplasms; Estrogen Antagonists; Eye; Female; Follow-Up Studies; Humans; Incidence; Macula Lutea; Middle Aged; Retinal Diseases; Tamoxifen; Toremifene

Efficacy and safety of toremifene (TOR) 60 mgs/dayly/o.r. was compared with tamoxifen (TAM) 40 mgs/dayly/o.r. in a group of postmenopausal women with advanced breast cancer, without previous systemic therapy for advanced breast cancer.. The study was a prospective double-blind randomized trial. All treated patients presented with positive estrogen receptors. Main end points were response rates, toxicity profile analysis, time to progression and survival. WHO and ECOG criteria were employed for response evaluation while toxicity was assesed according to WHO guidelines. Curves were constructed by means of Kaplan-Meier methodology and were compared by means of log-rank test.. From January 1996 to January 1999 a total of 217 patients were included in the study (106 in the TOR branch and 111 in the TAM arm). Both groups of patients were homogeneous regarding the main prognostic factors. A response rate of 64% (68/106) was observed in the TOR group as compared with a 52% (58/111) in the TAM group. Median times to progression and overall survival were not significantly different. A lower incidence of undesirable effects was apreciated in the TOR arm.. Our data suggest that TOR is an efficient and well-tolerated agent for the therapy of postmenopausal women with hormonal positive receptors advanced breast cancer, and must be considered an alternative to TAM as first line therapy for ER+ advanced breast cancer patients and as well as an adjuvant treatment.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease-Free Survival; Double-Blind Method; Estrogen Antagonists; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Postmenopause; Prospective Studies; Survival Analysis; Tamoxifen; Toremifene

To assess and compare the gynaecological consequences of the use of 2 antioestrogens we examined 167 postmenopausal breast cancer patients before and during the use of either tamoxifen (20 mg/day, n = 84) or toremifene (40 mg/day, n = 83) as an adjuvant treatment of stage II-III breast cancer. Detailed interview concerning menopausal symptoms, pelvic examination including transvaginal sonography (TVS) and collection of endometrial sample were performed at baseline and at 6, 12, 24 and 36 months of treatment. In a subgroup of 30 women (15 using tamoxifen and 15 toremifene) pulsatility index (PI) in an uterine artery was measured before and at 6 and 12 months of treatment. The mean (+/-SD) follow-up time was 2.3 +/- 0.8 years. 35% of the patients complained of vasomotor symptoms before the start of the trial. This rate increased to 60.0% during the first year of the trial, being similar among patients using tamoxifen (57.1%) and toremifene (62.7%). Vaginal dryness, which was present in 6.0% at baseline, increased during the use of tamoxifen (26.2%) and toremifene (24.1%). Endometrial thickness increased from baseline (3.9 +/- 2.7 mm) to 6.8 +/- 4.2 mm at 6 months (P< 0.001), and no difference emerged between the 2 regimens in this regard. Before the start of the antioestrogen regimen, the endometrium was atrophic in 71 (75.5%) and proliferative in 19 of 94 (20.2%) samples; 4 patients had benign endometrial polyps. During the use of antioestrogen altogether 339 endometrial samples were taken (159 in tamoxifen group, 180 in toremifene group). The endometrium was proliferative more often in the tamoxifen group (47.8%) than in the toremifene group (32.2%) (P< 0.0001). 20 patients had a total of 24 polyps (17 in tamoxifen and 9 in toremifene group, P< 0.05) during the use of antioestrogens. One patient in the toremifene group developed endometrial adenocarcinoma at 12 months, and one patient had breast cancer metastasis on the endometrium. Tamoxifen failed to affect the PI in the uterine artery, but toremifene reduced it by 15.0% (P< 0.05) by 12 months. In conclusion, tamoxifen and toremifene cause similarly vasomotor and vaginal symptoms. Neither regimen led to the development of premalignant endometrial changes. Our data suggest that so close endometrial surveillance as used in our study may not be mandatory during the first 3 years of use of antioestrogen treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Endometrium; Estrogen Receptor Modulators; Female; Humans; Middle Aged; Postmenopause; Prospective Studies; Tamoxifen; Toremifene; Vagina; Vasomotor System

In this study we report bone mineral density (BMD) changes during clodronate and antioestrogen treatment in women with breast cancer having discontinued hormone replacement therapy (HRT) at the time of operation compared to women who had not used HRT immediately before the operation. 61 postmenopausal women with operable breast cancer were treated with the adjuvant antioestrogen tamoxifen 20 mg or toremifene 60 mg daily for 3 years. All patients were randomized to clodronate (1.6 g daily orally) or control groups for 3 years. 23 patients had recently (recent users) and 38 never or not for at least 1 year before operation used HRT (non-users). BMD of lumbar spine and femoral neck were measured before antiresorptive therapy (antioestrogens and clodronate) and at 1, 2, 3 and 5 years thereafter. All patients were disease-free at the time of BMD measurements. Patients who had recently used HRT had more significant bone loss as compared to HRT non-users at 3 years in lumbar spine - 3.0% vs. + 1.2% (P< 0.001), but not in femoral neck - 0.4% vs. + 1.7% (P = 0.27). Adding 3-year clodronate treatment to antioestrogen therapy improved BMD marginally at 3 years: lumbar spine + 1.0% vs. -1.7% (P = 0.01) and femoral neck + 2.4% vs. -0.4% (P = 0.12). This was also seen at 5 years of follow-up, 2 years after termination of the antiresorptive therapy: HRT recent users vs. HRT non-users in lumbar spine -6.5% vs. +0.5% (P< 0.0001) and in femoral neck -4.8% vs. -1.5% (P = 0.38); and clodronate vs. controls in lumbar spine -1.0% vs. -3.2% (P = 0.06) and in femoral neck -0.1% vs. -5.2% (P = 0.001, respectively). The type of endocrine therapy (tamoxifen and toremifene) had no significant influence on BMD changes. We conclude from this study that postmenopausal women who have recently discontinued HRT experience more rapid bone loss than HRT non-users. Neither 3-year antioestrogen therapy alone nor antioestrogen together with clodronate could totally prevent the bone loss related to HRT withdrawal in lumbar spine, even though clodronate seemed to retard it.

Topics: Aged; Bone Density; Breast Neoplasms; Clodronic Acid; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Female; Follow-Up Studies; Humans; Middle Aged; Postmenopause; Tamoxifen; Toremifene; Treatment Outcome

The purpose of the study was to compare hormonal effects of three toremifene doses, 20 mg (TOR20), 40 mg (TOR40) and 60 mg (TOR60) administered daily, in postmenopausal women with advanced breast cancer.. The study was randomized and open label in three parallel groups. Biochemical variables were identified as the serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone binding globulin (SHBG). The changes were compared with objective clinical responses and to progression-free time. Adverse reactions and liver function test (aspartate aminotransferase, ASAT) were assessed for safety.. A total of 260 patients were randomly grouped (90 to TOR20, 81 to TOR40 and 89 to TOR60). Of these patients 29, 29 and 22 completed at least 3 months of treatment and the results were analyzed for biochemical variables. All treatments had intrinsic estrogen agonist activity by decreasing of serum FSH and LH and by increasing of SHBG during the first 3 months (P < 0.01). Dose TOR20 showed slightly longer times to exert maximum estrogenic effects than did the two higher doses. No increases in liver function tests were seen in any of the groups. Objective response rates were 24.4, 39.5 and 32.6% (P = 0.01) and median times-to-progression were 206, 189 and 196 days in TOR20, TOR40 and TOR60, respectively (P = 0.913). Fewer responses were observed in the TOR20 group than in TOR40 (P = 0.05). Adverse events were reported in 19, 23 and 30 patients in the treatment groups (P = 0.20). The most frequently reported events were hot flushes and nausea. These were mostly mild or moderate, and only 1.5% of treatments was discontinued due to toxicity.. Toremifene doses of 40 and 60 mg daily were effective and safe treatments of breast cancer in postmenopausal women, and no differences in their biochemical or clinical effects were seen. Toremifene at 20 mg/day had similar but slightly less potent antiestrogenic and estrogenic effects than the two higher doses.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged; Postmenopause; Sex Hormone-Binding Globulin; Toremifene

Tamoxifen protects against myocardial infarction through mechanisms that are poorly understood. We studied the effects of tamoxifen and another antiestrogen, toremifene, on the production of vasoconstrictive endothelin-1 and of vasodilatory nitric oxide in 44 postmenopausal patients with breast cancer. These started treatment, in randomized order, with either tamoxifen (20 mg/day; n = 25) or toremifene (40 mg/day; n = 19). Plasma samples collected before treatment and after 6 and 12 months of both regimens were assayed for endothelin-1 with a specific radioimmunoassay and for nitrite/nitrate with a method based on the Griess reaction. The antiestrogen group as a whole showed a fall in endothelin-1 at 6 months (5.9 +/- 3.3%; p = 0.06) (mean +/- SE) and at 12 months (7.1 +/- 5.5%; p = 0.03). This fall was solely due to toremifene, the use of which was associated with falls in endothelin-1 at 6 months (12.9 +/- 4.7%; p = 0.01) and 12 months (9.2 +/- 6.2%; p = 0.06). The antiestrogen regimen failed to affect plasma nitric oxide significantly but nevertheless the ratio between nitric oxide and endothelin-1 rose by 31.6 +/- 13.3% at 6 months and by 35.6 +/- 15.3% at 12 months in the antiestrogen users, an effect similar in the tamoxifen and toremifene groups. We conclude that antiestrogens may protect against myocardial infarction by preventing the release of endothelin-1 and by shifting the balance between nitric oxide and endothelin-1 to the dominance of the former. Our data predict that toremifene and tamoxifen at the doses studied here will provide similar cardiovascular protection.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Endothelin-1; Estrogen Antagonists; Female; Humans; Middle Aged; Myocardial Infarction; Nitrates; Postmenopause; Tamoxifen; Toremifene

Because estrogens stimulate the synthesis and release of leptin in the adipocytes, the effect of antiestrogens on the circulating leptin levels were studied.. Thirty postmenopausal patients with breast cancer were randomized to start either with tamoxifen (20 mg/day, n=15) or toremifene (40 mg/day, n=15), and the patients were examined and serum leptin concentrations measured before the study and at 6 and 12 months.. The baseline leptin concentrations ranged from 4.4 to 60.0 microg/l (15.3+/-13.1 microg/l, mean+/-S.D.), and it correlated positively with the body mass index (BMI) of the subjects (r=0.73, P=0.0001). Taking as a whole the antiestrogen regimen was associated with elevated leptin levels at 6 months (19.5+/-13.8 microg/l, P=0.0001) but no excess increase in leptin levels were seen at 12 months (20.9+/-13.5 microg/l, NS). Subgroup analysis showed no difference between the effects of tamoxifen or toremifene on leptin. BMI increased in 21 women (from 26.2+/-4.3 to 27.3+/-4.8 kg/m2, P=0.0001) at 6 months, but not after that; in nine women BMI did not change. There was no significant correlation between the change in leptin levels and the change in BMI in either group implying that antiestrogens may specifically stimulate leptin production.. Antiestrogens may stimulate the synthesis and release of leptin in the adipocytes. This effect of antiestrogens resembles the effect of estrogen and consequently stimulation of leptin production can be added to the estrogenic effects of antiestrogens.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Estrogen Receptor Modulators; Female; Humans; Leptin; Middle Aged; Postmenopause; Tamoxifen; Toremifene

In this multicenter trial, toremifene 40 mg/d was compared with tamoxifen 20 mg/d, both given orally for 3 years to postmenopausal, axillary node-positive women after breast surgery.. The first 899 patients (toremifene, n = 459; tamoxifen, n = 440) of the total of 1,480 patients accrued to the trial were included in this scheduled safety analysis. The mean follow-up time was 3.4 years.. The two treatment groups were well balanced with respect to patient and disease characteristics. The subjective side-effect profile was similar in both treatment groups. Slightly more vascular complications (deep vein thromboses, cerebrovascular events, and pulmonary embolisms) were seen among tamoxifen-treated patients (5.9%) as compared with toremifene-treated patients (3.5%) (P: =.11), whereas bone fractures (P: =.09) and vaginal leukorrhea (P: =.05) were more common in the toremifene group. The number of subsequent second cancers was similar. The breast cancer recurrence rate was 23.1% (n = 106) in the toremifene group and 26.1% (n = 115) in the tamoxifen group (P: =.31). When only patients with estrogen receptor (ER)-positive cancer were considered (n = 556), the risk for breast cancer recurrence was nonsignificantly lower among the toremifene-treated women, with a hazards ratio of 0.74 (90% confidence interval, 0.52 to 1.04; P: =.14). The mean time to breast cancer recurrence and overall survival were similar in both groups.. The side-effect profile of toremifene resembles that of tamoxifen. The efficacy of toremifene seems to be no less than that of tamoxifen. The trend for fewer breast cancer recurrences in the ER-positive subgroup is encouraging, but a longer follow-up is needed to confirm this.

Topics: Antineoplastic Agents, Hormonal; Axilla; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estrogen Receptor Modulators; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Middle Aged; Postmenopause; Prospective Studies; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15-20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40 mg toremifene or 20 mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40 mg toremifene and 20 mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.

Topics: Age Factors; Antineoplastic Agents, Hormonal; Body Mass Index; Breast Neoplasms; Chemotherapy, Adjuvant; Cholesterol; Female; Humans; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Middle Aged; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Triglycerides

Tamoxifen and toremifene are two mostly used antiestrogens in the treatment of breast cancer. To compare their effect on bone in postmenopausal breast cancer patients we measured the urinary output of two bone resorption markers, pyridinoline (Pyr) and deoxypyridinoline (Dpyr) as well as bone density (BMD) in 30 breast cancer patients using either tamoxifen (20 mg/day, n = 15) or toremifene (40 mg/day, n = 15) as adjuvant treatment of stage II breast cancer for 1 year. The urinary output of Pyr and Dpyr were assessed before and after 6 and 12 months of the antiestrogen regimen. Lumbar and femoral BMD were measured by dual energy X-ray absorptiometry (DXA) before and after 12 months of treatment. Both tamoxifen and toremifene were associated with significant decreases in Pyr (mean fall 19.6% and 12.6%, respectively) and Dpyr (mean fall 21.6% and 15.5%, respectively) at 6 months. After 12 months' treatment, Pyr decreased by 30.8% and Dpyr by 21.2% in women using tamoxifen and significantly less in women using toremifene (10.1% and 4.9%, respectively). BMD in the lumbar spine decreased by 1.8% in the toremifene group but increased by 0.4% in the tamoxifen group; in the proximal femur, BMD increased slightly during both tamoxifen and toremifene treatment in all sites measured. Individual changes in Pyr and Dpyr at 6 months showed no significant relation to the change in BMD at 12 months. We conclude that tamoxifen (20 mg/day) and toremifene (40 mg/day) reduce the bone resorption similarly, and this can be detected by falls in urinary output of Pyr and Dpyr at 6 months of treatment.

Topics: Amino Acids; Biomarkers; Bone Density; Breast Neoplasms; Cohort Studies; Estrogen Antagonists; Female; Humans; Middle Aged; Postmenopause; Tamoxifen; Time Factors; Toremifene

Antiestrogens are used in the treatment, and sometimes even in the prophylaxis, of breast cancer. Tamoxifen is the most commonly used antiestrogen, but toremifene is gaining in popularity. We compared here the effects of tamoxifen and toremifene on bone metabolism and density in 30 postmenopausal patients with breast cancer, who were randomized to receive tamoxifen (20 mg/day, n = 16) or toremifene (40 mg/day, n = 14) for 1 yr. Biochemical markers of bone resorption [urinary hydroxyproline, serum cross-linked carboxyterminal telopeptide of type I collagen, urinary cross-linked aminoterminal telopeptide of type I collagen (NTx)] and bone formation [serum bone-specific alkaline phosphatase, osteocalcin, and aminoterminal and carboxyterminal propeptide of type I procollagen] were assessed before treatment and at 6 and 12 months of the antiestrogen regimen. Bone mineral density (BMD) in the lumbar spine and proximal femur (neck, trochanter, and Ward's triangle) was measured using dual-energy x-ray absorptiometry before treatment and at 12 months of treatment. Urinary NTx decreased after 6 months' use of tamoxifen (mean fall: 33%) and of toremifene (mean fall: 16%). Use of tamoxifen was associated with a significant decrease in osteocalcin (mean fall: 25%) and aminoterminal propeptide of type I procollagen (mean fall: 22%), whereas toremifene failed to influence these markers. Tamoxifen increased BMD, on average, by 2% in the lumbar spine, 1% in the femoral neck, and 5% in Ward's triangle. Toremifene failed to increase BMD at any site measured, and in contrast, a slight trend toward a fall (-0.3 to -0.9%) in BMD was seen in patients treated with toremifene. Falls in urinary NTx, from baseline to 6 months, correlated significantly with changes in the lumbar spine BMD (r = -0.57, P = 0.0002) in the whole patient series. We conclude that tamoxifen (20 mg/day) increases BMD in postmenopausal breast cancer patients, whereas toremifene (40 mg/day) merely prevents the increasing age-associated fall in BMD. More prolonged studies on bone metabolism, comparing these two antiestrogens, are needed; but even now, clinicians should be aware of these differences between tamoxifen and toremifene.

Topics: Aged; Antineoplastic Agents, Hormonal; Bone and Bones; Bone Density; Bone Development; Bone Resorption; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Middle Aged; Postmenopause; Tamoxifen; Toremifene

The effect of clodronate on bone mineral density (BMD) was studied in 121 post-menopausal breast cancer women without skeletal metastases. In addition, two antioestrogens, tamoxifen and toremifene, were compared in their action on bone mineral density. Patients were randomized to have an adjuvant antioestrogen treatment either 20 mg of tamoxifen or 60 mg of toremifene daily for 3 years. In addition all patients were randomized to have 1600 mg of oral clodronate daily or to act as control subjects. BMD of the lumbar spine and femoral neck were measured by dual-energy radiographic absorptiometry before therapy and at 1 and 2 years. At 2 years, clodronate with antioestrogens markedly increased BMD in the lumbar spine and femoral neck by 2.9% and 3.7% (P = 0.001 and 0.006 respectively). There were no significant changes in BMD in the patients given antioestrogens only. No significant differences were found between tamoxifen and toremifene on bone mineral density. Clodronate with antioestrogens significantly increased bone mass in the lumbar spine and femoral neck. Both antioestrogens, tamoxifen and toremifene, similarly prevented bone loss in the lumbar spine and femoral neck.

Topics: Analysis of Variance; Antineoplastic Agents, Hormonal; Bone Density; Breast Neoplasms; Chemotherapy, Adjuvant; Clodronic Acid; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged; Postmenopause; Prospective Studies; Tamoxifen; Toremifene

To compare the efficacy and safety of high doses (200 or 240 mg/d) of toremifene (Fareston) to standard doses (20 or 40 mg/d) of tamoxifen (Nolvadex) in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown advanced breast cancer, we pooled data from two randomized, three-arm clinical trials. Of the 733 patients included in the overview, 369 were randomized to high-dose toremifene and 364, to tamoxifen. At median follow-up of 19 months, disease had progressed in over 70% of the patients. Response rates were 25.2% in the high-dose toremifene arm and 19.8% in the tamoxifen arm (P = .087). The two treatments appeared to be statistically equivalent with respect to risk for disease progression and survival. Reversible SGOT elevation was observed in 26 tamoxifen-treated patients vs 64 high-dose toremifene recipients (P < .001) and nausea in 33 vs 50 patients (P = .085). Reversible corneal keratopathy was diagnosed in two patients on tamoxifen and eight on high-dose toremifene (P = .061). Treatment had to be discontinued in 17.3% of patients in the high-dose toremifene arm and 20.1% in the tamoxifen arm. Discontinuation due to toxicity was rare, and toxicity did not differ significantly between the treatments. Toremifene, in doses up to 240 mg/d, is an effective, safe treatment for postmenopausal women with ER-positive/unknown advanced breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Middle Aged; Postmenopause; Survival; Tamoxifen; Time Factors; Toremifene; Treatment Outcome

In an open phase II study conducted in Finland and Latvia, 73 postmenopausal women were treated with 240 mg of toremifene (Fareston) as first-line therapy for advanced breast cancer. Among the 56 patients evaluable for responses, 59% achieved objective responses [complete response (CR) plus partial response (PR)], 29% showed no change (NC), and 12% had progressive disease (PD). When all treated patients were included, the objective response rate was 47%. Several very long durations of responses up to 86 months and survival durations up to 95 months were observed. In assessable patients, the best objective response rates were seen in those with soft-tissue (74%) and visceral (60%) disease. In 54% of patients with very large inoperable primary cancers, a PR was achieved. Half of patients reported side effects, about 60% of which were mild; 30%, moderate; and 5%, severe. Based on response rate and safety, high-dose toremifene is useful as first-line therapy for advanced breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Postmenopause; Survival; Toremifene; Treatment Outcome

The Finnish Breast Cancer Group (FBCG) started the first multicenter trial of toremifene (Fareston) in the adjuvant setting in 1992. The primary aim of the trial is to compare the efficacy and side effects of toremifene and tamoxifen (Nolvadex) as adjuvant therapies for postmenopausal node-positive breast cancer patients. About 830 patients have been enrolled in the trial to date. An interim analysis of the first 500 patients, performed after a mean follow-up of 18 months, showed no significant difference between toremifene and tamoxifen with regard to efficacy or side effects. The study includes additional protocols aimed at examining some side effects, including ocular problems and the formation of DNA adducts in the endometrium and leukocytes, as well as possible additional benefits, such as effects on lipid levels and bone density. Toremifene also is being studied in two other trials in Europe. These studies, which are being coordinated by the International Breast Cancer Study Group (IBCSG), have enrolled approximately 600 patients to date.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Tamoxifen; Toremifene

The study was planned to compare, in a prospective double-blind randomized trial, the efficacy and safety of toremifene (TOR) and tamoxifen (TAM) in post-menopausal patients with advanced breast cancer who have not had prior systemic therapy for advanced disease. Four hundred and fifteen post-menopausal patients with oestrogen receptor (ER)-positive or ER-unknown advanced breast cancer were randomly assigned to receive daily either 60 mg TOR or 40 mg TAM. The patients were stratified to measurable and non-measurable but evaluable groups. They were assessed for response to therapy, time to progression (TTP), time to treatment failure (TTF), response duration, overall survival and drug toxicity. Two hundred and fourteen patients were randomized into TOR and 201 into TAM treatment. The response rate (complete + partial) was 31.3% for TOR and 37.3% for TAM (P = 0.215). The 95% confidence interval (CI) for the 6% difference was -15.1% to 3.1%. The median TTP was 7.3 months for TOR and 10.2 months for TAM (P = 0.047). The 95% CI for the hazard ratio of 0.80 was 0.64-1.00. A percentage of the TOR patients (9.8%) and the TAM patients (18.9%) discontinued the treatment prematurely (P = 0.011) for various reasons. Consequently, the median TTF of 6.3 vs 8.5 months did not differ significantly (P = 0.271). The hazard ratio was 0.89 and the subsequent 95% CI 0.73-1.09. The median overall survival was 33.0 months for TOR and 38.7 months for TAM (P = 0.645). The hazard ratio was 0.94 with 95% CI of 0.73-1.22. The transient difference in TTP may be related to an imbalance in ER content of the tumours. When only patients with ER-positive tumours were considered (n = 238), no difference between two treatments was seen (P = 0.578). TAM was associated with an overall slightly higher frequency of adverse drug reactions than TOR (44.3 vs 39.3%) and a higher discontinuation rate due to these events (3.5% vs 0.9%). Treatment-emerged moderate dizziness (P = 0.026) and cataracts (P = 0.026) were more frequent among TAM than among TOR patients. In conclusion, TOR (60 mg day(-1)) and TAM (40 mg day(-1)) are equally effective and safe in the treatment of advanced post-menopausal ER-positive or ER-unknown breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Double-Blind Method; Estrogen Antagonists; Female; Humans; Middle Aged; Postmenopause; Prospective Studies; Scandinavian and Nordic Countries; Survival Rate; Tamoxifen; Toremifene; Treatment Outcome

Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Estrogen Antagonists; Female; Humans; Middle Aged; Postmenopause; Quality of Life; Tamoxifen; Toremifene

Efficacy and safety of toremifene 60 and 240 mg daily (TOR 60 and TOR 240) are compared to 40 mg tamoxifen daily (NFV 40) in postmenopausal women with advanced estrogen receptor (ER) positive of ER unknown breast cancer. The study is randomized in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safely was reported according to WHO criretia. Altogether 463 patients were randomized (157 to TOR 60, 157 to TOR 240 and 149 to TAM 40). By data cut-off, after 20.5 months medianfollow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7% in TOR 60, TOR 240 and TAM 40, respectively. TOR 60 and TAM 40 show statistically equivalent efficacy and the difference between TOR 240 and TAM 40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR 60), 6.1 (TOR 240) and 5.0 (TAM 40) months and corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR 60 and TAM 40 are statistically equivalent and the difference between TOR 240 and TAM 40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion TOR 60 and TAM 40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not significantly improved response rate and time to progression. In postmenopausal women, toremifene (60 mg) daily is an effective and safe treatment of advanced ER positive or ER unknown breast cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease Progression; Drug Administration Schedule; Female; Humans; Middle Aged; Postmenopause; Tamoxifen; Toremifene; Treatment Outcome

To evaluate whether a novel antiestrogen, toremifene, has similar antiatherogenic effects as tamoxifen.. Forty-nine postmenopausal patients with node-positive breast cancer were randomized in a trial that compared the effects of tamoxifen and toremifene on serum lipoproteins. Tamoxifen was given at 20 mg and toremifene at 60 mg orally per day for 3 years. Serum concentrations of apolipoprotein (apo) A-I, A-II, and B, and lipoprotein(a) [Lp(a)], cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol were measured before and after 12 months of antiestrogen therapy.. Both antiestrogens significantly reduced serum total and LDL cholesterol and apo B levels. However, the response of HDL cholesterol to treatments was clearly different between the groups. Toremifene increased the HDL level by 14%, whereas tamoxifen decreased it by 5% (P = .001). As a consequence, both cholesterol-to-HDL and LDL-to-HDL ratios decreased more in the toremifene than tamoxifen group (P = .008 and P = .03, respectively). Toremifene also increased the apo A-I level (P = .00007) and apo A-I-to-A-II ratio (P = .018). Both tamoxifen and toremifene decreased the Lp(a) concentration significantly (change, 34% v 41%).. These results provide positive evidence that toremifene has antiatherogenic properties with potency to improve all lipoproteins that are associated with increased coronary heart disease (CHD) risk.

Topics: Antineoplastic Agents, Hormonal; Apolipoproteins; Breast Neoplasms; Cholesterol; Estrogen Antagonists; Female; Humans; Lipids; Lipoproteins; Middle Aged; Postmenopause; Tamoxifen; Toremifene; Triglycerides

In pre-clinical and limited clinical studies, high doses ( > or = 200 mg/day) of the triphenylethylene derivative toremifene showed activity in estrogen receptor (ER) negative and ER-unknown metastatic breast cancer after progression on tamoxifen, and a mechanism of action independent of hormone receptor binding was speculated. The CALGB conducted a Phase II trial (CALGB 8945) to test the efficacy of high dose toremifene in a population of patients who had hormone receptor-negative, metastatic breast cancer with limited prior chemotherapy exposure, good performance status, and measurable disease. Twenty eligible patients received toremifene at a dose of 400 mg/day orally for 8 weeks. Toxicity was minimal. Nausea was reported by 20% of the patients, lightheadedness by 20%, weight loss by 20%, and hot flashes by 15%. There was no grade 3-4 toxicity. No objective responses were observed, and 5 of 6 patients with stable disease at 8 weeks developed progressive disease at 11 to 33 weeks. High dose toremifene (400 mg/day) is well-tolerated but imparts no detectable activity in hormone receptor-negative, metastatic breast cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptors, Estrogen; Receptors, Progesterone; Toremifene; Treatment Outcome

Antiestrogens have been widely used in the treatment of breast cancer patients. We wanted to compare the uteral and vaginal effects of tamoxifen to those of toremifene. Thirty-one gynecologically asymptomatic postmenopausal breast cancer patients with an intact uterus were randomized to receive 20 mg of tamoxifen (N = 16) or 60 mg of toremifene (N = 15) as an adjuvant treatment. Gynecological examination with vaginal ultrasonography, Pap smear, endometrial biopsy, hysteroscopy, and curettage was performed before the treatment, and at 6 and 12 months of treatment. Endometrial thickness was found to increase significantly during the treatment to the same extent in both groups. Proliferation or other estrogenic effects in the endometrium were observed in 8 of 14 patients in the tamoxifen group and in 3 of 10 patients in the toremifene group. Three polyps occurred and previously present uterine fibroids increased in size in 3 of 10 patients during the study. Estrogenic changes in Pap smear were observed in all patients. There was no significant difference between tamoxifen and toremifene in any of the parameters investigated. Our results suggest that tamoxifen and toremifene produce comparable estrogenic effects in the uterus and vagina.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Postmenopause; Prospective Studies; Tamoxifen; Toremifene; Uterus; Vagina

To perform a randomized three-arm comparison of tamoxifen (TAM; 20 mg/d) and two separate doses of toremifene (TOR; 60 mg/d [TOR60] and 200 mg/d [TOR200]) in postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer.. Six hundred forty-eight patients with hormone receptor-positive or -unknown metastatic breast cancer were randomly assigned to receive TAM (n = 215), TOR60 (n = 221), or TOR200 (n = 212).. The combined response rates (by intent to treat) were as follows;: TAM, 44%; TOR60, 50%; and TOR200, 48%. Complete and partial response rates were as follows: TAM, 19%; TOR60, 21%, and TOR200, 23% (not statistically different). Median times to progression and overall survival were not significantly different. Adverse events (lethal, serious but nonlethal, and important but non-life-threatening) were similar in all three arms, except that patients in the TOR200 arm had a statistically significantly increased rate of nausea (37% v 26% and 26% for TOR200, TAM, and TOR60, respectively; P = .027). Quality-of-life assessments were not different among the three arms.. The activity, toxicity, and side effects of TOR in postmenopausal women with hormone receptor-positive or -unknown metastatic breast cancer are similar if not equivalent to those of TAM. We detected no clear evidence of a dose-response effect for TOR. TOR60 is an effective and safe agent for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer and can be considered an alternative to TAM as first-line treatment for such patients.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Middle Aged; Postmenopause; Quality of Life; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Survival Rate; Tamoxifen; Toremifene; Treatment Outcome

Long-term effects of tamoxifen and toremifene, a new antiestrogen that closely resembles tamoxifen, were investigated on serum lipids and cholesterol metabolism.. The study group consisted of 24 postmenopausal Finnish women with advanced breast cancer from an international multicenter study of 415 patients. Cholesterol metabolism was evaluated by measuring the cholesterol precursor (delta 8-cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis) and plant sterol (markers of cholesterol absorption) and cholestanol levels by gas-liquid chromatography.. Tamoxifen and toremifene lowered significantly serum low-density lipoprotein (LDL) cholesterol levels after 12 months of treatment by 16% and 15%, with no change in high-density lipoprotein (HDL) cholesterol or serum triglyceride levels. Serum delta 8-cholestenol was increased 40- and 55-fold during toremifene and tamoxifen treatment, respectively, while the increase of desmosterol less than doubled and was lacking for lathosterol by toremifene. Plant sterols and cholestanol were only inconsistently increased in serum.. Tamoxifen and toremifene inhibit the conversion of delta 8-cholestenol to lathosterol so that serum total and LDL cholesterol levels are lowered by downregulation of cholesterol synthesis. Thus, inhibition of the delta 8-isomerase may be the major hypolipidemic effect of these agents. Reduced risk of coronary artery disease will probably occur also during long-term toremifene treatment, because the drug reduces cholesterol and its synthesis, similarly to tamoxifen.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cholesterol; Double-Blind Method; Estrogen Antagonists; Female; Humans; Middle Aged; Postmenopause; Tamoxifen; Toremifene

In a combined phase I-II study, the hormonal effects of toremifene (TOR) were investigated in 30 patients. Half of the patients received continuous therapy of TOR 60 mg and half 300 mg of TOR orally daily. Serum concentrations of oestradiol (E2), progesterone (PROG), testosterone (TE), follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin (PRL), human growth hormone (hGH) and sex hormone binding globulin (SHBG) were monitored prior to the treatment and at the second, sixth, eighth and twelfth weeks. The influence of TOR upon the hypothalamo-hypophyseal axis was investigated by the TRH (thyroid-stimulating hormone releasing hormone) functional test using 400 micrograms intravenous injection of TRH for stimulation of PRL secretion. The concentration of E2 decreased during the TOR therapy with 60 mg and 300 mg causing 82 and 71% decreases, respectively (non-significant). PRL was significantly (P < 0.001) suppressed. Both these effects reflect the anti-oestrogenic action of TOR. SHBG increased significantly at both doses of TOR, probably due to a direct oestrogen-like effect of TOR in the liver. TE decreased as a consequence of the elevated SHBG. The TRH-induced PRL release was suppressed by both doses of TOR. There were 17 and 27% reductions at 12 weeks in the 60 and 300 mg groups, respectively. Other hormones measured were not significantly affected by TOR. The hormonal effects of 60 and 300 mg doses of TOR did not differ significantly. Anti-oestrogenic (i.e. decrease of E2), and partially oestrogenic (i.e. increase of SHBG) properties as well as the antiprolactinic effects of TOR may have an overall beneficial effect in the clinical management of breast cancer patients.

Topics: Adult; Aged; Breast Neoplasms; Dose-Response Relationship, Drug; Estradiol; Female; Gonadotropins, Pituitary; Growth Hormone; Humans; Hypothalamo-Hypophyseal System; Middle Aged; Progesterone; Sex Hormone-Binding Globulin; Testosterone; Time Factors; Toremifene

In order to determine the usual dose in the first line therapy and a high dose in the second or third line therapy, a dose finding study of a novel antiestrogen NK 622 (toremifene citrate) was performed in patients (pts) with advanced or recurrent breast cancer. NK 622 was orally administered daily once for more than 8 weeks. In pts without previous drug therapy or in pts with cancer relapse after adjuvant therapy, the response rates [(CR + PR)/total] were 24.1% (7/29), 13.8% (4/29), 20.0% (1/5) and 40.0% (2/5) at doses of 40, 60, 120 and 240 mg/day, respectively. A 40 mg/day dose showed an objective response only in postmenopausal pts with estrogen receptor (ER) positive or unknown cancer. At a dose of 60 mg/day, some of the responding cases were premenopausal pts or pts with ER(-) cancer. In pts with cancer relapse during adjuvant therapy or in those with previous therapy and/or radiation, response rates were 25.0% (2/8), 0% (0/4), 13.5% (5/37) and 10.3% (4/39) at doses of 40, 60, 120 and 240 mg/day, respectively. Response was more frequent in pts with ER (+) cancer than with ER (-) cancer. The response rates in pts with previous therapy including tamoxifen (TAM) except medroxyprogesterone (MPA) were 14.3% (4/28) at a 120 mg/day dose and 6.1% (2/33) at a 240 mg/day dose. In pts with previous therapy including TAM, MPA and other antitumor agents, the rate was 18.2% (2/11) at a 120 mg/day dose. Side effects such as elevation of GOT, GPT and serum Ca level, decrease of hemoglobin, anorexia, nausea/vomiting, fatigue, dizziness and hot flush were observed. These side effects were moderate in grade and reversible. Dose dependency of side effects was not clearly observed in grade and incidence. From these results, NK 622 is expected to be a safe drug with efficacy in first line therapy at a dose of 40 mg/day and in second or third line therapy at a dose of 120 mg/day.

Topics: Administration, Oral; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Humans; Nausea; Neoplasm Recurrence, Local; Toremifene

Efficacy and safety of high dose administration of NK 622 (toremifene citrate) were studied in tamoxifen (TAM)--failed patients with breast cancer. The patients included in the study were the following failure cases in TAM therapy: unresponded cases in TAM therapy (TAM unresponded cases), temporary responded (CR, PR) but progressed cases in TAM therapy (TAM temporary responded cases), and those relapsing during TAM adjuvant therapy or within 6 months after the adjuvant therapy (TAM adjuvant failed cases). NK 622 of a 120 mg/day dose were orally given daily once at least for 8 weeks. The response rates in evaluable cases were 6.3% (1/16) in TAM unresponded cases, 11.1% (1/9) in TAM temporary responded cases, 15.4% (4/26) in TAM adjuvant failed cases, and 11.8% (6/51) in total cases including 1 CR and 5 PR cases. Long NC in which duration of NC maintained for more than 6 months was observed in 18.8% (3/16) of TAM unresponded cases, 22.2% (2/9) of TAM temporary responded cases, 11.5% (3/26) of TAM adjuvant failed cases, and 15.7% (8/51) of total cases. Rates of response and long NC were 14.3 and 19.0% in postmenopausal patients with estrogen receptor positive cancer, respectively. A median value of duration to the onset of response was 34 days (15-137). Median duration of response and long NC were 127 days (39-381) and 238.5 days (178-281), respectively. Adverse effects were experienced in 3 (5.1%) of 59 patients: nausea in 1, vertigo in 1 and increase of GOT, GPT, LDH and gamma-GTP in another 1. The side effects were moderate and reversible. From these results, NK 622 seems to become a safe and effective drug for TAM-failed patients with breast cancer by using a 120 mg/day dose.

Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Resistance; Female; Humans; Middle Aged; Tamoxifen; Toremifene

To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen.. One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease.. The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen.. We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

Topics: Aged; Breast Neoplasms; Drug Resistance; Female; Humans; Middle Aged; Survival Analysis; Tamoxifen; Toremifene; Treatment Outcome

Efficacy and safety of NK 622 (toremifene citrate) were compared with tamoxifen (TAM) by a double blind test in patients with advanced or recurrent breast cancer. NK 622 and TAM were given orally for 12 weeks or more at daily doses of 40 and 20 mg/body, respectively. Eligible cases in NK622 and TAM groups were both 57 patients. No significant difference was observed in patient characteristics between either group. Response rates were 26.3% (8 CR and 7 PR, 15/57) in the NK 622 group and 28.1% (3 CR and 13 PR, 16/57) in the TAM group. Median values of duration to onset of CR were 91 days in the NK 622 group and 169 days in the TAM group. The duration was significantly shorter with the NK 622 group. Median duration of efficacy in CR and PR cases was 155 days in the NK 622 group and 154.5 days in the TAM group. Adverse effects were encountered in 7 patients (12.3%) of each of the 2 groups. The side effects were fatigue, hot flush, WBC decrease, abnormal values in liver function tests, etc. in the NK 622 group and anorexia, nausea, eruption, feeling of warmth, sweating, dry mouth, dizziness, abnormal values in liver function tests, etc. in the TAM group. Administration was discontinued in one patient with eruption and another patient with abnormal values of liver function tests in the TAM group, while there was no such case in the NK 622 group. Including the discontinued cases, the side effects were moderate and reversible in both groups. The patients in whom a drug was determined as useful or more numbered 24/57 (42.1%) in the NK 622 group and 23/57 (40.4%) in the TAM group. There was not significant difference between the 2 groups in the above results except the duration to onset of CR. From these results, NK 622 is expected to show comparable efficacy, safety, and usefulness in patients undergoing TAM treatment for advanced or recurrent breast cancer.

Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Double-Blind Method; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Tamoxifen; Toremifene

Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with progressive disease during TAM-treatment. To elucidate possible cross-resistance between these two antiestrogens, we compared their anti-tumor activity in a randomized, double-blind, cross-over study. 66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a median age of 63 years (range 38-82) were included. Patients were randomized to TAM 40 mg/day or TOR 240 mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was done. The response rate with first line TOR was 29% (95% confidence limits 10-41%) and with TAM 42% (95% confidence limits 25-61%). Response rates and response durations, survival and toxicity were not significantly different between the two treatments. 44 patients progressing on first line TAM or TOR were evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over-looking a response rate of 20% or more is less than 1%. In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with advanced breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Double-Blind Method; Drug Resistance; Female; Humans; Middle Aged; Remission Induction; Survival Rate; Tamoxifen; Toremifene

Toremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites, N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1-3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Humans; Menopause; Middle Aged; Tamoxifen; Toremifene

A phase I study of NK 622 (toremifene citrate), a novel antiestrogen, was conducted in female patients with cancer. Patients received a single oral dosing or daily once oral dosing for five consecutive days. Any adverse effects were not experienced in the single dosing of 40 or 60 mg of NK 622. In the daily administration of 10, 20, 40, 60, 120, 240 and 480 mg/day, one of three patients who received 20 mg/day experienced grade 1 anorexia, three of four patients received 240 mg/day experienced adverse effects: Grade 1 leukopenia in one patient, Grade 1 general hot flush in one patient, and Grade 1 nausea, hot flush in the face and vertigo, Grade 2 anorexia, fatigue, dull headache and general hot flush in another one patient. These symptoms recovered to normal levels after treatment. Serum hormone levels were examined in postmenopausal patients, and a significant increase of the sex hormone binding globulin level was observed in the patients received 120 and 240 mg/day doses. Serum levels of NK 622 determined as free base (TOR) reached the peak levels in 2 to 4 hours after administration on the 1st and 5th day in daily treatment, while a metabolite N-demethyltoremifene (TOR-1) reached the peak level in 4 to 170 hours. Maximum serum levels and area under the concentration versus time curves of TOR and TOR-1 increased dose-dependently. These values also increased by repetition of the treatment. Half-lives of TOR and TOR-1 in serum ranged in 74.5 to 148.9 hours and 154.1 to 653.1 hours, respectively. From these results, it was concluded that safety and efficacy of NK 622 should be assessed by using 240 mg or less doses in clinical phase II studies where breast cancer patients received long term treatment with NK 622.

Topics: Administration, Oral; Adult; Aged; Anorexia; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Leukopenia; Middle Aged; Toremifene

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Topics: Administration, Oral; Breast Neoplasms; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Female; Half-Life; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Tamoxifen; Toremifene

46 postmenopausal women with estrogen receptor positive breast cancer entered a phase II study with a novel antiestrogen, toremifene. Patients had either recurrent or primarily inoperable advanced disease. No prior or concurrent cytostatic or hormonal treatment was allowed. Eight patients (17%) achieved complete response (CR), 17 (37%) partial response (PR) and 13 (28%) had stabilization of their disease at least for three months. The mean durations of responses were 52 +, 53 + and 27 + weeks, respectively, with 5 patients in CR, 6 in PR and 1 with no change (NC) still continuing the treatment. No significant differences could be seen in response rates according to the concentration of estrogen receptors or presence of progesteron receptors in this group of patients. Toxicity was not a problem, in general, the treatment was well tolerated. Two side effects (sweating and vertigo) were classified as severe and one patient after achieving PR interrupted the treatment because of tremor.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Humans; Middle Aged; Multicenter Studies as Topic; Tamoxifen; Toremifene

Nine patients with measurable lesions of locally advanced or recurrent breast cancer have been treated with toremifene 200 mg daily. A response rate of 33% [complete remission (CR) + partial remission (PR)] or 78% [CR + PR + no change (NC)] has been achieved so far. As all our patients had previously relapsed on anti-oestrogen therapy (tamoxifen), we postulate that our response rate was achieved by a direct oncolytic effect.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Clinical Trials as Topic; Estrogen Antagonists; Female; Humans; Tamoxifen; Toremifene

Thirteen postmenopausal women with advanced local or metastatic breast cancer were treated with the antiestrogen toremifene at a daily dose of 200 mg. All patients had failed previous treatment with different types of endocrine therapy and/or cytotoxic drugs. Objective response was only seen in one patient. Treatment was usually well tolerated but in three cases the drug had to be withdrawn due to side effects.

Topics: Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Female; Humans; Middle Aged; Tamoxifen; Toremifene

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.

Topics: Adult; Breast Neoplasms; Estradiol; Estrogen Antagonists; Female; Follicle Stimulating Hormone; Hormones; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Middle Aged; Progesterone; Prolactin; Sex Hormone-Binding Globulin; Tamoxifen; Testosterone; Thyrotropin-Releasing Hormone; Toremifene

Topics: Aged; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Finland; Humans; Middle Aged; Multicenter Studies as Topic; Receptors, Estrogen; Tamoxifen; Toremifene

The predictive value of estrogen receptor (ER) concentrations was evaluated in a group of 113 postmenopausal patients with estrogen-receptor-positive (ER greater than 7 fmol/mg protein) advanced breast cancer. In 103 patients, tumors were also sampled for progesterone receptor (PgR) determination. All patients were treated with toremifene, a novel antiestrogen, 60 mg daily. The median ER in 51 responders was 78 fmol/mg protein, and in 62 nonresponders, 51 fmol/mg protein; the median PgR levels were 40 and 37 fmol/mg protein, respectively. The response rate in patients with ER less than 50 fmol/mg protein was 38%, and 51% in the group with ER greater than 50 fmol/mg protein (not significant [NS]). The response rate in patients with PgR less than 10 fmol/mg protein was 42%, and in patients with greater than 10 fmol/mg protein, 44%. The duration of response in patients with ER greater than 50 fmol/mg protein was significantly longer than with lower ER levels (P = 0.002). PgR was not associated with the duration of response. In Cox's multiple regression analysis, ER was an independent prognostic factor (P = 0.005) for response duration. Thus, the ER concentration of tumor tissue predicts the duration of response but not the response rate to toremifene in patients with advanced breast cancer. The PgR status does not predict the response rate or the duration of response.

Topics: Aged; Bone Neoplasms; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Menopause; Middle Aged; Predictive Value of Tests; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Remission Induction; Tamoxifen; Toremifene

A randomized clinical trial performed in 50 female patients with advanced breast cancer showed 60 mg/day and 240 mg/day toremifene and 40 mg/day tamoxifen to be nearly equally effective. Partial, with few exceptions, response lasting 5-31 months was observed in 35-50% of cases whereas another 35-50% of patients showed no change. Toxicity was low.

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Latvia; Lung Neoplasms; Menopause; Middle Aged; Remission Induction; Tamoxifen; Toremifene; USSR

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Climacteric; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Estrogens; Female; Gonadotropins; Humans; Middle Aged; Nausea; Neoplasms; Remission Induction; Sex Hormone-Binding Globulin; Tamoxifen; Toremifene; United States

The efficacy of high dose toremifene (240 mg daily) in postmenopausal women with advanced breast cancer is investigated in this ongoing study. At present, 38 patients are fully evaluable. Ten patients have CR (26%), 16 PR (42%) (objective response rate 68%), 8 NC (21%), and 4 PD (11%). Most objective responses are in soft tissue tumors (14/17, 82%). The response rate is equally high in patients with positive or unknown estrogen receptor (ER) status. Median duration of responses and survival are not yet evaluable. Of 48 patients evaluable for side-effects, 22 (46%) experienced some kind of toxicity, which was mild in 64% of cases, moderate in 29%, and mostly of estrogenic type. The study will continue to confirm the results thus far obtained.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Chi-Square Distribution; Drug Evaluation; Estrogen Antagonists; Female; Finland; Follow-Up Studies; Humans; Latvia; Menopause; Middle Aged; Remission Induction; Tamoxifen; Toremifene

Toremifene has proven to be an effective and well tolerated antiestrogenic compound in the treatment of locally advanced and metastatic breast cancer. Results of phase II studies reveal that the efficacy using a 60 mg daily dose is comparable to tamoxifen. Since toremifene is less toxic in high doses than tamoxifen, in many clinical studies greater than or equal to 200 mg daily doses are used. For more accurate comparison of toremifene and tamoxifen five different clinical phase III studies have been initiated. By December 1, 1989, there were altogether 650 patients accrued into these studies. Two of the studies are double blind comparison of the drugs, one conducted in Finland, Sweden, and Norway, and the other in Denmark. Three open studies are going on, one in the Soviet Union, one in West Germany (BRD), and the third in the USA and Canada. To clarify dose-dependency of toremifene action, a daily dose from 60 mg up to 240 mg is used in these studies compared to 20-40 mg daily doses of tamoxifen. The results of these studies are still too early for critical evaluation, since in the double blind studies no interim comparison of the drugs is possible, and the results of the BRD and USA-Canada open studies will not be analyzed before sufficient patients for statistical evaluation have been included. Preliminary results of the Soviet trial comparing 60 and 240 mg toremifene doses with 40 mg of tamoxifen show that the response rate is highest in the 240 mg toremifene arm, although there are no statistically significant differences. Statistical significance in clinical studies like these is an important aspect of reliability, which based on trial protocols will be critically evaluated and discussed.

Topics: Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Estrogen Antagonists; Female; Humans; Neoplasm Metastasis; Remission Induction; Tamoxifen; Toremifene

Adenofibroma is a rare benign Müllerian mixed tumor composed of epithelial and mesenchymal cells. This tumor may occasionally be associated\ with toremifene therapy which is used as an adjuvant drug for breast cancer.. We describe a case of a 55-year-old woman with adenofibroma of the endometrium. This patient was receiving toremifene after surgery and\ neoadjuvant chemotherapy for breast cancer. She underwent a total abdominal hysterectomy and bilateral salpingectomy. There was no evidence of\ tumor residual or recurrence at 32 months of MRI follow-up.. In conclusion, we report a rare case of endometrial adenofibroma in a patient receiving toremifene. It must be borne in mind that long-term\ toremifene therapy may increase the frequency of endometrial neoplasms.

Topics: Adenofibroma; Breast Neoplasms; Endometrial Neoplasms; Female; Humans; Middle Aged; Toremifene

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Aromatase Inhibitors; Bilirubin; Breast Neoplasms; Female; Humans; Letrozole; Liver; Middle Aged; Retrospective Studies; Toremifene; Young Adult

CYP2D6 gene polymorphism has a profound impact upon the effect of tamoxifen as adjuvant endocrine therapy in breast cancer. However, it had never been reported whether the adverse drug reactions vary by CYP2D6 metabolic status for patients treated with tamoxifen or toremifene. We conducted a retrospective study in breast cancer patients to investigate the impact of CYP2D6 metabolic status on liver dysfunction events, gynecological events and dyslipidemia events. According to CYP2D6*10 (100C → T) genotype, the enrolled patients were further categorized into four cohorts (extensive metabolizers taking tamoxifen [EM + TAM], extensive metabolizers taking toremifene [EM + TOR], intermediate metabolizers taking tamoxifen [IM + TAM], and intermediate metabolizers taking toremifene [IM + TOR]). A total of 192 patients were included in the study, with a median follow-up time of 26.2 months. In EM + TAM cohort, the risks of liver dysfunction events (P = .004) and gynecological events (P = .004) were significantly higher compared to EM + TOR cohort. In IM + TAM cohort, the risks of liver dysfunction events (P = .14) and gynecological events (P = .99) were not significantly different from IM + TOR cohort. A significant decrease of total cholesterol was observed in EM + TAM cohort around 1 year after taking tamoxifen (P < .001). Significant interactions between CYP2D6 metabolic status and endocrine agents were observed in terms of liver dysfunction events (P-interaction = .007) and gynecological events (P-interaction = .026). These findings suggested that CYP2D6 gene polymorphism played a significant role in predicting liver dysfunction, gynecological diseases and lipid metabolism changes among patients taking tamoxifen or toremifene.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cohort Studies; Cytochrome P-450 CYP2D6; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Humans; Retrospective Studies; Tamoxifen; Toremifene

This study aimed to reveal the treatment patterns and clinical outcomes of diverse palbociclib-based regimens in Han patients with estrogen receptor-positive (ER+) metastatic breast cancer in routine clinical practice.. The clinical data of patients with ER+ metastatic breast cancer treated with palbociclib were collected from the National Cancer Center database. The efficacy profile of palbociclib in this Han population was evaluated, especially for various combination regimens. The efficacy of palbociclib-based therapy in patients with prior everolimus treatment was also assessed.. A total of 186 patients from 89 cities in 18 provinces in China were enrolled. The median progression-free survival (PFS) was similar among different palbociclib-combined groups ( P  = 0.566): 10.0 months (95% confidence interval [CI] 3.8-16.1) in the +exemestane group, 9.7 months (95% CI 6.3-13.1) in the +letrozole group, 7.8 months (95% CI 5.5-10.2) in the +fulvestrant group, 7.2 months (95% CI 3.2-11.3) in the +toremifene group, and 6.1 months (95% CI 1.2-11.0) in the +anastrozole group. Thirty-four patients (18.3%) had received everolimus for their metastatic disease before the prescription of palbociclib. The disease control rate was significantly lower in patients who had received previous everolimus than in the everolimus-naïve group (50.0% vs . 82.2%, P  < 0.001). Patients pre-treated with everolimus had significantly worse PFS than those in the everolimus-naïve group (3.4 months vs . 8.8 months, P   =  0.001). After propensity score matching, patients pre-treated with everolimus had similar PFS (4.4 months, 95% CI 0.5-8.2) compared with everolimus-naïve patients (6.1 months, 95% CI 4.7-7.5, P   =  0.439).. Various palbociclib-based regimens have promising efficacy in ER+ metastatic breast cancer in real-world settings, even in patients who had been pre-treated with everolimus.

Topics: Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Fulvestrant; Humans; Letrozole; Piperazines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Toremifene

Antiestrogen agents have been reported to enhance the anticoagulant activity of warfarin. The use of tamoxifen with warfarin has been contraindicated. However, warfarin in combination with toremifene has not been reported. We report a case in which warfarin was combined with toremifene and applied warfarin dose prediction models to predict the dose of warfarin.. We report the case of a 50-year-old woman with a history of breast cancer, who underwent long-term toremifene therapy after mastectomy. The patient was treated with warfarin after prosthetic valve replacement and had a fluctuating international normalized ratio (INR) following the concomitant administration of toremifene. We applied the warfarin dose prediction model to adjust the warfarin dose during treatment. Finally, her INR stabilized with a lower dose of warfarin, and there was no serious bleeding during the 1-year follow-up.. Warfarin does not have a serious interaction with toremifene in this case, but it needed about 37.5% dose reduction which was comparable to the interaction of some common antibiotics with warfarin.

Topics: Anticoagulants; Breast Neoplasms; Female; Humans; International Normalized Ratio; Mastectomy; Middle Aged; Toremifene; Warfarin

To evaluate the prognosis of estrogen receptor-positive breast cancer patients with CYP2D6*10 mutant genotypes under tamoxifen or toremifen therapy.. Estrogen receptor-positive breast cancer patients were selected and CYP2D6*10 genotypes (C/C, C/T, and T/T) were determined by Sanger sequencing. Patients were divided into tamoxifen, toremifene, or tamoxifen + toremifene groups according to prior therapy. The correlation between CYP2D6*10 genotype and disease-free survival was analyzed.. In total, 293 estrogen receptor-positive breast cancer patients treated with tamoxifen or toremifene between 2008 and 2017 were studied. Median follow-up was 39 months (10-141). Of these, 107 (36.52%), 112 (38.23%), and 74 (25.26%) patients had C/C, C/T, and T/T genotypes, respectively. Genotype was significantly associated with disease-free survival in tamoxifen patients. Patients with C/T and T/T genotypes showed worse disease-free survival than patients with a C/C genotype. Genotype and disease-free survival in toremifene and tamoxifen+toremifene patients were not correlated. Of patients with a C/T genotype, toremifene or tamoxifen+toremifene groups showed better disease-free survival than tamoxifen patients. Although disease-free survival of patients with a T/T genotype in the three groups was not statistically different, tamoxifen patients showed worse disease-free survival. There was no correlation between different treatments and disease-free survival in patients with a C/C genotype. Cox proportional hazard analysis revealed toremifene patients had a better prognosis than tamoxifen patients; toremifene was an independent protective factoremifene for disease-free survival.. Tamoxifen was less effective in patients with CYP2D6*10 C/T and T/T genotypes. Estrogen receptor-positive breast cancer patients with a CYP2D6*10 mutation genotype have a better prognosis with toremifen than tamoxifen.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; China; Cytochrome P-450 CYP2D6; Female; Genotype; Humans; Prognosis; Receptors, Estrogen; Tamoxifen; Toremifene

Tamoxifen (TAM) and Toremifene (TOR), two kinds of selective estrogen receptor modulators (SERMs), have equal efficacy in breast cancer patients. However, TAM has been proved to affect serum lipid profiles and cause fatty liver disease. The study aimed to compare the effects of TAM and TOR on fatty liver development and lipid profiles.. This study performed a retrospective analysis of 308 SERMs-treated early breast cancer patients who were matched 1:1 based on propensity scores. The follow-up period was 3 years. The primary outcomes were fatty liver detected by ultrasonography or computed tomography (CT), variation in fibrosis indexes, and serum lipid profiles change.. The cumulative incidence rate of new-onset fatty liver was higher in the TAM group than in the TOR group (113.2 vs. 67.2 per 1000 person-years, p < 0.001), and more severe fatty livers occurred in the TAM group (25.5 vs. 7.5 per 1000 person-years, p = 0.003). According to the Kaplan-Meier curves, TAM significantly increased the risk of new-onset fatty liver (25.97% vs. 17.53%, p = 0.0243) and the severe fatty liver (5.84% vs. 1.95%, p = 0.0429). TOR decreased the risk of new-onset fatty liver by 45% (hazard ratio = 0.55, p = 0.020) and showed lower fibrotic burden, independent of obesity, lipid, and liver enzyme levels. TOR increased triglycerides less than TAM, and TOR increased high-density lipoprotein cholesterol, while TAM did the opposite. No significant differences in total cholesterol and low-density lipoprotein cholesterol are observed between the two groups.. TAM treatment is significantly associated with more severe fatty liver disease and liver fibrosis, while TOR is associated with an overall improvement in lipid profiles, which supports continuous monitoring of liver imaging and serum lipid levels during SERM treatment.

Topics: Adult; Breast Neoplasms; Fatty Liver; Female; Humans; Lipids; Middle Aged; Retrospective Studies; Tamoxifen; Toremifene

Acquired resistance occurs in metastatic hormone receptor-positive breast cancer patients. The addition of interferon beta/interleukin-2 immunotherapy to first-line salvage hormone therapy (HT) prolonged progression-free (PFS) and overall survivals (OS) in 26 patients, as compared with 30 historical controls and literature data. This was a 2 : 1 ratio case-control retrospective observational study. The cases were from an open pilot study, started in 1992, and controls were recruited in 2006. The planned mean follow-up time was the time at which more than 80% of controls progressed. The median PFS was significantly longer in the cases than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). Also, median OS was significantly longer in the cases, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029). When analysis of the 2 groups was adjusted for the disease-free interval (DFI), hormone receptor status, HER2, site of metastases and molecular-targeted therapies, the hazard ratio for PFS and for OS in the cases increased from 2.347 to 3.090 and from 1.874 to 2.147, respectively. This occurred in spite of the higher proportion of controls (82% vs 7.1%) treated with aromatase inhibitors (AIs), while selective oestrogen receptor modulators (SERMs) were given to 92.9% of the cases and to 18% of the control group (p < 0.0001). Immunotherapy significantly prolonged PFS and OS during conventional first-line HT. A multi-centre randomised clinical trial is advised to enter this immunotherapy into clinical practice. KEY MESSAGES: • Acquired resistance occurs in metastatic endocrine-dependent breast cancer patients. • Interferon beta-interleukin-2 immunotherapy added to first-line salvage hormone therapy prolonged progression-free (PFS) and overall (OS) survivals in 26 patients of a pilot study as compared with 30 historical controls. • In this 2:1 ratio case-control prospective observational study, the PFS median time was significantly longer in the study group than that in controls, 33.1 (95% CI 24.5-41.8) vs 18 (95% CI 12.1-23.8) months (p < 0.0001). • Also, the OS median time was significantly longer in the study group, 81 vs 62 (95% CI 48.1-75.9) months (p < 0.0029).

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Case-Control Studies; Female; Humans; Immunotherapy; Letrozole; Male; Middle Aged; Receptor, ErbB-2; Retrospective Studies; Selective Estrogen Receptor Modulators; Survival Analysis; Tamoxifen; Toremifene

We performed a retrospective study on the efficacy and safety of sirolimus (an mTOR inhibitor) in hormone receptor (HR)-positive advanced breast cancer and searched for biomarkers to predict its efficacy.. All patients with HR-positive metastatic breast cancer treated with sirolimus plus endocrine therapy between December 2017 and July 2018 at the Cancer Hospital, Chinese Academy of Medical Sciences were consecutively and retrospectively reviewed. Mutations in circulating tumour DNA (ctDNA) were assayed for 1021 tumour-related genes via gene panel target capture-based next-generation sequencing.. Thirty-six patients with metastatic breast cancer treated with sirolimus plus endocrine therapy were included. The progression-free survival (PFS) rates between the sirolimus group and everolimus group were similar, and the median PFS was 4.9 months and 5.5 months, respectively (hazard ratio 1.56, 95% CI 0.86-2.81, P = 0.142). The objective response rate in the 36 patients was 19.4%, and the clinical benefit rate was 41.7%. Lipid metabolism disorder was the most common adverse event (69.4%), and 13.9% of patients had stomatitis. Most (94.4%) adverse events were grade 1-2. Twenty patients (55.6%) underwent ctDNA analysis before receiving sirolimus therapy. For patients who received less than 3 lines of chemotherapy, those with PI3K/Akt/mTOR pathway alterations had a better response to sirolimus than those without alterations, with a median PFS of 7.0 months vs 4.3 months (hazard ratio = 0.01, 95% CI 0.00-0.34, P = 0.010).. Sirolimus is a potentially effective treatment option for patients with HR-positive advanced breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Biomarkers, Tumor; Breast Neoplasms; China; Circulating Tumor DNA; Everolimus; Female; Fulvestrant; Humans; Middle Aged; Progression-Free Survival; Retrospective Studies; Signal Transduction; Sirolimus; Tamoxifen; TOR Serine-Threonine Kinases; Toremifene

HER2-positive breast tumors are found in 25-30% of patients with breast cancer and are characterized by aggressive course and reduced sensitivity to both chemotherapy and hormone therapy. The aim of the work was to study the possibilities of enhancing the therapeutic effect of anti-estrogen drug toremifene by combining it with biguanide, metformin, on the HER2-positive breast cancer model in FVB/N HER-2/neu transgenic mouse. Male FBV/N mice with intramuscularly transplanted HER2-positive mammary gland tumor from a female mouse of the same strain have been given toremifene (30 mg/kg, orally daily) or metformin (100 mg/kg, orally daily) that had a moderate antitumor effect (decrease the area under the kinetic curve of tumor growth by 1.6 and 1.5 times, respectively, when compared with intact control). Co-administration of these drugs in the same doses had a more pronounced effect (the area under the kinetic curve of tumor growth decreased by 3.1 times compared to intact control; p<0.05). After 10 days, in group receiving toremifene all 10 mice developed inguinal-scrotal hernias, and in group that received toremifene plus metformin - only 5 of 10 (p=0.0325). By the 15

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Breast Neoplasms, Male; Disease Models, Animal; Female; Male; Metformin; Mice; Mice, Transgenic; Receptor, ErbB-2; Toremifene

The relationship between anti-estrogen drugs and macular telangiectasia type 2 (MacTel-2) remains unknown. Here we report a case with anti-estrogen maculopathy resembling MacTel-2 with improved visual function and macular morphology following cessation of anti-estrogen drugs.. A 53-year-old woman presented with a 5-month history of central vision loss and anorthopia in both eyes. She had received oral tamoxifen followed by toremifene for 69 months. Funduscopy, fluorescein angiography, and optical coherence tomography (OCT) revealed MacTel-2-like findings OU. Fundus autofluorescence (FAF) showed hyper-autofluorescence at the fovea OU. Visual acuity, macular morphology on OCT, and FAF findings gradually improved after cessation of anti-estrogen drugs.. In the present case, visual acuity, macular morphology, and impairment of the retinal pigment epithelium (RPE) improved following cessation of anti-estrogen drugs, suggesting the relationship between retinal toxicity of anti-estrogen drugs and the development of MacTel-2-like findings. From these results and the previous observations, toxicity of both photoreceptor and RPE cells caused by anti-estrogen drugs may contribute to the development of anti-estrogen maculopathy similar to MacTel-2.

Topics: Breast Neoplasms; Estrogen Antagonists; Female; Fluorescein Angiography; Humans; Middle Aged; Retina; Retinal Telangiectasis; Tamoxifen; Tomography, Optical Coherence; Toremifene; Visual Acuity; Withholding Treatment

An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.. The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.. Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.. TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Female; Genotype; Hot Flashes; Humans; Hydroxylation; Middle Aged; Phenotype; Polymorphism, Genetic; Selective Estrogen Receptor Modulators; Smoking; Tamoxifen; Toremifene

Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC-MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor-positive breast cancer (ER + ).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC-MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63 μg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20 μg/L).

Topics: Breast Neoplasms; Chromatography, High Pressure Liquid; Clomiphene; Doping in Sports; Drug Monitoring; Enzyme-Linked Immunosorbent Assay; Female; Healthy Volunteers; High-Throughput Screening Assays; Humans; Selective Estrogen Receptor Modulators; Solid Phase Extraction; Tamoxifen; Tandem Mass Spectrometry; Testosterone Congeners; Toremifene

Exemestane (EXE), exemestane + everolimus (EXE + EVE), toremifene (TOR), and fulvestrant (FUL) are second-line endocrine therapies for postmenopausal hormone receptor-positive (HR +)/human epidermal growth factor receptor 2-negative (HER2 -) metastatic breast cancer (mBC) in Japan. Although the efficacy of these therapies has been shown in recent studies, cost-effectiveness has not yet been determined in Japan.. This study aimed to examine the cost-effectiveness of second-line endocrine therapies for the treatment of postmenopausal women with HR + and HER2 - mBC.. A Markov model was developed to analyze the cost-effectiveness of the therapies over a 15-year time horizon from a public healthcare payer's perspective. The efficacy and utility parameters were determined via a systematic search of the literature. Direct medical care costs were used. A discount rate of 2% was applied for costs and outcomes. Subgroup analysis was performed for non-visceral metastasis. A series of sensitivity analyses, including probabilistic sensitivity analysis (PSA) and threshold analysis were performed.. Base-case analyses estimated incremental cost-effectiveness ratios (ICERs) of 3 million and 6 million Japanese yen (JPY)/quality-adjusted life year (QALY) gained for TOR and FUL 500 mg relative to EXE, respectively. FUL 250 mg and EXE + EVE were dominated. The overall survival (OS) highly influenced the ICER. With a willingness-to-pay (WTP) threshold of 5 million JPY/QALY, the probability of TOR being cost-effective was the highest. Subgroup analysis in non-visceral metastasis revealed 0.4 and 10% reduction in ICER from the base-case results of FUL5 500 mg versus EXE and TOR versus EXE, respectively, while threshold analysis indicated EVE and FUL prices should be reduced 73 and 30%, respectively.. As a second-line therapy for postmenopausal women with HR +/HER2 - mBC, TOR may be cost-effective relative to other alternatives and seems to be the most favorable choice, based on a WTP threshold of 5 million JPY/QALY. FUL 250 mg is expected to be as costly and effective as EXE. The cost-effectiveness of EXE + EVE and FUL 500 mg could be improved by a large price reduction. However, the results are highly sensitive to the hazard ratio of OS. Policy makers should carefully interpret and utilize these findings.

Topics: Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cost-Benefit Analysis; Everolimus; Female; Fulvestrant; Health Care Costs; Humans; Japan; Markov Chains; Middle Aged; Models, Economic; Postmenopause; Quality-Adjusted Life Years; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Toremifene

Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. A total of 230 breast cancer patients who received adjuvant TAM (n = 115) or TOR (n = 115) at the National Cancer Center were analyzed. The CYP2D6 *10 genotype was not significantly associated with DFS in patients who received TOR (p = 0.737). Patients treated with TOR had a higher 5-year disease-free survival (DFS) rate than those treated with TAM (89.6% vs. 80.9%, p = 0.009). TOR treatment remained an independent prognostic marker of DFS in multivariate analysis compared with TAM (hazard ratio = 0.51; p = 0.014). For all of the 50 CYP2D6 *10 T/T genotype patients, TOR treatment group had a significantly higher 5-year DFS rate than TAM group (90.9% vs. 67.9%, p = 0.031). For the remaining 170 CYP2D6 *10 C/C or C/T genotype patients, there was no significant difference between the 5-year DFS rates of the TOR and TAM groups (89.2% vs. 85.1%, p = 0.188). The advantage of adjuvant TOR over TAM in Chinese breast cancer patients might be caused by the significant benefit obtained by the CYP2D6 *10 T/T patients, who accounted for one-fifth of the overall population. TOR might be a good option for adjuvant endocrine therapy in this subgroup of patients in China.

Topics: Breast Neoplasms; Chemotherapy, Adjuvant; Cytochrome P-450 CYP2D6; Disease-Free Survival; Female; Genotype; Humans; Middle Aged; Retrospective Studies; Tamoxifen; Toremifene

The criteria for biological postmenopause have not been clearly defined, although determining the menopausal status is crucial for selecting agents for adjuvant endocrine therapy for patients with breast cancer. The long-term effects of adjuvant toremifene(TOR)and anastrozole(ANA)on serum follicle-stimulating hormone(FSH)and estradiol(E2)levels in Japanese women were examined using data from a prospective randomized study that mainly studied serum lipids and bone metabolism for 2 years. The study medications were administered orally daily at 40 mg and 1 mg for TOR and ANA, respectively. Sixty-nine patients were randomly assigned to the TOR group(n=36)or ANA group(n=33). FSH and E2 levels were measured using chemiluminescent immunoassay. The mean ages of the patients in the TOR and ANA groups were 62.5 and 60.0 years, respectively. None of the patients experienced menstruation during the course of the study. The baseline serum FSH level in the TOR group(69.6mIU/mL)decreased to 59.2%, 54.6%, and 50.0% at 6, 12, and 24 months, respectively, after therapy commencement. The FSH levels ranged from 8.6 to 68.1mIU/mL and were<20mIU/mL in 2 patients(9.5%; 8.6 and 14.4mIU/mL). The serum FSH levels in the ANA group did not change markedly over 24months. The baseline serum E2 level in the ANA group(11.6 pg/mL)decreased to 72.4%, 70.7%, and 61.2%at 6, 12, and 24months, respectively, after therapy commencement. The serum E2 level in the TOR group did not change markedly over 24 months. When switching to other endocrine agents as adjuvant therapy for patients with breast cancer treated with TOR, the serum FSH level decreased to half of the preinitiation level, and one-tenth of the FSH levels was<20mIU/mL, while the postmenopausal serum E2 level was maintained.

Topics: Anastrozole; Aromatase Inhibitors; Breast Neoplasms; Estradiol; Female; Follicle Stimulating Hormone; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Toremifene

The aim of this study was to identify the effect of selective estrogen receptor modulator (SERM) on non-alcoholic fatty liver disease (NAFLD) in Asian women.. We retrospectively evaluated fatty liver development and/or serum alanine aminotransferase (ALT) elevation during SERM treatment in 1061 women who were diagnosed and treated with breast cancer in 2005 at Asan Medical Center.. 45 of 618 SERM-treated patients with normal ALT at baseline experienced ALT elevation during SERM treatment. Among the 112 SERM-treated patients who underwent liver imaging test, fatty liver was observed in 47 and both fatty liver and ALT elevation developed in 16 of 102 SERM-treated patients with normal baseline ALT. The cumulative rates of ALT elevation (10.7 vs. 4.3%; P = 0.002), fatty liver (48.5 vs. 20.9%; P < 0.001), and both fatty liver and ALT elevation (17.7 vs. 7.1%; P = 0.02) at 60 months were significantly higher in the SERM group than non-SERM group. By multivariate analysis, SERM treatment increased the risk of ALT elevation (hazard ratio [HR], 2.20; P = 0.01), fatty liver development (HR, 3.59; P < 0.001), and both fatty liver and ALT elevation (HR, 4.98; P = 0.01). After discontinuation of SERM, elevated serum ALT normalized in 39 (92.9%) and there were no instances of liver-related death or progression to liver cirrhosis in patients who experienced fatty liver or ALT elevation.. Although SERM treatment is significantly associated with NAFLD in Asian women, considering the tolerability and reversibility of NAFLD induced by SERM, it can be continued with liver function monitoring in relevant patients.

Topics: Adult; Aged; Alanine Transaminase; Antineoplastic Agents, Hormonal; Asian People; Breast Neoplasms; Fatty Liver; Female; Humans; Middle Aged; Republic of Korea; Retrospective Studies; Risk Factors; Tamoxifen; Toremifene; Withholding Treatment

Selective estrogen receptor modulator (SERM)-associated nonalcoholic fatty liver disease (NAFLD) might be related to treatment efficacy in patients with breast cancer because of circulating estrogen antagonism. The aim of the study was to investigate the relationship between NAFLD and survival outcomes in patients with breast cancer who were treated with tamoxifen or toremifene. This single-center, retrospective, cohort study included 785 eligible patients who received tamoxifen or toremifene, after curative resection for breast cancer, at the Sun Yat-sen University Cancer Center between January 2005 and December 2009. Data were extracted from patient medical records. All patients underwent abdominal ultrasonography, at least once, at baseline and at the annual follow-up. Patients who were diagnosed with NAFLD on ultrasonography were classified into the NAFLD or the non-NAFLD arm at the 3-year follow-up visit. Univariate and multivariate Cox regression analyses were conducted to evaluate any associations between NAFLD and disease-free survival (DFS) or overall survival (OS). One hundred fifty-eight patients were diagnosed with NAFLD. Patients who developed NAFLD had better DFS and OS compared with those who did not. Univariate analyses revealed that the 5-year DFS rates were 91.56% and 85.01% for the NAFLD and non-NAFLD arms, respectively (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.37-0.96; log-rank P = 0.032). The 5-year OS rates were 96.64% and 93.31% for the NAFLD and non-NAFLD arms, respectively (HR, 0.39; 95% CI, 0.16-0.99; log-rank P = 0.039). Multivariate analysis revealed that NAFLD was an independent prognostic factor for DFS, improving the DFS rate by 41% compared with that in the non-NAFLD arm (HR, 0.59; 95% CI, 0.36-0.96; P = 0.033). SERM-associated NAFLD was independently associated with improved DFS and might be useful for predicting treatment responses in breast cancer patients treated with SERMs.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Female; Humans; Middle Aged; Non-alcoholic Fatty Liver Disease; Prognosis; Regression Analysis; Retrospective Studies; Selective Estrogen Receptor Modulators; Survival Analysis; Tamoxifen; Toremifene; Ultrasonography

A 67-year-old woman underwent total mastectomy, postoperative radiation therapy, and adjuvant hormonal therapy more than 9 years 4 months previously. There were no symptoms of recurrence for 3.5 years after completing adjuvant hormonal therapy. A hard mass appeared on the front chest wall and was diagnosed as recurrence of breast cancer histopathologically. A computed tomography (CT) scan revealed multiple metastases in the left side of the chest wall, in the left Level Ⅱ axillary lymph nodes, and in the left lung. The patient was prescribed high-dose tremifene (HD-TOR 120 mg/day). After less than 4 months, she presented with general fatigue and yellow skin, and was admitted with grade 4 hyperbilirubinemia and grade 3 hepatic dysfunction (AST and ALT). CT and magnetic resonance imaging (MRI) showed no abnormal findings in the liver or biliary tract. Drug-induced liver injury (DILI) caused by HD-TOR was suspected and this therapy was discontinued. The liver dysfunction showed a tendency to improve with conservative treatment and the patient was discharged on the 10th day of illness. She had almost recovered after 5.5 months. A liver biopsy, a drug-lymphocyte stimulation test, and other detailed examinations were not performed, but we judged this case to be one of liver failure caused by HD-TOR-induced DILI.

Topics: Aged; Antineoplastic Agents, Hormonal; Biopsy; Breast Neoplasms; Female; Humans; Liver Failure; Lung Neoplasms; Lymphatic Metastasis; Toremifene

This study clarifies the relationship between clinical and laboratory patterns, in endocrine-responsive metastatic breast cancer patients treated with a cyclic beta-interferon and interleukin-2 sequence added to anti-estrogens. In 31 patients, a regular laboratory and immunological assessment was made. During clinical benefit, as opposed to progression, a significant increase in the total number of lymphocytes, CD4+, CD8+, NK cells, CRP and IL-12 was confirmed. Also, a significant CEA, TPA, CA15.3 decrease occurred 24-72h after interleukin-2 administration. At the progression, both basally and after interleukin-2 stimulation, the mean values of CD4+ plus CD25+ cells were more than twice higher than during clinical benefit, with a decrease of CD4+ plus CD8+ (Teffector)/CD4+CD25+ (Treg) ratio. Moreover, a significant increase for CEA and for all 3 markers (standardized values) was found 24-72h after interleukin-2 administration. In patients who survived less than 5years, the Treg cell increase occurred at a significantly shorter time interval than in those who survived longer than 5years (20 vs 45.5months, respectively; P=0.001). These data show laboratory evidence of the effect of immunotherapy as well as that of hormone resistance occuring concomitantly with a laboratory pattern compatible with immune inhibition.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoembryonic Antigen; Cytokines; Disease Progression; Disease-Free Survival; Female; Humans; Immunity, Cellular; Immunotherapy; Interferon-beta; Interleukin-2; Letrozole; Middle Aged; Mucin-1; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Nitriles; Proportional Hazards Models; Selective Estrogen Receptor Modulators; T-Lymphocytes; Tamoxifen; Tissue Polypeptide Antigen; Toremifene; Triazoles

Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.. A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.. The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.. This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Topics: Androstadienes; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Biomarkers, Tumor; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Enzyme Activators; ErbB Receptors; Erlotinib Hydrochloride; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Variation; Humans; Indazoles; Letrozole; MCF-7 Cells; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-vav; Quinazolines; RNA Interference; RNA, Small Interfering; Tamoxifen; Toremifene; Triazoles

Aromatase inhibitors(AI)have established efficacy as first-line therapy in postmenopausal patients with hormone-sensitive metastatic breast cancer(MBC). However,the use of endocrine therapy has not yet been established for second-line and later therapy. Our study examined the efficacy of high-dose toremifene therapy(HD-TOR)in patients with MBC resistant to AIs.. A retrospective analysis was carried out to determine outcomes in 85 postmenopausal patients with MBC resistant to AIs who began HD-TOR between May 2001 and October 2011. The patients received toremifene 120 mg once daily on consecutive days.. The objective response rate(ORR)was 21.2%,the clinical benefit rate(CBR)was 41.2%,and the median time to treatment failure(TTF)was 7.3 months. The CBR was high in patients with ER-positive status(p=0.045),no visceral metastasis(p=0.037),HD -TOR as first- or second-line therapy(p=0.007),no history of tamoxifen(TAM)therapy(p=0.019),and no history of chemotherapy(p=0.017). Multivariate analysis showed that ER-positive status(p=0.005, odds ratio: 0.064)and no visceral metastasis(p=0.034, odds ratio: 0.323)were independent predictors of efficacy. The TTF was significantly longer in patients with ER-positive status(p=0.019)and no history of TAM therapy(p=0.015). Multivariate analysis showed that ER-positive status(p=0.025, hazard ratio: 0.377)and no history of TAM therapy(p=0.002, hazard ratio: 0.422)were independent predictors of efficacy. No patient discontinued HDTOR therapy due to adverse events.. HD-TOR is an effective endocrine therapy for patients with MBC who have failed AIs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Postmenopause; Retrospective Studies; Toremifene

We evaluated the clinical significance of indoleamine 2,3-dioxygenase(IDO)activity during toremifene(TOR)therapy for aromatase inhibitor(AI) / -resistant metastatic breast cancer. IDO activity can be measured using the tryptophan/kynurenine (Trp/Kyn)ratio. Trp and Kyn were measured using high performance liquid chromatography(HPLC). The response rate of TOR therapy for AI-resistant metastatic breast cancer patients was 21.9%, and the clinical benefit rate was 62.5%. The serum Trp/Kyn ratio was significantly lower in AI-resistant metastatic breast cancer patients with distant metastases than in patients who had local recurrence. During TOR therapy, IDO activity was significantly decreased in the TOR responder group compared to the TOR non-responder group. IDO activity correlated with the number of metastatic lesions treated during TOR therapy. These results suggest that the Trp/Kyn ratio is a useful measurement in evaluating the immunological metastatic status during endocrine therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Middle Aged; Neoplasm Metastasis; Toremifene

Toremifene(TOR)is a selective estrogen receptor modulator(SERM). A high dose of 120 mg TOR(HD-TOR) has been used for recurrent breast cancer in Japan, but there is still insufficient evidence regarding the efficacy of HD-TOR.. HD-TOR was administered for recurrent or metastatic breast cancer between January 2003 and May 2012. The primary end point of the study was the tumor response rate. Bone metastasis cases were excluded from the efficacy analysis, but were included in the safety population.. A total of 21 patients registered in the study and the 2 patients with bone metastasis only were excluded from the efficacy analysis. The median follow-up period was 8. 3 months. None of the patients in the study had a CR, 4 had a PR(21. 1%), 9 had SD(47. 4%), and 6 had PD(31. 6%). Eight of the 9 SD cases had a long-term SD. The ORR was 21. 1% and the CB rate was 63. 2%. The median TTP of CB cases was 18. 3 months. None of the patients discontinued treatment because of a grade 3 or grade 4 adverse effects.. In summary, the current study showed that HD-TOR may lead to a CB for recurrent breast cancer in first- or second-line treatment rather than thirdline. In particular, HD-TOR may give a benefit in highly endocrine-sensitive cases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Toremifene

Low-grade endometrial stromal sarcoma (ESS) is a rare neoplasm that is generally estrogen-receptor- and progesterone-receptor-positive and develops in premenopausal women. Although tamoxifen treatment is associated with an increased risk of ESS, the effect of other selective estrogen receptor modulators, including toremifene, on the risk of ESS is not clear. A 61-year-old postmenopausal woman was treated with toremifene as an adjuvant therapy for breast cancer. A cystic mass developed during the treatment, with gradual growth in the uterine myometrium. The patient was treated with hysterectomy and bilateral salpingo-oophorectomy, and the tumor was diagnosed as low-grade ESS (stage IA) with estrogen-receptor and progesterone-receptor. The patient discontinued toremifene and has been progression-free for 21 months. Our data suggest that toremifene might be associated with the development of ESS in certain patients through its estrogen-like effects in the uterus.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Hysterectomy; Middle Aged; Postmenopause; Sarcoma, Endometrial Stromal; Toremifene

Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy.. Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses.. Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors.. Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinosarcoma; Female; Humans; Japan; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Risk Factors; Survival Analysis; Tamoxifen; Toremifene; Uterine Neoplasms

In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen.. Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups.. Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer.. Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.

Topics: Adult; Antineoplastic Agents, Hormonal; Antineoplastic Protocols; Breast Neoplasms; Cohort Studies; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Premenopause; Receptors, Estrogen; Receptors, Progesterone; Reproducibility of Results; Retrospective Studies; Tamoxifen; Toremifene

Aromatase inhibitors(AIs)are frequently employed for advanced or metastatic postmenopausal breast cancer as first-line hormone therapy. However, it is unknown which hormonal agent is the most appropriate after AI has failed.. Five hormone-responsive postmenopausal women who used AI as a first-line hormone therapy for advanced or metastatic breast cancer, but AI failed, received high-dose toremifene therapy(HD-TOR: 120mg/day)in our hospital. Efficacy and safety were evaluated.. Patients were all-hormone sensitive, and only one case had HER2 overexpression. All patients had received anastrozole(ANA)as first-line hormone therapy. Of a total of 5 cases, 3 were evaluated as partial responses(PR), 1 was a long stable disease(L-SD), and 1 was a progressive disease(PD). The overall response rate (RR)was 60. 0%(3/5 cases)and the clinical benefit rate(CB)was 80. 0%(4/5 cases). Grade 1 dry mouth was observed in one case as an adverse event.. HD-TOR as a second-line therapy is optimal for advanced or metastatic AI resistance postmenopausal breast cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Toremifene; Treatment Outcome

The relation between the use of tamoxifen and gynecologic tumors has been documented. In this case, a 58-year-old postmenopausal woman had been treated with tamoxifen for 5 years followed by toremifene for 1.5 years due to the presence of stage II estrogen receptor-positive breast cancer. The patient was found to have a stage Ic granulosa cell tumor of the ovary despite undergoing annual gynecologic examinations. This report presents a case of granulosa cell tumor of the ovary after the long-term use of tamoxifen and toremifene.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma, Ductal, Breast; Female; Granulosa Cell Tumor; Humans; Middle Aged; Neoplasms, Second Primary; Ovarian Neoplasms; Tamoxifen; Toremifene

Recently, many patients have been treated with aromatase inhibitors(AI), either in an adjuvant setting or as a treatment for recurrence. The efficacy and safety of high-dose toremifene(HD-TOR)were evaluated in 18 patients with advanced/recurrent breast cancer. Twelve of the 18 patients had received AI just prior to the study treatment. The clinical benefit rate was 56%(PR: 28%, long SD: 28%). Progression-free median survival was 5. 5 months. Adverse events were mild and toremifene was well-tolerated. The results suggest that HD-TOR should be considered early on as a second-line treatment, or as a later treatment option for AI-resistant breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Recurrence; Salvage Therapy; Toremifene

We present a case in which a 46-year-old woman underwent mastectomy (Bt+AX) for right breast cancer (T4bN0M0, Stage IIIB) at the age of 42. A histopathological examination confirmed her cancer to be an invasive ductal carcinoma n (-),ER (+), PgR (+),HER 2 (1+). For postoperative medication therapy, she was taking goserelin plus tamoxifen for 2 years and tamoxifen thereafter. A right adrenal tumor was discovered during a follow-up CT scan and MRI after the operation. There was no indication of metastasis in any other location. A laparoscopic right adrenalectomy was performed to establish a definitive diagnosis and to cure the cancer. According to the histopathological examination, the tumor was ER (+), PgR (+), and HER2 (0) and metastasized from the breast. After this operation, the regimen was changed to high- dose toremifene as endocrine therapy. No recurrence of the cancer has been reported 2 years and 4 months after the operation. In most cases, metastasis to the adrenal gland is due to systemic metastasis as seen in the last stage of breast cancer, and a solitary adrenal gland metastasis from breast cancer is extremely rare. The combination of surgical removal and medication for solitary distant metastasis from breast cancer may be effective in improving the long-term survival rate.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Recurrence; Toremifene

Cytotoxic and apoptotic effects of toremifene-diethylenetriamine pentaacetic acid (TOR-DTPA), formed by conjugation of TOR and DTPA, on the MCF-7 cell line were evaluated. TOR-DTPA was synthesized and qualified via gas chromatography-mass spectrometry system, thin layer chromatography, and high performance liquid chromatography methods. To screen the biological properties of TOR-DTPA at determined concentrations, our ongoing effort was to evaluate apoptotic and cytotoxic effects on the MCF-7 cell line. Trypan blue dye exclusion test, XTT, ELISA, and TUNEL assays were utilized to evaluate cytotoxicity and apoptosis. TOR-DTPA has no cytotoxic and limited apoptotic effect on the MCF-7 cell line according to the results of in vitro studies. It is concluded that the lack of obvious apoptotic and cytotoxic effects allows the already proposed ligand, TOR-DTPA, to be improved as a novel hydrophilic ligand for breast imaging.

Topics: Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; Female; Gas Chromatography-Mass Spectrometry; Humans; Ligands; Pentetic Acid; Selective Estrogen Receptor Modulators; Toremifene

A 78-year-old woman diagnosed with left breast cancer (T2N1M0, Stage II B) was given breast-conserving therapy with axillary dissection. Pathological findings of the tumor were: 2.5 cm in size, invasive ductal carcinoma, nuclear grade 3, positive lymphatic invasion and pN1a. ER and PgR were both positive, and HER2 was negative. Administration of anastrozole (1 mg/day) and UFT (300 mg/day) was performed as adjuvant therapy for 8 months. However, several subcutaneous nodules appeared in the left breast and left axilla, after 11 months. Cytology and histology of nodules indicated metastatic invasive ductal carcinoma. We began high-dose toremifene therapy (120 mg/day) (HD-TOR) for treatment of recurrence and complete remission (CR), and was obtained after 8 months in all recurrent lesions. In this study, we demonstrated a case of aromatase inhibitor-tolerant metastatic breast cancer revealing CR following high-dose toremifene therapy.

Topics: Aged; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Biopsy, Fine-Needle; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Lymphatic Metastasis; Remission Induction; Toremifene

Aromatase inhibitors (AI) have largely replaced tamoxifen as the first-line of treatment for postmenopausal women with advanced or metastatic hormone-receptor-positive breast cancer. However, there is no established strategy for treating AI refractory cases. In this study, we investigated the efficacy of high-dose Toremifene therapy (HD-TOR). From January 2001 through April 2010, nineteen patients received 120 mg of TOR daily. The overall response rate was 36.8% (CR; 1, PR; 6), and the clinical benefit was 47.4%. The clinical benefit rate to each of the metastatic organs were: lung, 42.9%; bone, 13%; liver, 25%; and lymph node, 40%. A higher clinical benefit rate was observed in lung or lymph node metastases. The clinical benefit rate of HD-TOR as first to third-line therapy was 50%, which was more effective than that of fourth-line therapy. Our data suggests that HD-TOR may be one of the effective treatment strategies for patients with AI refractory advanced or metastatic hormone receptor-positive breast cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Recurrence; Retrospective Studies; Toremifene

A 91-year-old woman was diagnosed as having ER-positive breast cancer, and was treated with primary endocrine therapy because she refused to undergo surgery under general anesthesia. The patient was treated with letrozole as the initial endocrine therapy, but was judged to have progressive disease after 11 months. During letrozole treatment, the patient could not achieve an effect greater than stable disease. Thereafter, she received toremifene treatment (40 mg/day). After three months of this treatment, the patient achieved a partial response. The response was maintained for 12 months, and the patient then underwent lumpectomy under local anesthesia. In conclusion, toremifene could be an effective preoperative primary endocrine regimen for elderly breast cancer patients.

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Biopsy; Breast Neoplasms; Female; Humans; Letrozole; Neoadjuvant Therapy; Nitriles; Salvage Therapy; Toremifene; Triazoles

To explore the regulation mechanism of the reversal of breast cancer resistance protein-mediated multidrug resistance by toremifene.. Two recombinant plasmids (pcDNA3-promoter-BCRP and pcDNA3-CMV-BCRP) were designed to express the wild-type full-length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a CMV promoter as control, respectively. Two recombinant plasmids were transfected into ERα-positive MCF-7 and ERα-negative MDA-MB-231 breast cancer cell lines. Four kinds of BCRP expressing cell lines of MCF-7/Promoter-BCRP, MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP were established in which BCRP was promoted by the BCRP promoter and a CMV promoter as control, respectively. The drug resistant cells were treated with toremifene. Then RT-PCR, Western blot, mitoxantrone efflux assays and cytotoxicity assay were performed to detect the reversal function of BCRP by toremifene on the drug resistance cell lines.. Toremifene significantly downregulated BCRP mRNA levels in a dose-dependent manner in ERα-positive MCF-7/Promoter-BCRP cells than that of untreated control cells. In MCF-7/Promoter-BCRP cells, toremifene at the dose of 0.1, 1 and 10 µmol/L decreased BCRP mRNA expression by 29.5% (P < 0.05), 68.1% (P < 0.01) and 97.4% (P < 0.01), respectively. After being treated with toremifene and 17β-estradiol, the BCRP mRNA level in MCF-7/Promoter-BCRP cells was 64.2% ± 1.3%, significantly higher than that of toremifene treatment control cells (3.8% ± 0.2%,P < 0.01). Furthermore, the effect of toremifene on BCRP protein is similar in BCRP mRNA. Toremifene obviously increased the mitoxantrone fluorescence intensity and decreased the efflux activity by 47.3% (P < 0.05) in MCF-7/promoter-BCRP cells when compared with the untreated control, whereas intracellular accumulation of mitoxantrone obviously decreased and the efflux activity increased by 61.5% were observed in combination with 17β-estradiol when compared with toremifene treatment alone. The results therefore suggested that toremifene reversed mitoxantrone resistance in MCF-7/Promoter-BCRP cells. However, in MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP cells, toremifene or in combination with 17β-estradiol did not affect intracellular mitoxantrone uptake.. Taken together, our findings indicate that expression of BCRP is downregulated by toremifene, via a novel transcriptional mechanism which might be involved in the ERE of BCRP promoter through ER-mediated to inactivate the transcription of BCRP gene.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Cytomegalovirus; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Mitoxantrone; Neoplasm Proteins; Plasmids; Promoter Regions, Genetic; Recombinant Proteins; Response Elements; RNA, Messenger; Toremifene

Aromatase inhibitors (AIs) have been employed as adjuvant therapy or as treatment for recurrent cases. However, when AI treatment fails, it is unclear which endocrine therapy is the most appropriate to introduce at this point and how effective it will be. In this study, we investigated the efficacy and safety of toremifene (TOR, Fareston(®)), a selective estrogen receptor modulator (SERM).. Patients with recurrent or advanced breast cancer who had measurable or evaluable lesions, and were diagnosed as having progressive disease during AI treatment and subsequently given TOR at 120 mg/day (TOR120) as endocrine therapy were selected and analyzed retrospectively in relation to their medical history.. Of a total of 83 cases examined, 80 were evaluable. The objective response rate (ORR) was 15.0% (12/80), the clinical benefit (CB) rate was 45.0% (36/80), and median time to failure (TTF) was 7.8 months. TOR120 was also effective in the progressive disease cases relapsed on AI treatment. When TOR120 was used, as a first-, second- or third-line treatment, the CB rate was 57% (32/56); this fell to 17% (4/24) when TOR120 was used as a fourth-line or later treatment. There was no response in the five estrogen receptor (ER)-negative cases, compared with an ORR of 15% (10/67) in ER-positive cases. In cases with a human epidermal growth factor receptor 2 (HER2) score of 0, 1+, and 2+, the ORR was 11% (7/61), while there was no response in the five cases with scores of 3+. TOR120 was effective in cases previously treated with tamoxifen (TAM), with an ORR and CB rate of 12 and 29%, respectively. The last AI used was anastrozole in 30 cases and examestane in 46; the response rates to TOR120 were similar in both groups. With regard to adverse effects, hot flushes and/or night sweating was observed in 10 and 12 cases, respectively, but all of them were categorized as grade 1, and the treatment was rated excellent in acceptability.. TOR120 was rated excellent in acceptability, and high efficacy was observed when it was used up to third-line treatment for AI-failure cases, although this study may show some selection bias because of the retrospective study. In addition, it was also considered effective for TAM-failure cases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Disease Progression; Drug Resistance; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Postmenopause; Retrospective Studies; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Treatment Outcome

Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette half transporter, confers multidrug resistance (MDR) to a series of antitumor agents such as mitoxantrone, daunorubicin, SN-38, and topotecan, and often limits the efficacy of chemotherapy. Recent studies have indicated that a putative estrogen response element (ERE) is located in the promoter region of the BCRP gene. However, whether and how BCRP is regulated transcriptionally by toremifene (TOR) remains unknown. In the present study, two plasmid vectors have been designed to express the wild-type full-length BCRP cDNA enforced driven by its endogenous promoter containing a functional ERE and a constitutive cytomegalovirus (CMV) promoter as control, respectively, which were transfected into estrogen-responsive MCF-7 and estrogen-independent MDA-MB-231 human breast adenocarcinoma cell lines. We showed that toremifene alone significantly downregulated BCRP mRNA and protein levels in estrogen receptor α (ERα)-positive MCF-7 cells in a dose-dependent manner, and the inhibitory effect was partially reversed by estrone (E(1)). Furthermore, gel shift assays demonstrated that specific binding of ERα to the ERE in the BCRP promoter is essential for transcriptional inhibition of BCRP by toremifene. Interestingly, toremifene alone increased the cellular accumulation of mitoxantrone in BCRP-transfected cells, suggesting that TOR indeed inhibits BCRP-mediated drug efflux and overcome drug resistance. To the best of our knowledge, this is the first report describing a direct effect of toremifene on BCRP. Our results thus indicate that toremifene by itself downregulates BCRP expression to reverse BCRP-mediated atypical multidrug resistance via a novel transcriptionally mechanism, which might be involved in TOR-ER complexes binding to the ERE of BCRP promoter to repress transcription of BCRP gene.

Topics: Adenocarcinoma; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Electrophoretic Mobility Shift Assay; Estrogen Receptor alpha; Estrone; Female; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Mitoxantrone; Neoplasm Proteins; Promoter Regions, Genetic; RNA, Messenger; Selective Estrogen Receptor Modulators; Toremifene; Transcription, Genetic; Transfection

Estrogen is involved in the development of breast and endometrial cancers, and tamoxifen, an antiestrogen, is associated with an increased risk of endometrial cancer. Recently, tamoxifen use is suggested to be associated with the development of aggressive endometrial tumors. We performed a retrospective study to clarify the effects of tamoxifen (TAM) and toremifene (TOR) on clinicopathological features of endometrial cancer subsequently developed in breast cancer patients.. Endometrial cancer patients diagnosed at our institution from 2000 through 2008 were studied.. Of 194 patients with endometrial cancer, 18 (9.3%) developed breast cancer before endometrial cancer diagnosis. Mean age was 66 years, and the median time interval between breast and endometrial cancer diagnosis was 10 years (range, 1.5 -32 years). Nine patients developed aggressive tumors(serous, clear cell, small cell carcinoma, and carcinosarcoma), and the remaining nine developed endometrioid tumor. Patients with aggressive tumor had a lower 5-year disease-specific survival (0% vs 88%, p<0.01). Ten patients had used TAM and/or TOR, and six had not; aggressive tumors developed in six of 10 TAM/TOR users, and in one of six nonusers (p=0.15), and the 3-year disease-specific survival rate was not different between TAM/TOR users and nonusers (62% vs 53%, p=0.84). Time intervals from breast cancer and endometrial cancer diagnosis were 10-16 years for TAM users and 5-6 years for TOR users (p=0.02).. Tamoxifen/toremifene use for breast cancer did not affect the prognosis of subsequent endometrial cancer in our small study; however, further studies were warranted. The use of toremifene may be associated with a shorter interval from breast cancer to endometrial cancer diagnosis compared to tamoxifen.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Tamoxifen; Toremifene

We have performed pelvic magnetic resonance imaging (MRI) in patients undergoing breast cancer surgery before and after adjuvant drug therapy. Our purpose was to detect any radiographic uterine changes induced by various types of adjuvant therapy on pre- and postmenopausal patients by evaluating prospectively performed MRI.. Between September 2004 and December 2007, a total of 41 women with breast cancer (11 premenopausal, 30 postmenopausal) were enrolled. All underwent MRI of the pelvis before and after drug therapy, and uterine changes were evaluated. Postoperative drugs used were selective estrogen receptor modulators (SERMs) including tamoxifen and toremifene (n = 18), aromatase inhibitors (n = 13), and anticancer drugs (n = 10).. Only the postmenopausal patients receiving SERMs showed a significant increase in endometrial thickness: from 2.4 +/- 0.4 mm before therapy to 4.5 +/- 2.6 mm after therapy (P = 0.0485). No statistically significant endometrial change was evident in postmenopausal patients treated with aromatase inhibitors (P = 0.573) or anticancer drugs (P = 0.754). Also, in premenopausal patients treated with SERMs or anticancer drugs, the change in endometrial thickness was not statistically significant (P = 0.958, 0.370).. This prospective study using MRI has demonstrated that uterine changes associated with adjuvant drugs for breast cancer occur exclusively in postmenopausal patients receiving SERMs.

Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Analysis of Variance; Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Endometrium; Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Middle Aged; Postmenopause; Prospective Studies; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene; Uterus

Multidrug resistance proteins such as P-glycoprotein (P-gp) are potential targets for improving the efficacy of paclitaxel (PTX), a mitotic inhibitor used in cancer chemotherapy. The selective estrogen receptor modulator toremifene (TOR) moderate P-gp was related to a drug resistance in vitro. A comparison of PTX alone with PTX+TOR in hormone-receptor-positive metastatic breast cancer patients (MBC) was conducted to determine the therapeutic value of adding TOR to a PTX regiment. Thirteen MBC patients received 80 mg/m2 PTX weekly (PTX group) and 14 MBC patients received the same weekly dose of PTX plus 120 mg/day TOR daily (PTX+TOR group). All 27 patients were repeatedly treated with a combination of PTX and TOR as long as disease progression or unmanageable severe adverse events were defined. The PTX group was compared with PTX+TOR group with respect to best overall response, response rate, clinical benefit rate, time to progression, adverse events and toxic profile of PTX and TOR. No significant difference in response rate was observed between the PTX group and the PTX+TOR group. However, clinical benefit rate and time to progression improved significantly in the PTX+TOR group in comparison with the PTX group. TOR did not significantly enhance the adverse events of PTX. These results suggested that combined treatment of PTX and TOR for MBC patients improves a patient response over PTX alone.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Paclitaxel; Receptors, Estrogen; Toremifene

Multidrug resistance protein could be a target for improving the efficacy of paclitaxel (PXL). Toremifene (TOR) may moderate P-gp-related drug resistance in vitro. Some P-gp moderators may change the pharmacokinetic parameters of PXL in vivo. A pharmacokinetic (PK) study in metastatic breast cancer patients (MBC) was conducted to determine the safety and efficacy of PXL and TOR.. Fifteen patients received 80 mg/m(2) PXL (i.v.) weekly and 120 mg/body TOR (p.o.) daily. For the pharmacokinetic study, PXL was administered on days 1, 8, 15, 32, and 39; TOR was given from day 18 to the end of study. On days 1, 8, 15, 18, 32, and 39, blood samples were collected from the patients who received either PXL alone or PXL + TOR, and these were analyzed by high-performance liquid chromatography.. Among the 15 patients enrolled in the study, one showed a partial response, and eight had a stable disease. TOR caused no specific adverse events that were greater than grade 3, and its toxicity profile in combination with PXL was similar to that of PXL monotherapy. The PK profile of PXL was similar with or without TOR. The PK parameters of PXL indicated no inter- or intra-patient variability in previously treated patients with MBC. No increased PXL toxicity was observed.. The PK profile of combined PXL and TOR was similar to that of PXL monotherapy. The addition of TOR to PXL in previously treated patients with MBC appears safe.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bone Neoplasms; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Staging; Paclitaxel; Prognosis; Survival Rate; Tissue Distribution; Toremifene; Treatment Outcome

The main purpose of this research was to study an impact of hormonotherapy on changes of the arterial blood pressure in patients with breast cancer. Case histories of 135 patients with the breast cancer and accompanying arterial hypertension (AH) were investigated. According to prescription of hormonotherapy, all patients were divided into two groups. In the first group were included 62 patients; they were treated with 20 mg Tamoxifen. In the second group were included 73 patients; they were treated with 60 mg of Toremifen. In both investigated groups the medicine has been prescribed inside, daily, not less than during two years. Arterial hypertension (AH) was diagnosed when blood pressure was above 140/90 mmHg. In each group there were two subgroups--patients which do not underwent course of treatment for AH and patients which underwent course of treatment for AH. The research revealed that antihypertensive therapy of patients with the breast cancer and accompanying arterial hypertension in most cases allows to prevent progression of AH. Besides, it is necessary to notice that hormonotherapy with Tamoxifen, in comparison with Toremifen, in a greater degree promotes progressing of AH. For antihypertensive treatment Moeksipril was recommended. Monotherapy with Moeksipril showed good antihypertensive effect in patients with mild AH.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Blood Pressure; Breast Neoplasms; Disease Progression; Drug Therapy, Combination; Echocardiography; Electrocardiography; Female; Follow-Up Studies; Humans; Hypertension; Middle Aged; Neoplasm Staging; Practice Guidelines as Topic; Retrospective Studies; Tamoxifen; Toremifene; Treatment Outcome

We have established estrogen-independent and antiestrogen-resistant cell lines from hormone-dependent MCF-7 breast cancer cells by long-term culture in the absence of estrogen, or in the presence of antiestrogen toremifene, respectively. By using a cDNA microarray we compared gene expression profiles among estrogen-independent, antiestrogen-resistant and long-term estrogen-treated MCF-7 cells. We also determined how the expression of the differentially expressed genes has developed during the long-term culture of the cell lines. Of the screened 1176 cancer-related genes, FOSL1, TIMP1, L1CAM, GDF15, and MYBL2 were found to be differentially expressed between the cell lines. A change in FOSL1 and TIMP1 expression could be attributed to the development of antiestrogen resistance, whereas induced L1CAM expression was implicated in the development of estrogen-independent growth of the cells. Estrogen regulated genes GDF15 and L1CAM became regulated by toremifene in the later passage number of toremifene-resistant cells, which might be an indication of the developed estrogen-agonistic activity of toremifene in these cells. Our findings suggest a pattern where the hormone-responsive cancer cells, which survive E2 deprivation and/or antiestrogen treatment, first acquire necessary changes in gene expression for transition to maximal growth in the new hormonal environment. Then, after prolonged treatment with antiestrogen, the antiestrogen-resistant cells may eventually generate an E2-agonistic response to antiestrogen, probably acquiring additional growth advantage.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Estrogen Receptor Modulators; Estrogens; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Toremifene

The patient was a 56-year-old female. At the age of 35 years, she had under gone left mastectomy and axillary lymph node dissection for breast cancer. After surgery, hormonal therapy was continued for 3 years. Then, no treatment was performed. In this study, single therapy with an AI agent was started to treatbilateral supraclavicular fossa/mediastinal lymphnode metastases. After 6 months, a partial response(PR)was achieved. However, progression of the disease(PD)was noted after 1 year. Thereafter,the regimen was switched to single high-dose(120mg/day)TOR therapy. CT revealed the disappearance of the bilateral supraclavicular fossa lymphnodes and a marked reduction of the other lymphnodes. Currently, the patient is being treated, with an interval of 10 months from the start of TOR therapy.

Topics: Anastrozole; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Mastectomy; Middle Aged; Nitriles; Tomography, X-Ray Computed; Toremifene; Triazoles

The efficacy of aromatase inhibitors(AI)has been established for adjuvant and metastatic breast cancer. However, decision making regarding treatment becomes difficult after AI treatment. Recently, high-dose toremifene(HD-TOR, TOR 120 mg daily)showed efficacy in these patients. We attempted to study retrospectively the efficacy and safety of HD-TOR treatment. Seven patients received HD-TOR. The overall response rate was 29%(PR 2)and clinical benefit (CR, PR, long SD)was 57%(PR 2, long SD 7). HD-TOR may be an optional treatment for MBC after AI treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance; Female; Humans; Middle Aged; Retrospective Studies; Toremifene

Toremifene citrate is expected to prevent drug resistance in cancer patients by inhibiting p-glycoprotein activity. The safety and efficacy of combination therapy with high-dose toremifene citrate and paclitaxel were investigated. Between December 2003 and June 2004, 15 women with a mean age of 53 years old with metastatic breast cancer were enrolled. The administration schedule was 80 mg/m2 of paclitaxel given on Days 1, 8, and 15, and 120 mg/day of toremifene citrate orally administered starting on Day 18. On Days 32 and 39, paclitaxel was concurrently administered again. Toxicities, response rate, and time to treatment failure were assessed. All patients had been treated with endocrine or chemotherapy. Grade 3 leukopenia occurred in 2 patients on the administration of paclitaxel alone, and grade 3 febrile neutropenia occurred in 1 patient given the combination therapy. There was no grade 3 or greater non-hematological toxicity. There was no complete response and 1 partial response, producing a response rate of 6.7%. Median time to treatment failure was 2.7 months. Combination therapy of paclitaxel and toremifene was safe and well tolerated with minimal toxicity. Further clinical trials targeting patients with functional p-glycoprotein are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Paclitaxel; Toremifene

Recently, aromatase inhibitors (AI) are widely used in postoperative adjuvant therapy for breast cancer. Nevertheless, studies of postoperative therapeutic strategies for recurrent breast cancer are insufficient.. Data on 12 post-menopausal advanced/recurrent breast cancer patients in our department during June 2003- April 2007 were used for this study. No patient had responded to high-dose toremifene (TOR), a third-generation AI. Their therapeutic outcomes were analyzed retrospectively. The median observation period of the subjects was 16.1 months (4.0-40.9 months). Subjects were all hormone-sensitive. Overexpression of HER2 protein was found in only one case. During AI therapy immediately prior, exemestane (EXE) and anastrozole (ANA) had been given in nine and three cases, respectively.. The complete response rate of AI therapy was 16.7% (2/12). The clinical benefit rate was 58.3% (7/12). The median of time to progression (TTP) was 33.8 weeks. Neither the presence nor absence of past history of treatment with tamoxifen (TAM) or other chemotherapies affected the anti-tumor effect. Analysis by the site of metastasis or recurrence revealed that the therapeutic effects were better for non-life-threatening cases in the lung, pleura, soft tissue, etc. The severities of adverse effects were all less than grade 2; the major ones were flushing and sweating.. Results show that high-dose TOR given at an early stage can provide clinical benefits for post-menopausal advanced/recurrent breast cancer not responding to AI.

Topics: Aged; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Receptor, ErbB-2; Toremifene

A 55-year old woman, who underwent left mastectomy (Bt+Ax), was revealed to have sternum metastasis by postoperative 99mTc bone scanning(T1bN1M1). She received daily aromatase inhibitor (anastrozole), as a primary systemic endocrine therapy, and biweekly pamidronate for metastatic breast cancer. However, she depended on folk medicine a year later, at which time the primary treatment was discontinued. Another year later, the bone metastases developed with increased serum levels of tumor markers (CEA, CA19-9, and NCC-ST-439). Then, she underwent three different regimens of systemic chemo-endocrine therapy over the following three years, including CAF+MPA as the first-line, paclitaxel (PTX) + anastrozole as the second-line, and S-1+anastrozole as the third-line regimen. She recently completed 10 courses of the fourth-line regimen[tri-weekly docetaxel (DOC) and high-dose toremifene (TOR 120 mg/day)], which reduced levels of 99mTc accumulation in the multiple bone metastases and levels of the serum tumor markers to the normal range. No severe adverse events occurred except peripheral thrombovasculitis (grade 2) in her left anterior arm during the fourth regimen. She recently maintains the current status by taking a regular dose (40 mg/day) of toremifene for 5 months. Combination treatment with DOC and high-dose TOR can be one of the worthwhile regimens as systemic chemo-endocrine therapy for patients with advanced breast cancer who develop bone metastases.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Docetaxel; Female; Humans; Middle Aged; Taxoids; Toremifene

A 5 6-year-old woman, who underwent breast-conserving surgery and radiation (60 Gy) therapy in July, 1992, at the age of 40, was diagnosed with pT1aN0M0, pStage I. She was administered tamoxifen (TAM) as adjuvant therapy. However, she underwent microdochectomy for DCIS in her contralateral breast in June, 1998. TAM was given till August, 1999. In June, 2006, at the age of 54, 14 years after initial surgery, CT revealed extensive liver masses which were diagnosed as liver metastasis by liver biopsy. Receptor status was positive for ER and PgR, and negative for HER2. AC was started as a first-line chemotherapy ( 4 courses), but did not prove effective. She refused second-line chemotherapy, so letrozole was selected, and subsequently resulted in PR of the liver metastasis. However, 8 months later, with a liver metastasis relapse, exemestane followed by tamoxifen, medroxyprogesterone acetate, and high-dose toremifene were administered sequentially, resulting in long-time disease control. In conclusion, endocrine therapy might be an effective option even in a visceral crisis, if metastatic tumors have showed slow growth and there is positive hormone receptor status.

Topics: Androstadienes; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Letrozole; Liver Neoplasms; Medroxyprogesterone; Middle Aged; Neoplasm Recurrence, Local; Nitriles; Tamoxifen; Toremifene; Triazoles

This study was aimed at developing a hydrophilic radioligand as an antiestrogen drug derivative to be used for imaging breast tumors. Toremifene [TOR; 4-chloro-1,2-diphenyl-1-(4-(2-(N,N-di-methylamino)ethoxy)phenyl)-1-butene, as citrate salt] was selected as the starting material to be derived, since it has been used extensively as an antiestrogen drug for treatment and prevention of human breast cancer. An antiestrogen drug derivative, TOR attached to diethylenetriamine pentaacetic acid (DTPA), was synthesized by two experimental treatments, including a purification and a reaction step. We described the synthesis of this TOR derivative, (3Z)-4-{4-[2-(dimethylamino) ethoxy] phenyl}-3,4-diphenylbut-3-en-1-ylN,N-bis[2-(2,6-dioxomorpholin-4-yl)ethyl]glycinate (TOR-DTPA), in detail. Mass spectroscopy confirmed the expected structures. TOR-DTPA was labeled with technetium-99m ((99m)Tc), using stannous chloride (SnCl(2)) as the reducing agent. Biodistribution studies were performed on female Albino Wistar rats. Quality controls, radiochemical yield, and stability studies were done utilizing high-performance liquid chromatography, radioelectrophoresis, thin-layer chromatography, and thin-layer radiochromatography methods. The synthesized compound was found to be hydrophilic and anionic, with high stability for the duration of the testing period in vitro. The results indicated that the radiolabeled compound has estrogen-receptor specificity, especially for the breast tissue. It is highly possible that this compound could be used for imaging breast tumors as a novel technetium-labeled hydrophilic estrogen derivative radioligand.

Topics: Animals; Breast Neoplasms; Chromatography, High Pressure Liquid; Estrogen Receptor Modulators; Female; Humans; Models, Molecular; Pentetic Acid; Rats; Rats, Wistar; Selective Estrogen Receptor Modulators; Tablets; Technetium; Tissue Distribution; Toremifene

A comparison of paclitaxel (PTX) alone with PTX+toremifene (TOR) in hormone receptor negative metastatic breast cancer (MBC) patients was conducted to determine the therapeutic value of adding TOR to a PTX regimen. Eight MBC patients received 80 mg/m2 PTX weekly (PTX group) and six MBC patients received the same weekly dose of PTX plus 120 mg/day TOR daily (PTX+TOR group). Patients were repeatedly treated with a combination of PTX and TOR as long as a disease progression or unmanageable severe adverse events were defined. The PTX group was compared with the PTX+TOR group with respect to best overall response, response rate, clinical benefit rate, time to progression, adverse events and toxic profile of PTX and TOR. No significant difference in response rate was observed between the PTX group and the PTX+TOR group. However, a clinical benefit rate and time to progression improved significantly in the PTX+TOR group in comparison with the PTX group. TOR did not significantly enhance the adverse events of PTX. These results suggested that the combined treatment of PTX and TOR for MBC patients improved a patient response over PTX alone.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Synergism; Female; Humans; Middle Aged; Neoplasm Metastasis; Paclitaxel; Toremifene

This study aimed to define a gene expression profile associated with response to anti-estrogen treatment in estrogen receptor alpha (ERalpha)-positive breast cancer from elderly patients and to identify possible candidate genes associated with resistance by detecting those modulated by treatment. Using cDNA microarrays containing 16 702 unique clones, 21 pre-treatment and 11 paired post-treatment samples collected in a neo-adjuvant toremifene trial on elderly patients with operable and locally advanced ERalpha-positive breast cancer were profiled. Gene expression profiles generated from pre-treatment samples were correlated with treatment-induced tumor shrinkage and compared with those obtained from post-treatment paired samples to define genes differentially modulated following anti-estrogen treatment. Correlation analysis on 21 pre-treatment samples highlighted 53 genes significantly related to treatment response (P<0.001). Genes involved in cell cycle and proliferation were more frequently upregulated in responders compared with non-responders. Class comparison analysis identified 101 genes significantly modulated independently of treatment response; 82 genes were modulated in non-responders, whereas only 8 genes were differently expressed after treatment in responders. Gene expression profiles appear to be more frequently modulated by anti-estrogen treatment in non-responding patients and may harbor interesting genes possibly involved in anti-estrogen resistance, including clusterin, MAPK6, and MMP2. This concept was corroborated by in vitro studies showing that silencing of CLU restored toremifene sensitivity in the ER anti-estrogen-resistant breast cancer cell line T47D. Integration between neo-adjuvant therapy and transcriptional profiling has therefore the potential to identify therapeutic targets to be challenged for overcoming treatment resistance.

Topics: Aged; Biopsy; Breast Neoplasms; Chemotherapy, Adjuvant; Clusterin; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Selective Estrogen Receptor Modulators; Toremifene

Topics: Angiofibroma; Angiomyoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Neoplasms, Second Primary; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Toremifene; Vaginal Neoplasms

Antiestrogens represent the first line of therapy in the treatment of estrogen receptor-positive (ER+) breast cancer patients. Unfortunately, up to 40% of patients develop resistance associated with progression and frequently die for metastatic breast cancer. The molecular events leading to pharmacological resistance are not completely understood. We attempted to verify in an experimental model the role of cytoplasmic clusterin (CLU), a cytoprotective protein found to be up-regulated in antiestrogen-resistant patients, following neoadjuvant treatment with toremifene. The role of cytoplasmic clusterin in modulating response to two antiestrogens (toremifene and tamoxifen) was studied in two ER+ anti-estrogen-sensitive cell lines (MCF-7, 734B) and one ER+ antiestrogen-resistant cell line (T47D) using siRNA strategy. Resistant cells were characterised by higher levels of cytoplasmic clusterin than sensitive cells, and antiestrogen treatments up-regulated clusterin levels in both sensitive and resistant cell lines. Treatment with siRNA completely abolished cytoplasmic clusterin expression in all cell lines, but its down-regulation resulted in a significant decrease of cell growth only in the resistant line. We therefore concluded that: i) basal clusterin levels are higher in antiestrogen resistant cells, ii) clusterin is up-regulated following antiestrogen treatment independently of the sensitivity of the cell line, iii) down-regulation of cytoplasmic clusterin restores sensitivity to toremifene in the antiestrogen-resistant cell line. Such results support the concept that targeting CLU could represent a promising therapeutic strategy in association with antiestrogen treatment in breast cancer patients.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Clusterin; Drug Screening Assays, Antitumor; Drug Synergism; Estrogen Receptor Modulators; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Medical Oncology; Models, Biological; Neoplasm Metastasis; Tamoxifen; Toremifene

We evaluated the effects of combined treatment with the antiestrogen agent toremifene (TOR) and local hyperthermia (LHT) on the MCF-7 breast cancer cell line.. BALB/c mice implanted with MCF-7 cells were divided into six treatment groups: a control group, a TOR30 group (given 30 mg/kg/day), a TOR120 group (given 120 mg/kg/day), an LHT group (43.5 degrees C), a TOR30 + LHT group, and a TOR120 + LHT group. The effects of the treatments on tumor cells, estrogen receptor (ER) expression, and cell cycle kinetics were measured after 21 days. We calculated the apoptotic index and vascular density inside the tumors and evaluated the efficacy of the transmigration of TOR into the tumors.. The antitumor effects were significantly greater in both combined therapy groups than in any of the single therapy groups. Estrogen receptor expression was weaker in the combined therapy groups than in the single therapy groups, and there were more G0/G1-phase cells and fewer S-phase cells in both combined therapy groups than in the single therapy groups. The apoptotic index was increased and the tumor vascular density was decreased in the combined therapy groups.. We attributed the effects of this combined therapy to the induction of apoptosis, the decrease in vascular density, and the increase and decrease in G0/G1-phase and S-phase cells, respectively, in the tumors.

Topics: Analysis of Variance; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Breast Neoplasms; Cell Cycle; Combined Modality Therapy; Female; Flow Cytometry; Hyperthermia, Induced; Mice; Mice, Inbred BALB C; Mice, Nude; Toremifene; Tumor Cells, Cultured

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0: Stage IIIC) achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 38-year-old woman with slight anemia who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesteron receptor, and negative for HER2/neu protein expression. She received 6 cycles of tri-weekly FEC (C: 500 mg, E: 60 mg, F: 500 mg/m2) and 16 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The anemia and the bleeding from the tumor disappeared after FEC chemotherapy. The response for breast tumor after paclitaxel and toremifene therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt + Ax: Auchincloss) with skin transplantation was performed. She had no recurrence during one year after the operation. Paclitaxel and Toremifene therapy was effective for advanced breast tumor, and can improve a patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Magnetic Resonance Imaging; Neoplasm Staging; Paclitaxel; Tomography, X-Ray Computed; Toremifene; Ultrasonography

We report a case of recurrence of skin and lymph nodes from asynchronous breast cancer achieving a significant improvement of QOL by toremifene and paclitaxel therapy. The patient was a 49-year-old woman who received both sides of muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) had a skin redness of her left breast. Aspiration biopsy cytology for the skin led to a diagnosis of Class V. Skin biopsy for the part of the redness was performed. The pathological diagnosis was an invasive ductal carcinoma, negative for estrogen receptor and positive for progesteron receptor, and negative for HER2/neu protein expression. Ultrasonography showed the subpectral and the inflaclavicular lymph nodes swelling and the skin metastasis. Enhancement CT showed no metastasis of brain, lung, liver, and other organs. Although she had already received 6 cycles of tri-weekly FEC (C: 500 mg, E 60 mg, F: 500 mg/m2) after previous operation, we performed 7 cycles of weekly paclitaxel (80 mg/m2) with toremifene (120 mg/day). The response for the lesion of lymph nodes metastasis after paclitaxel and toremifene therapy was evaluated as a complete response. The subpectoral and the inflaclavicular lymph nodes metastasis disappeared. However, the skin redness of her left breast was still remained. She had received a radiation therapy (30 Gy) for skin metastasis. After radiation therapy, we performed a skin biopsy for the part of the redness. The pathological diagnosis was no carcinoma of skin. She had no recurrence during the two years after the treatment. Paclitaxel and toremifene therapy was effective for a recurrent breast tumor and could improve patient's QOL and the clinical outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lymphatic Metastasis; Mastectomy, Radical; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Skin Neoplasms; Toremifene; Ultrasonography

Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.8+/-1.3 microM, 1+/-0.3 microM and 60.4+/-17.2 microM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000 microg/day), atamestane (1000 microg/day), tamoxifen (100 microg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.

Topics: Androstenedione; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aromatase; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Mice; Mice, SCID; Prognosis; Toremifene; Transfection; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The use of radiation therapy (RT) after breast-conserving surgery (BCS) is inconsistent in patients treated with hormonal therapy (HT). We sought to identify factors influencing the decision to use RT in this setting.. Patients in the North American Fareston vs. Tamoxifen Adjuvant (NAFTA) trial who had BCS were evaluated for factors influencing the use of RT using univariate and multivariate analyses.. Of the 1,811 patients enrolled in the NAFTA trial, 1,222 (67.4%) had BCS. Of these, 241 (19.7%) did not have RT. There were no significant differences in tumor grade, lymphovascular invasion, estrogen receptor status, or nodal status between those who received RT and those who did not. On univariate analyses, patients who did not receive RT were more likely to be older (median 72 versus 66 years, P < .001), have larger tumors (median 1.35 versus 1.10 cm, P = .009), and be progesterone negative (18.3% versus 13.1%, P = .048). Surgeons in the West were most likely to omit RT, whereas those in the Midwest were least likely to omit it (26.7% versus 7.2%, P < .001). Surgical oncologists were more likely to omit RT after BCS than general surgeons (21.8% versus 13.7%, P < .001). Academic affiliation (P < .001), number of breast procedures performed per year (P = .017), and the percentage of breast practice (P = .019) also correlated with whether or not RT was used. On multivariate analysis, patient age (P < .001), geographic region (P = .006), and surgeon specialty (P = .027) remained significant.. Patient age, geographic region, and surgeon training influence the decision to use RT after BCS in patients receiving HT.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Mastectomy, Segmental; Middle Aged; Professional Practice Location; Radiotherapy, Adjuvant; Receptors, Estrogen; Specialties, Surgical; Tamoxifen; Toremifene

We have reported important benefits and survival with an immunotherapy schedule in patients with endocrine-dependent breast cancer and distant metastases. Here clinical outcome is updated and its correlation with new immunological data is shown. In 32 evaluated breast cancer patients with endocrine-dependent distant metastases treated with a new immunotherapy schedule (cyclic administration of beta-interferon and interleukin-2), cellular immunity, cytokines and CRP were related to the clinical course. Estimated and true 5-10 year overall survival rates from first line antiestrogen and distant metastases were higher than previously reported in a similar population. Interleukin-2 administration was followed by a significant increase in total lymphocytes, CD4+, CD8+, CD16+56+ (NK) cells, IL-6, IL-12, and CRP (from P<0.04 to P<0.000) but no change in IL-10 and TGFbeta1 during clinical benefit. During progressive disease no change was observed in the former parameters, concomitant with a significant increase in IL-10 (P=0.020) and a significant decrease in TGFbeta1 (P=0.023). These findings confirm that cellular immunity is significantly stimulated by IL-2 only during clinical benefit. Furthermore, these results demonstrate that different changes of proinflammatory cytokines, CRP and inhibiting factors are consistent with associated clinical benefit or with disease progression, respectively.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; C-Reactive Protein; Cytokines; Disease Progression; Female; Humans; Immunity, Cellular; Interferon-beta; Interleukin-2; Middle Aged; Neoplasm Metastasis; Neoplasms, Hormone-Dependent; Survival Analysis; Tamoxifen; Toremifene

The patient was a 76-year-old woman, who found a mass in her left breast around summer of 2003 but ignored it. She visited our hospital in April 2004 because of dyspnea and low-back pain. As there was a mass accompanied by partial ulceration all over the left precordium and bilateral pleural effusion, she was admitted for further evaluation and treatment. The patient was judged to be almost in a life-threatening condition, and thus thoracentesis was performed to remove pleural fluid, and chemotherapy with FEC was also performed. In addition, the patient was placed on oral exemestane (EXE). After four courses of therapy with FEC were completed, the drug was changed to paclitaxel (PTX) and chemotherapy was continued for another 3 months. It was confirmed that the tumor size had been reduced markedly and that the volume of pleural effusion had not increased. The patient was in a state of remission for a short time, but subsequently the tumor size increased again and the tumor bled continually in small amounts. The chemotherapeutic drug was changed to capecitabine, while EXE, which had been continued, was withdrawn and oral administration of 120 mg/day of toremifene (TOR) was started. However, the tumor size was not reduced. TOR was continued, while capecitabine was changed to docetaxel (DOC). Then, the tumor size was reduced again, until the breast became almost flat after 3 months and the patient no longer bled from the tumor. The volume of pleural effusion did not increase, nor did the patient have any more dyspnea. At present, she has been in a state of remission and is living at home with a certain QOL.

Topics: Aged; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Cyclophosphamide; Docetaxel; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Humans; Paclitaxel; Pleural Effusion, Malignant; Pleural Neoplasms; Quality of Life; Remission Induction; Taxoids; Toremifene

The patient was a 36-year-old woman, who found a mass in her right breast around April 2002, visited a physician in June, and was referred to our department because of suspected right breast cancer. It was confirmed that the cancer had metastasized to the right axillary lymph nodes and the skin of the right breast. After undergoing an operation on July 11 (Bt+Ax), the patient was placed on tamoxifen (TAM). Then, the course was followed while the patient was treated with CEF and 5'-DFUR. In April 2004, she had a recurrence manifesting itself as bone metastasis, partly because of poor compliance with the hospital-visit and dosing schedules. After chemotherapy with paclitaxel, etc., combination therapy with docetaxel (DOC), capecitabine, and high-dose (120 mg/day) toremifene (TOR) was started on October 15, 2004. Subsequently, because the patient firmly resisted hair loss, chemotherapy was continued with a double-drug regimen with capecitabine and high-dose TOR. Treatment was temporarily discontinued because the patient developed hand-foot syndrome, which was probably attributable to capecitabine, but the symptoms improved after administration of vitamin B(6). Thereafter,the patient complied well with the dosing schedule, and no new metastatic focus has been detected by any examination as of October 2005. These findings suggest that the double-drug regimen with capecitabine and high-dose TOR is an effective treatment for patients who can not be treated with anthracyclines or taxanes.

Topics: Adult; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Capecitabine; Combined Modality Therapy; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Lymph Nodes; Lymphatic Metastasis; Mastectomy, Segmental; Neoplasm Recurrence, Local; Quality of Life; Toremifene

A 47-year-old woman was admitted to our hospital for advanced breast cancer with multiple liver metastases and liver dysfunction in January 2004. EC (EPI combined with CPA), weekly PTX, and AI were performed but were not effective for that tumor. Therefore, high-dose TOR was started. Liver dysfunction recovered after administration of TOR, and primary tumor and liver metastases were evaluated as a partial response (PR). The same therapy has been performed for six months with no evidence of deterioration.

Topics: Anastrozole; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Middle Aged; Nitriles; Quality of Life; Remission Induction; Toremifene; Triazoles

High-dose toremifene therapy (120 mg/day) is useful for the recurrence of receptor-positive breast cancer. However, some reports show that combination therapy of high-dose toremifene and chemotherapy exhibits additive effects. Twelve patients were given oral chemotherapy (capecitabine, 5'-DFUR+CPA, S-1) with high-dose toremifene. The overall response rate was 41.7%, in addition to 58.3% with no change beyond three months. Adverse events were restricted to headache, stomatitis and nausea. Average time to progressive (TTP) was 5.8 months. It was shown that high-dose toremifene and oral chemotherapy were useful for breast cancer recurrence without severe side effects.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Quality of Life; Skin Neoplasms; Tegafur; Toremifene

Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients. It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator (SERM). To test these hypotheses, we have established novel MCF-7 cell line-derived in vitro models of anti-estrogen- and progestin-resistant and estrogen-independent breast cancer by long-term culture in the presence of toremifene and medroxyprogesterone acetate (MPA) and in the absence of estradiol, respectively. Using cell growth and multiprobe ribonuclease protection assays, the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied. Progesterone receptor (PR) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors (SMRT) and amplified in breast cancer-1 (AIB1) expression increased in anti-estrogen-resistant cells. Estrogen caused PR and ERbeta upregulation in all cell lines, but we did not observe increased agonist activity of anti-estrogen measured by regulation of these estrogen target genes. Basal ERalpha levels and estrogenic growth response were decreased and p300/CBP-associated factor (pCAF) and AIB1 upregulated by estrogen in progestin-resistant cells, but coregulator levels were unchanged. Estrogen-independent cells were still estrogen-responsive and PR, nuclear receptor corepressor (N-CoR) and SMRT expression was increased whereas steroid receptor coactivator-1 (SRC-1a) and CBP-related protein p300 (p300) expression decreased. Their growth was inhibited by toremifene, but estradiol was able to abrogate this effect, which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Proliferation; DNA-Binding Proteins; Drug Resistance, Neoplasm; Estradiol; Estrogen Receptor beta; Female; Gene Expression Profiling; Gene Silencing; Hormone Replacement Therapy; Humans; Medroxyprogesterone Acetate; Nuclear Receptor Co-Repressor 2; Progestins; Receptors, Progesterone; Repressor Proteins; Toremifene; Transcription, Genetic; Tumor Cells, Cultured; Up-Regulation

Others have reported ocular toxicity after adjuvant chemoendocrine therapy, but this study looked at ocular toxicity in similarly treated patients from large randomized clinical trials.. Information was retrieved on incidence and timing of ocular toxicity from the International Breast Cancer Study Group (IBCSG) database of 4948 eligible patients randomized to receive tamoxifen or toremifene alone or in combination with chemotherapy (either concurrently or sequentially). Case reports of patients with ocular toxicity were evaluated to determine whether ocular toxicity occurred during chemotherapy and/or hormonal therapy. Additional information was obtained from participating institutions for patients in whom ocular toxicity occurred after chemotherapy but during administration of tamoxifen or toremifene.. Ocular toxicity was reported in 538 of 4948 (10.9%) patients during adjuvant treatment, mainly during chemotherapy. Forty-five of 4948 (0.9%) patients had ocular toxicity during hormone therapy alone, but only 30 (0.6%) patients had ocular toxicity reported either without receiving any chemotherapy or beyond 3 months after completing chemotherapy and, thus, possibly related to tamoxifen or toremifene. In 3 cases, retinal alterations, without typical aspects of tamoxifen toxicity, were reported; 4 patients had cataract (2 bilateral), 12 impaired visual acuity, 10 ocular irritation, 1 optical neuritis, and the rest had other symptoms.. Ocular toxicity during adjuvant therapy is a common side effect mainly represented by irritative symptoms due to chemotherapy. By contrast, ocular toxicity during hormonal therapy is rare and does not appear to justify a regular program of ocular examination. However, patients should be informed of this rare side effect so that they may seek prompt ophthalmic evaluation for ocular complaints.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Databases, Factual; Eye; Eye Diseases; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Tamoxifen; Toremifene; Visual Acuity

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Topics: Breast Diseases; Breast Neoplasms; Canada; Evidence-Based Medicine; Female; Gynecology; Humans; Menstruation Disturbances; Pain; Pain Management; Pain Measurement; Quality of Life; Societies, Medical; Toremifene; Treatment Outcome

Tamoxifen (TAM) causes cancer in rat liver and human endometrium, whereas the carcinogenicity of its chlorinated analogue toremifene (TOR) has not been observed. To elucidate the genotoxicity of TOR, the capability of forming DNA adducts by TOR was examined in the leukocytes of patients treated with TOR. Leukocytes were collected from 27 breast cancer patients (57.7 +/- 11.4 years old) taking TOR (40 mg/day for 25 patients, 80 mg/day for one patient, and 120 mg/day for one patient; average duration, approximately 12 months) and 20 untreated breast cancer patients (58.2 +/- 12.3 years old). The DNA extracted was analyzed by (32)P-postlabeling/high-performance liquid chromatography. No DNA adducts were detected in the leukocytes of either TOR-treated or nontreated patients. Our results contrast to the previous observation detecting TAM-DNA adducts in several patients treated with TAM, indicating that TOR is less genotoxic to humans.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chromatography, High Pressure Liquid; DNA Adducts; DNA, Neoplasm; Female; Humans; Leukocytes; Middle Aged; Toremifene

The purpose of this analysis was to determine predictors of early distant metastasis in elderly breast cancer patients receiving hormonal therapy.. We analyzed data from 938 patients in the North American Fareston Tamoxifen Adjuvant Trial>or=65 years old to determine predictors of early metastatic disease.. The median patient age was 73 (range 65 to 100). With a median follow-up of 34 months, 17 patients (1.8%) developed distant metastases. The median time to distant metastasis was 21 months. On univariate analysis, significant predictors of distant metastatic disease were as follows: progesterone receptor status (P=.032), lymphovascular invasion (P=.020), tumor grade (P=.007), tumor size (P<.01), and number of metastatic nodes (P<.01). On multivariate analysis, only the number of positive nodes (P=.029) remained significant. Patients with >or=4 positive nodes were more likely to develop early metastases than those with 0 to 3 positive nodes (odds ration 20.304; 95% confidence interval 2.777-148.456, P=.003).. Lymph node status in the elderly breast cancer patient treated with hormonal therapy alone is a strong predictor of early distant recurrence.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Mastectomy; Risk Factors; Tamoxifen; Time Factors; Toremifene

Hormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). The two receptors are coded by different genes and their tissue expression varies across organs. ERalpha is predominantly expressed in reproductive tissues (uterus, breast, ovaries) liver and central nervous system, whereas ERbeta is expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, central nervous system and prostate. More than seventy molecules that belong to the SERMS class have been described. There are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydronaphtylenes, indoles and benzopyrans. All of these non-hormonal compounds are capable of activating the ER, reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. Estrogens reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. They are also beneficial for the relief of menopausal symptoms. An ongoing debate that extends over the decades, relates to to overall benefit/risk profile of estrogen or estrogen-progestin therapy since these therapies can increase the risk of serious health disorders, such as breast cancer. SERMs have increased our understanding of hormone-receptor regulatory mechanisms. Their development has permitted a targeted efficacy profile avoiding some of the side effects of the hormone therapy. Their clinical utility relies today mostly on the effects on breast cancer and bone.

Topics: Biomarkers; Bone Density; Bone Remodeling; Breast Neoplasms; Female; Humans; Postmenopause; Raloxifene Hydrochloride; Risk Factors; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Long-term use of tamoxifen is associated with a two- to threefold increased risk of endometrial cancer in postmenopausal women. Toremifene is another triphenylethylene antiestrogen, which is as effective as tamoxifen in postmenopausal breast cancer. Thus far, its use has not been associated with an increased risk of endometrial cancer. K-ras codon 12 mutations seem to be important in endometrial carcinogenesis, and these mutations have been found in endometrial samples of patients on tamoxifen. The present study was undertaken to investigate if there is any difference in the frequency of endometrial K-ras mutations among patients treated with tamoxifen or toremifene.. Endometrial samples were taken from 23 postmenopausal breast cancer patients (tamoxifen, n = 11; toremifene, n = 12) before and after 36 months of treatment. DNA was isolated from formalin-fixed paraffin-embedded samples using a routine proteinase K digestion protocol. K-ras mutations in codon 12 were screened using real-time PCR and melting curve analysis in LightCycler equipment. Wild-type PNA oligomer was used to increase the sensitivity of the assay.. All baseline samples contained wild-type K-ras, while 10/23 (43%) of the follow-up samples carried a codon 12 mutation. Mutations were identified in 3 of the 11 in the tamoxifen group and in 7 of the 12 in the toremifene group. Seven were transitions (G-->A), and three were transversions (two G-->T, one G-->C). One of the mutations in the toremifene group was associated with a polypoid endometrium. All the other mutations were found in an atrophic (n = 6) or proliferative (n = 3) endometrium.. Both tamoxifen and toremifene induce endometrial K-ras codon 12 mutations. The significance of this finding to endometrial carcinogenesis remains to be elucidated.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Endometrium; Female; Genes, ras; Humans; Mutation; Postmenopause; Prospective Studies; Tamoxifen; Toremifene

The patient was a 70-year-old woman, who became aware of a mass in her right breast in 2001, but left it untreated. On March 10, 2003, she visited a nearby doctor with the chief complaint of dyspnea. Since a large painful mass was palpable in the right breast, advanced right breast cancer was suspected, and the patient was referred to our department. Examination revealed the presence of right axillary lymph node metastasis, left pleural effusion, and left atelectasis, and the patient was admitted to our hospital on an emergency basis. Two cycles of CMF were begun on April 2, but CT indicated NC to PD. Therefore, exemestane (EXE, 25 mg/day), was administered on May 13. While the size of the primary lesion was partially decreased, the tumor marker levels were increasing markedly. Administration of EXE was therefore discontinued, and toremifene (TOR, 120 mg/day), was begun. The systemic condition began to improve one month after the start of TOR administration. Two months later, the primary lesion had decreased in size. At after 9 months of TOR treatment, the size of the primary lesion and the tumor marker levels continued to decrease, and both the left pleural effusion and the left atelectasis disappeared.

Topics: Aged; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Lymph Nodes; Lymphatic Metastasis; Methotrexate; Pleural Effusion; Remission Induction; Salvage Therapy; Toremifene

The putative presence of a mutation in codon 12 of the K-ras gene was investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated breast cancer patients. DNA was extracted from fresh cytologic samples of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients. Mutations were detected by enriched PCR and an enzyme-linked mini-sequence assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples, and in only one TOR-treated endometrium (P<0.003). In 24 premenopausal patients, K-ras mutation was found in seven (43.8%) of 16 patients with less than 47 months of TAM treatment, while none was found in eight patients with more than 48 months of TAM treatment (P<0.03). In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in three (15.8%) of 19 patients with less than 23 months of TAM treatment, while it was found in 16 (61.5%) of 26 patients with 24-47 months of TAM treatment and nine (52.9%) of 17 patients with more than 48 months of TAM treatment (P=0.002). The presence of K-ras mutation is significantly influenced by the duration of TAM treatment and menstrual status of the patients. TOR may have a lower potential genotoxicity than TAM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Codon; Endometrium; Female; Genes, ras; Humans; Middle Aged; Mutation; Tamoxifen; Toremifene; Ultrasonography

Tamoxifen (Tam) is widely used in chemotherapy of estrogen receptor-positive breast cancer. It inhibits proliferation and induces apoptosis of breast cancer cells by estrogen receptor-dependent modulation of gene expression, but recent reports have shown that Tam (especially at pharmacological concentrations) has also rapid nongenomic effects. Here we studied the mechanisms by which Tam exerts rapid effects on breast cancer cell viability. In serum-free medium 5-7 microM Tam induced death of MCF-7 and MDA-MB-231 cells in a time-dependent manner in less than 60 min. This was associated with release of mitochondrial cytochrome c, a decrease of mitochondrial membrane potential and an increase in production of reactive oxygen species (ROS). This suggests that disruption of mitochondrial function has a primary role in the acute death response of the cells. Accordingly, bongkrekic acid, an inhibitor of mitochondrial permeability transition, was able to protect MCF-7 cells against Tam. Rapid cell death induction by Tam was not associated with immediate activation of caspase-9 or cleavage of poly (ADP-ribose) polymerase. It was not blocked by the caspase inhibitor z-Val-Ala-Asp-fluoromethylketone either. Diphenylene ionodium (DPI), an inhibitor of NADPH oxidase, was able to prevent Tam-induced cell death but not cytochrome c release, which suggests that ROS act distal to cytochrome c. The pure antiestrogen ICI 182780 (1 microM) could partly oppose the effect of Tam in estrogen receptor positive MCF-7 cells, but not in estrogen receptor negative MDA-MB-231 cells. Pre-culturing MCF-7 cells in the absence of 17beta-estradiol (E(2)) or in the presence of a low Tam concentration (1 microM) made the cells even more susceptible to rapid death induction by 5 or 7 microM Tam. This effect was associated with decreased levels of the anti-apoptotic proteins Bcl-X(L) and Bcl-2. In conclusion, our results demonstrate induction of a rapid mitochondrial cell death program in breast cancer cells at pharmacological concentrations of Tam, which are achievable in tumor tissue of Tam-treated breast cancer patients. These mechanisms may contribute to the ability of Tam therapy to induce death of breast cancer cells.

Topics: Antineoplastic Agents, Hormonal; Apoptosis; Bongkrekic Acid; Breast Neoplasms; Caspase 9; Cell Line, Tumor; Cytochromes c; Drug Screening Assays, Antitumor; Enzyme Activation; Estradiol; Estrogens; Female; Fulvestrant; Humans; Membrane Potential, Mitochondrial; Mitochondria; Onium Compounds; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Tamoxifen; Toremifene

Toremifene (TOR), a selective estrogen receptor modulator (SERM), showed efficacy equivalent to Tamoxifen (TAM) in terms of the objective response rate, stable disease, time to progression and overall survival in patients with metastatic breast cancer (MBC). High-dose TOR is also effective for patients with TAM-resistant breast cancer. We tried to study retrospectively the efficacy and the safety of high-dose TOR treatment for patients with MBC in our hospital. Ten patients received TOR 120 mg daily. Most of the patients were treated with one or more endocrine agents before high-dose TOR. Objective response and clinical benefits were found in 3 patients (30%) and 7 patients (70%), respectively. Median time to progression and median overall survival were 9 months and 21.5 months, respectively. In our study,we found the efficacy for patients with hormone receptor negative, TAM resistance and aromatase inhibitor (AI)-resistance breast cancer. Adverse events induced by high-dose TOR treatment were tolerable. High-dose TOR may be one of the optional treatments for patients with MBC after TAM and AI treatment.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hot Flashes; Humans; Middle Aged; Neoplasm Metastasis; Postmenopause; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Selective Estrogen Receptor Modulators; Survival Analysis; Toremifene

The aim of this study was to determine whether serum matrix metalloproteinase (MMP) -2 and MMP-9 levels could predict overall and disease-free survival in primary node-positive breast cancer.. MMP-2 and MMP-9 levels were quantitatively measured in serum after surgery from 133 patients with primary node-positive breast cancer using enzyme-linked immunoassays. All of the patients received adjuvant therapy, postmenopausal endocrine treatment (tamoxifen or toremifen for 3 years) and premenopausal six cycles of CMF chemotherapy. The follow-up time for all of the patients was 5 years.. Overall survival (OS) and disease-free survival (DFS) rates were better among patients with low MMP-2 levels than in patients with high levels (OS, 91% versus 75%, P = 0.020; DFS, 82% versus 58%, P = 0.005). The appearance of bone and visceral metastases was also significantly lower in patients with low serum MMP-2 levels (bone metastases, 10% versus 23%, P = 0.050; visceral metastases, 12% versus 34%, P = 0.018). The prognostic value of MMP-2 levels was most pronounced among a subgroup of estrogen receptor-positive patients (OS, 96% versus 78%, P = 0.052; DFS, 85% versus 58%, P = 0.014), whereas no significant difference was found among estrogen receptor-negative patients (OS, 73% versus 69%, P = 0.25; DFS, 73% versus 63%, P = 0.32). In multivariate analysis, MMP-2 level together with nodal status (NS), progesterone receptor (PgR), and tumor size (T) remained independent predictors for DFS (NS, P = 0.002; PgR, P = 0.004; T, P = 0.023; MMP2, P = 0.039) and OS (NS, P = 0.0002; PgR, P = 0.004; T, P = 0.004; MMP2, P = 0.032). MMP-9 levels did not correlate with survival.. The results suggest that serum postoperative MMP-2 level is a predictor of DFS and OS, and could help to stratify breast cancer patients with primary node-positive disease into low- and high-risk groups.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Multivariate Analysis; Prognosis; Proportional Hazards Models; Tamoxifen; Time Factors; Toremifene; Treatment Outcome

We report a 64-year-old woman who underwent mastectomy for stage II (T2N1M0) advanced breast cancer, in whom multiple spine metastases developed 18 months postoperatively. She received 6 cycles of CA (cyclophosphamide 500 mg/m2, ADM 50 mg/m2 3 wq) therapy and oral tamoxifen (20 mg/body) administration for adjuvant therapy. The multiple bone metastases of the spine were revealed by technetium bone scan. The level of serum tumor marker CA15-3 increased two times over the normal range 18 months after surgery. She also developed osteoporosis a few years later, so we selected high-dose toremifene administration (120 mg/body) as a second-line therapy. No adverse effects have occurred and bone metastases disappeared. Moreover, the tumor marker was also normalized 6 months after toremifene therapy started. It was shown that high-dose treatment of toremifene was useful for recurrent breast cancer with bone metastasis.

Topics: Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Mastectomy; Middle Aged; Remission Induction; Toremifene

The effect of toremifene on P-glycoprotein-mediated multidrug resistance (MDR) in breast and head and neck cancer cell lines was measured in vitro and in vivo. Pgp expression was low and high, respectively, in drug-sensitive (MCF7-S, KB) and drug-resistant (MCF7-R, MCF7-R1, KBV1) cell lines. Toremifene (7.5 microM) significantly enhanced cytoplasmic and nuclear accumulation of doxorubicin in drug-resistant cells. Toremifene (10 microM) increased the in vitro cytotoxicity of doxorubicin in drug-resistant breast cancer cells (13-fold and 21-fold for MCF7-R and MCF7-R1, respectively) without affecting the sensitivity of MCF7-S cells. Similarly, toremifene (10 microM) caused a 12-fold increase in the sensitivity of KBV1 cells to vinblastine. In contrast, toremifene (5 microM) reduced the net uptake of the radiolabelled Pgp substrate, Tc-99m-sestamibi, in the Pgp-overexpressing cell lines by factors of 0.32 and 0.42 for MCF7-R1 and KBV1 cells, respectively (p < 0.01), and, to a lesser extent, by corresponding factors of 0.89 and 0.86 in the drug-sensitive cell lines (p < 0.05 and p > 0.05, respectively). In nude mice bearing both KB and KBV1 xenograft tumours, significantly higher tumour levels of Tc-99m-sestamibi were recorded in KB tumours compared with KBV1 tumours. After 3 days of treatment with intraperitoneal toremifene (25 mg/kg), tumour levels of Tc-99m-sestamibi were reduced in KB and KBV1 tumours but only statistically significantly for KB tumours. Toremifene is a potent MDR modulating agent with respect to chemotherapeutic agents but has the opposite effect with respect to Tc-99m-sestamibi. This finding is of importance in view of the widespread use of Tc-99m-sestamibi as an imaging surrogate for a chemotherapeutic agent.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Mice; Microscopy, Fluorescence; Technetium Tc 99m Sestamibi; Toremifene; Vinblastine

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Interactions; Female; Humans; Middle Aged; Nurse's Role; Oncology Nursing; Patient Education as Topic; Patient Selection; Postmenopause; Selective Estrogen Receptor Modulators; Toremifene; Treatment Outcome

Effects of toremifene (TOR) in combination with paclitaxel (TXL) on various human breast cancer cell lines were evaluated. TOR and TXL exhibited additive effects on estrogen receptor (ER)-positive cancer cell lines, MCF-7 and T-47D, and a sub-additive effect on a tamoxifen (TAM)-resistant line, T-47D/TAM. To all three ER-negative cancer cell lines, the combined treatment also showed additive effects on MDA-MB-134VI, MDA-MB-231 and MDA-MB-453. Furthermore, a synergistic effect was observed on a multi-drug resistant (MDR) line, Adr. This synergistic effect was more potent in the combination with TOR than that with TAM. The combined treatment increased intracellular TXL, and the accumulation by TOR was 1.5-fold that by TAM. Consequently, the ratio of G2M arrested cells was higher, with statistical significance, in the TOR combination than in the TAM combination. In addition, these synergistic effects in MDR cells were also observed in the combination of TXL with major clinical active metabolites, N-desmethyl-TOR (TOR-1) and 4-hydroxy-TOR (TOR-2). These results suggest that the combination therapy of TOR and TXL might be an effective clinical treatment for breast cancer patients.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Synergism; Humans; Paclitaxel; Selective Estrogen Receptor Modulators; Toremifene; Tumor Cells, Cultured

Modern treatment of cancer of the breast is based on established prognostic factors (patient age, receptor status, tumor size, lymph node involvement, tumor grading), and thus takes the patient's individual risk profile into account. In addition to the antiestrogen, tamoxifen, new hormonal preparations, such as the aromatase inhibitors, hold out promise of improved results from adjuvant treatment in elderly women. In premenopausal women, additional hormone blockade by means of GnRH analogs is of advantage. Neoadjuvant (preoperative) chemotherapy protocols will enable rapid evaluation of new therapeutic options. When metastases have developed, treatment with hormonal drugs is indicated in the case of slowly progressing disease (low risk), while clinically progressive metastasization (high risk) requires cytostatic chemotherapy. Here, studies involving more recent substances with improved tolerability, and tumor-specific antibodies, confirm an improvement in the prognosis. The concentration of drug treatment in interdisciplinary centers is a necessary element of quality assurance and therapeutic optimization.

Topics: Adult; Age Factors; Aged; Anastrozole; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Enzyme Inhibitors; Estrogen Antagonists; Female; Humans; Immunotherapy; Letrozole; Meta-Analysis as Topic; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nitriles; Premenopause; Prognosis; Quality of Health Care; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Risk Factors; Selective Estrogen Receptor Modulators; Tamoxifen; Time Factors; Toremifene; Trastuzumab; Triazoles

The antiestrogen, tamoxifen, has been extensively used in the treatment and prevention of breast cancer. Although tamoxifen showed benefits in the chemotherapy and chemoprevention of breast cancer, epidemiological studies in both tamoxifen-treated breast cancer patients and healthy women indicated that treatment caused an increased risk of developing endometrial cancer. These troubling side effects lead to concerns over long-term safety of the drug. Therefore, it is important to fully understand the relationship between the antiestrogenic and the genotoxic mechanisms of tamoxifen, other antiestrogens, and their metabolites. Previously, we have shown that o-quinone formation from tamoxifen and its analogues, droloxifene and 4-hydroxytoremifene, may not contribute to the cytotoxic effects of these antiestrogens; however, these o-quinones can form adducts with deoxynucleosides and this implies that the o-quinone pathway could contribute to the genotoxicity of the antiestrogens in vivo. To further investigate this potential genotoxic pathway, we were interested in the role of estrogen receptor (ER)(1) alpha and beta since work with catechol estrogens has shown that ERs seem to enhance DNA damage in breast cancer cell lines. As a result, we investigated the binding affinities of 4-hydroxy and 3,4-dihydroxy derivatives of tamoxifen and toremifene to ER alpha and beta. The antiestrogenic activities of the metabolites using the Ishikawa cells were also investigated as well as their activity in ERalpha and ERbeta breast cancer cells using the transient transfection reporter, estrogen response element-dependent luciferase assay. The data showed that the antiestrogenic activities of these compounds in the biological assays mimicked their activities in the ER binding assay. To determine if the compounds were toxic and if ERs played a role in this process, the cytotoxicity of these compounds in ERbeta41(2) (ERbeta), S30 (ERalpha), and MDA-MB-231 (ER(-)) cell lines was compared. The results showed that the cytotoxicity differences between the metabolites were modest. In addition, all of the metabolites showed similar toxicity patterns in both ER positive and negative cell lines, which means that the ER may not contribute to the cytotoxicity pathway. Finally, we compared the amount of DNA damage induced by these metabolites in these cell lines using the comet assay. The catechols 3,4-dihydroxytoremifene and 3,4-dihydroxytamoxifen induced a greater amount of cellular sin

Topics: Binding, Competitive; Breast Neoplasms; Catechols; Cell Line, Tumor; Cell Survival; Comet Assay; DNA Damage; Drug Screening Assays, Antitumor; Estradiol; Estrogen Receptor Modulators; Female; Humans; Indolequinones; Quinones; Receptors, Estrogen; Tamoxifen; Toremifene

A population-based case-control study was performed to evaluate the risk of endometrial cancer related to tamoxifen or toremifene treatment. All patients with breast cancer diagnosis since 1980 in Finland who subsequently developed an endometrial cancer by the end of 1995 and 3 matched controls were identified among the 38,000 breast cancer patients of the Finnish Cancer Registry database. Detailed information on treatment of breast cancer and potential confounders was collected from hospital records. The OR for tamoxifen treatment (59 cases), adjusted for significant cofactors (increased risk associated with obesity, low parity and PR positivity) was 2.9 (95% CI 1.8-4.7). The OR for toremifene (3 cases) was 0.9 (95% CI 0.3-3.9). The OR related to adjuvant tamoxifen treatment reached its maximum 2-5 years after the beginning of treatment (OR 5.1, 95% CI 2.1-13), while the OR for tamoxifen used for palliative treatment of advanced breast cancer was especially high after a lag of over 5 years (OR 9.5, 95% CI 2.5-36). The risk increase due to tamoxifen was slightly higher if the age at initiation was below 55, and risk was more pronounced among patients with well-differentiated endometrial cancer than patients with cancers of clinical grades 2 or 3. According to our results, treatment with tamoxifen increases the risk of endometrial cancer. Due to the rare use of toremifene up to the mid-1990s, the risk assessment concerning it was inconclusive.

Topics: Breast Neoplasms; Case-Control Studies; Endometrial Neoplasms; Estrogen Antagonists; Estrogen Replacement Therapy; Female; Humans; Tamoxifen; Toremifene

We studied a new chemoendocrine therapy against recurrent breast cancer in order to evaluate its efficacy and toxicity. Sixteen eligible patients were treated with the therapy consisting of adriamycin/cyclophosphamide (AC) plus toremifene (TOR). Adriamycin (20 mg/m2) was administered intravenously on days 1 and 8, and cyclophosphamide (100 mg/body) was given orally on days 1 to 14 every 4 weeks. TOR (120 mg/day) was given orally daily. The median age of the patients was 52 years; 6 were premenopausal and 10 postmenopausal. As post-operative adjuvant therapy, anthracycline chemotherapy and tamoxifen were given to 4 and 9 patients, respectively. AC therapy was administered for 8.5 cycles (median). Four complete responses (25%), 8 partial responses (37.5%), 4 no change (25%) (including 2 long NC), and 2 progressive disease (12.5%) were obtained, for an overall response rate of 62.5%. The median duration of time to progression and survival were 13.2 months (0.7-30.4 months) and 22.8 months (13.7-44.8 + months), respectively. The frequent toxicities were leukopenia, nausea/vomiting, and alopecia, but these were clinically well tolerated. Our results suggest that the addition of high dose TOR to AC therapy is useful in the treatment of recurrent breast cancer.

Topics: Administration, Oral; Adult; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Leukopenia; Middle Aged; Nausea; Neoplasm Recurrence, Local; Survival Rate; Toremifene

A 64-year-old woman underwent muscle-preserving mastectomy for breast cancer in April 1999. She developed multiple lung metastases 3 months later. The metastases partially responded to 10 cycles of CAF (cyclophosphamide, adriamycin, 5-fluorouracil). However, her lung metastases worsened again 7 months later and CAF was not effective (progressive disease). We therefore began administration of low-dose paclitaxel (80 mg/m2/week) and high-dose toremifene (120 mg/day) alternately in April 2001. This alternative therapy brought a marked decrease in the lung metastases. After 4 cycles of this treatment, lung metastatic findings had disappeared from her chest X-ray. This alternative therapy is potentially effective against metastatic breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Mastectomy, Modified Radical; Middle Aged; Paclitaxel; Remission Induction; Toremifene

A 72-year-old female had undergone mastectomy at the age of 67 for right breast cancer (T2a, n1 alpha, positive for ER). In the surgery the pectoralis muscle was preserved. For adjuvant therapy, 20 mg/day of tamoxifen was orally administered for 5 years. Six years after surgery, relapse was detected in the right major pectoralis muscle. Irradiation at this site and oral administration of 120 mg/day of toremifene citrate were started. The patient had a medical history of diabetes, and the control of her blood sugar was poor. About 2 months after oral administration of toremifene citrate was started, flares with blebs and swelling were observed in the right lower leg, suggesting acute phlebothrombosis of the right lower limb. The symptoms were ameliorated by intravenous administration of heparin and an antibiotic. In administering a high dose of toremifene citrate to patients with complications, careful follow-up is needed.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Fibrinolytic Agents; Heparin; Humans; Leg; Neoplasm Recurrence, Local; Toremifene; Venous Thrombosis

Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo.. Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry.. Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min.. (99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; ATP Binding Cassette Transporter, Subfamily B; Breast; Breast Neoplasms; Drug Resistance, Multiple; Female; Humans; Immunohistochemistry; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Selective Estrogen Receptor Modulators; Technetium Tc 99m Sestamibi; Toremifene

EM-652 exerts pure antiestrogenic activity in the mammary gland and endometrium, while tamoxifen, the antiestrogen most widely used for the treatment of breast cancer, exerts mixed antiestrogenic-estrogenic activity in these tissues. Our objective was to compare the agonistic and antagonistic effects of EM-652 with tamoxifen and 5 other antiestrogens on the growth of ZR-75-1 human breast xenografts in ovariectomized nude mice. During the 23 weeks of treatment at a daily oral dose of 50 microg, EM-652 was the only compound that decreased tumor size relative to pretreatment values, whereas the 6 other antiestrogens only decreased to various extents the progression rate stimulated by estrone. Under estrone stimulation, all groups of animals had more than 60% of their tumors in the progression category except for the EM-652-treated group, where only 7% of the tumors progressed. In the absence of estrone stimulation, progression was seen in 60%, 33%, 21% and 12% of tumors in the tamoxifen-, idoxifene-, toremifene- and raloxifene-treated groups, respectively, while only 4% of tumors progressed in the EM-652-treated group. The agonistic and antagonistic actions of each antiestrogen were also measured on endometrial epithelial cell thickness. Our present findings indicate that EM-652, in addition to being the most potent antiestrogen on human breast tumor growth, has no agonistic effect in breast and endometrial tissues. Since previous data have shown benefits of EM-652 on bone density and lipid profile, this compound could be an ideal candidate for chemoprevention of breast and uterine cancers, while protecting against osteoporosis and cardiovascular disease.

Topics: Animals; Breast Neoplasms; Cell Division; Cell Size; Cinnamates; Endometrium; Epithelial Cells; Estrogen Antagonists; Estrone; Female; Humans; Kinetics; Mice; Mice, Nude; Neoplasm Transplantation; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Stilbenes; Tamoxifen; Toremifene; Tumor Cells, Cultured

Toremifene is an anti-estrogenic drug like tamoxifen. We assessed the body distributions after administration of toremifene and tamoxifen in order to evaluate their treatment regimens by measuring the concentrations in tissues. It is known that, after toremifene (TOR) or tamoxifen (TAM) is consecutively administered to breast cancer patients, TOR or TAM and their main active N-desmethyl-metabolites (TOR-1 or TAM-1) are detected in sera, tumor tissues, and lymph nodes. Accordingly, after we administered toremifene or tamoxifen to primary breast cancer patients previous to surgery, we measured the concentrations of TOR, TOR-1, TAM, TAM-1 in sera, tumor tissues, and lymph nodes. We found that the concentrations of TOR and TOR-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of toremifene 40 mg. Likewise, the concentrations of TAM and TAM-1 in sera, tumors, and lymph nodes reached a peak about 2 weeks after administration of tamoxifen, although the peak levels were lower than those of TOR or TOR-1. The concentrations of TAM-1 in lymph nodes were significantly and positively correlated to the duration of administration of TAM, and it was predicted that the concentration of TAM-1 in lymph nodes would reach a steady state at more than 4 weeks after administration of tamoxifen. The concentrations of TOR and TOR-1 were higher in tumors and lymph nodes than in sera. Furthermore, the concentrations of TOR and TOR-1 were significantly higher than those of TAM and TAM-1 in sera and tumors, respectively. Moreover, the concentration in tissue increased in a dose-dependent manner with administration of toremifene 120 mg. There were no significant differences between breast cancers positive and negative for estrogen receptors, with regard to the concentrations of TOR and TOR-1 in either sera, tumors, or lymph nodes. In conclusion, it would be expected that treatment with toremifene might be more effective for breast cancer than that with tamoxifen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Lymph Nodes; Middle Aged; Receptors, Estrogen; Tamoxifen; Tissue Distribution; Toremifene

A patient with lung and pleural metastases from breast cancer treated effectively with toremifene is reported. A 62-year-old woman underwent mastectomy for breast cancer, and had high levels of estrogen and progesterone receptor. After 2-years of adjuvant UFT therapy, lung and pleural metastases were seen on a chest x-ray. The patient received a high-dose of toremifene (120 mg/day). After five months with toremifene, a chest x-ray and CT scan showed the disappearance of lung and pleural metastases. No recurrence or metastases have been detected for twenty months to date. No serious side effects were noticed. High-dose toremifene might be an effective therapy for cases of postmenopausal metastatic breast cancer, with high levels of estrogen and progesterone receptor.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Lung Neoplasms; Middle Aged; Pleural Neoplasms; Selective Estrogen Receptor Modulators; Toremifene

The patient was a 53-year-old female who presented with a primary complaint of reddening of the left precordial skin. She had undergone mastectomy for cancer of the left breast 12 years and 4 months earlier and had received endocrine chemotherapy including TAM as a postoperative adjuvant therapy. A diagnosis of thoracic wall recurrence was made by chest CT and pathological examination of skin biopsy specimens. Toremifene (TOR) was administrated at 120 mg/day, and PR was maintained for 8 months. Even after the condition became PD, the patient has retained adequate QOL with combination therapies including radiotherapy, and is still treated on an outpatient basis 3 years after the beginning of the treatment.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Middle Aged; Selective Estrogen Receptor Modulators; Thoracic Neoplasms; Toremifene

Node-positive breast carcinoma is an aggressive disease. Postmenopausal patients benefit from antiestrogen adjuvant therapy. Predictive markers could, however, be useful in selecting these patients for different modalities of adjuvant therapy. Recently, we showed that MMP-2 (72 kD type IV collagenase/gelatinase A) is correlated with unfavorable prognosis in premenopausal breast carcinoma patients. Expression of the immunoreactive protein for MMP-2 was evaluated prospectively in this study in paraffin tissue sections from primary tumors of 100 postmenopausal, node-positive breast carcinoma patients treated with an adjuvant antiestrogen therapy. A specific MMP-2 monoclonal antibody in an avidin-biotin immunohistochemical staining was used. Sixty nine percent of the samples were MMP-2 positive. Eighty three percent of the MMP-2 negative patients lived for 5 years without a recurrence, while only 67% of the patients with an MMP-2 positive primary tumor were recurrence-free at that time (p < 0.05; log rank analysis). MMP-2 positivity showed a significant correlation with shortened survival in patients with a small primary tumor (T1-2) and a low axillary tumor burden. One hundred percent of these patients with an MMP-2 negative breast carcinoma survived for 5 years, compared to 73% of the MMP-2 positive cases alive at that time (p = 0.02). In conclusion, we show here that MMP-2 is a prognostic indicator in postmenopausal patients with node-positive breast carcinoma with a low tumor burden, and that it predicts a risk for failure in antiestrogen adjuvant therapy. It might have predictive value in selecting the most efficient adjuvant therapy in this set of patients.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Matrix Metalloproteinase 2; Middle Aged; Neoplasm Recurrence, Local; Postmenopause; Prognosis; Prospective Studies; Risk Factors; Tamoxifen; Toremifene

Estrogenicity is an important mechanism in hormonal carcinogenesis but not sufficient to explain the carcinogenic activity of all estrogens. Additional mechanisms, related to genetic alterations, in conjunction with estrogenicity mediated through the estrogen receptor, have been suggested. An environmental estrogen bisphenol-A (BP-A) and its analogs are widespread in our living environment. Because of the potential for human exposure, the possible relationship between carcinogenicity and estrogenicity of these bisphenols was studied using mammalian cells. We quantitatively compared the cell-transforming activity of BP-A and 4 of its analogs (BP-2, BP-3, BP-4 and BP-5) in Syrian hamster embryo (SHE) cells lacking estrogen-receptor expression. The transforming activity determined by the morphological transformation frequencies in SHE cells treated with the bisphenols ranked: BP-4 > BP-5 > BP-3 > BP-A > BP-2. We also compared the estrogenicity of the 5 bisphenols in MCF7 human breast cancer cells as determined by cell proliferation or progesterone receptor (PgR) expression assayed by RT-PCR. When MCF7 cells were treated with the bisphenols, the proliferative potency ranked: BP-A > BP-5 > BP-4 > BP-3 = BP-2. The level of mRNA for PgR in cells treated with the bisphenols was BP-A > BP-5 > BP-4 > BP-3 > BP-2. These indicate that the transforming activity does not correlate with the estrogenicity of the bisphenols, except for BP-2 that has the weakest activity at the both endpoints. In addition, our results suggest that bisphenols with few, if any, transforming and estrogenic activities could be altered by a modification of the chemical structure. Published 2001 Wiley-Liss, Inc.

Topics: Animals; Benzhydryl Compounds; Breast Neoplasms; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Colony-Forming Units Assay; Diethylstilbestrol; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Fetus; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; Molecular Structure; Phenols; Receptors, Progesterone; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship; Toremifene; Tumor Cells, Cultured

A 63-year-old woman underwent modified radical mastectomy with 3 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil) and MPA endocrine therapy for breast cancer. Because of nausea and general fatigue, she refused to continue this therapy and did not visit the hospital. When she came our hospital and 16 months later, she had developed multiple bone metastases. At the same time, she was suffering from lung tuberculosis. She was treated with toremifene at a dose of 120 mg/day without any side effects. After 3 months administration of toremifene, pain disappeared and her high serum CA15-3 and BCA225 dropped to within the normal range. On bone scintigrams, abnormal accumulation almost disappeared after 9 months of administration of toremifene. In this case, the patient was suffering from lung tuberculosis and did not desire intensive chemotherapy. Administration of high-dose toremifene was effective for multiple bone metastases without any side effects.

Topics: Antineoplastic Agents, Hormonal; Bone Neoplasms; Breast Neoplasms; Female; Humans; Middle Aged; Toremifene; Treatment Outcome; Tuberculosis, Pulmonary

A 36-year-old woman was admitted to our hospital because of general malaise in October 1999. She was diagnosed with bilateral breast cancer with bone marrow and liver metastases. Low-dose weekly paclitaxel (60 mg/body/week) combined with toremifene (120 mg/day) was started in December 1999. Myelofunction was recovered after 2 weeks of chemotherapy (CT), and the primary tumors and cervical/axillary lymphadenopathy disappeared after 4 weeks of CT. Bone marrow and liver metastases was no longer detected after 16 weeks of CT, and the case was evaluated as a complete response (CR). The same therapy has been performed for eight months and no evidence of recurrence has been observed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Liver Neoplasms; Paclitaxel; Remission Induction; Toremifene

Tamoxifen remains the endocrine therapy of choice in the treatment of all stages of hormone-dependent breast cancer. However, tamoxifen has been shown to increase the risk of endometrial cancer which has stimulated research for new effective antiestrogens, such as droloxifene and toremifene. In this study, the potential for these compounds to cause cytotoxic effects was investigated. One potential cytotoxic mechanism could involve metabolism of droloxifene and toremifene to catechols, followed by oxidation to reactive o-quinones. Another cytotoxic pathway could involve the oxidation of 4-hydroxytoremifene to an electrophilic quinone methide. Comparison of the amounts of GSH conjugates formed from 4-hydroxytamoxifen, droloxifene, and 4-hydroxytoremifene suggested that 4-hydroxytoremifene is more effective at formation of a quinone methide. However, all three substrates formed similar amounts of o-quinones. Both the tamoxifen-o-quinone and toremifene-o-quinone reacted with deoxynucleosides to give corresponding adducts. However, the toremifene-o-quinone was shown to be considerably more reactive than the tamoxifen-o-quinone in terms of both kinetic data as well as the yield and type of deoxynucleoside adducts formed. Since thymidine formed the most abundant adducts with the toremifene-o-quinone, sufficient material was obtained for characterization by (1)H NMR, COSY-NMR, DEPT-NMR, and tandem mass spectrometry. Cytotoxicity studies with tamoxifen, droloxifene, 4-hydroxytamoxifen, 4-hydroxytoremifene, and their catechol metabolites were carried out in the human breast cancer cell lines S30 and MDA-MB-231. All of the metabolites tested showed cytotoxic effects that were similar to the parent antiestrogens which suggests that o-quinone formation from tamoxifen, droloxifene, and 4-hydroxytoremifene is unlikely to contribute to their cytotoxicity. However, the fact that the o-quinones formed adducts with deoxynucleosides in vitro implies that the o-quinone pathway might contribute to the genotoxicity of the antiestrogens in vivo.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Breast Neoplasms; Cell Survival; Deoxyribonucleosides; DNA Adducts; Female; Glutathione; Indolequinones; Indoles; Microsomes, Liver; Quinones; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Tamoxifen; Toremifene; Tumor Cells, Cultured

The present study was conducted to reveal the effect of the nonsteroidal anti-oestrogen toremifene on the expression of cell-surface molecules involved in the immunogenicity of tumours or the sensitivity of tumour cells to apoptotic cell death. We studied the effect of toremifene on the expression of HLA-DR, ICAM-1, costimulatory molecules CD80 and CD86, and the tumour necrosis factor receptor (TNF-R) family molecules CD27, CD30, CD40, TNF-R1, TNF-R2 and Fas (CD95) on MCF-7 breast cancer and Jurkat T cells. In addition, the effect of toremifene on Fas-mediated apoptosis was studied. Toremifene did not affect Fas expression or Fas-mediated apoptosis in Fas-resistant MCF-7 or Fas-sensitive Jurkat cells, but was found to increase the expression of ICAM-1 in both cell lines. In addition, toremifene increased the expression of CD40 and CD80 on MCF-7 cells. The expression of ICAM-1 in tumours plays an important role in the interaction of tumour cells and effector cells of the immune system. Therefore, we suggest that toremifene may modulate the immunogenicity of tumour cells by increasing the expression of ICAM-1.

Topics: Antineoplastic Agents, Hormonal; Apoptosis; B7-1 Antigen; Breast Neoplasms; CD40 Antigens; Daunorubicin; fas Receptor; Female; HLA-DR Antigens; Humans; Intercellular Adhesion Molecule-1; Interferon-gamma; Jurkat Cells; Recombinant Proteins; Selective Estrogen Receptor Modulators; Toremifene; Tumor Cells, Cultured

Tamoxifen is widely prescribed for the treatment of hormone-dependent breast cancer, and it has recently been approved by the Food and Drug Administration for the chemoprevention of this disease. However, long-term usage of tamoxifen has been linked to increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. The resulting quinone methide has the potential to alkylate DNA and may initiate the carcinogenic process. To further probe the chemical reactivity and toxicity of such an electrophilic species, we have prepared the 4-hydroxytamoxifen quinone methide chemically and enzymatically, examined its reactivity under physiological conditions, and quantified its reactivity with GSH. Interestingly, this quinone methide is unusually stable; its half-life under physiological conditions is approximately 3 h, and its half-life in the presence of GSH is approximately 4 min. The reaction between 4-hydroxytamoxifen quinone methide and GSH appears to be a reversible process because the quinone methide GSH conjugates slowly decompose over time, regenerating the quinone methide as indicated by LC/MS/MS data. The tamoxifen GSH conjugates were detected in microsomal incubations with 4-hydroxytamoxifen; however, none were observed in breast cancer cell lines (MCF-7) perhaps because very little quinone methides is formed. Toremifene, which is a chlorinated analogue of tamoxifen, undergoes similar oxidative metabolism to give 4-hydroxytoremifene, which is further oxidized to the corresponding quinone methide. The toremifene quinone methide has a half-life of approximately 1 h under physiological conditions, and its rate of reaction in the presence of excess GSH is approximately 6 min. More detailed analyses have indicated that the 4-hydroxytoremifene quinone methide reacts with two molecules of GSH and loses chlorine to give the corresponding di-GSH conjugates. The reaction mechanism likely involves an episulfonium ion intermediate which may contribute to the potential cytotoxic effects of toremifene. Similar to what was observed with 4-hydroxytamoxifen, 4-hydroxytoremifene was metabolized to di-GSH conjugates in microsomal incubations at about 3 times the rate of 4-hydroxytamoxifen, although no conjugates were detected with MCF-7 cells. Finally, these data suggest that quinone

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cytochrome P-450 Enzyme System; Estrogen Receptor Modulators; Female; Glutathione; Humans; Hydroxylation; Indolequinones; Indoles; Mass Spectrometry; Oxidation-Reduction; Quinones; Rats; Rats, Sprague-Dawley; Tamoxifen; Toremifene; Tumor Cells, Cultured

FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Bone and Bones; Breast Neoplasms; Cholesterol; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Organ Size; Osteoporosis; Ovariectomy; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Reference Values; Tamoxifen; Toremifene; Transplantation, Heterologous; Tumor Cells, Cultured; Uterus

To determine whether plasma concentrations of toremifene citrate after administration of 120 mg/day of toremifene citrate given in three separate dose (t.i.d.) were similar to those when toremifene citrate was administered in a single daily doses (40 mg x 3 tablets), we examined changes in plasma concentrations of toremifene citrate (TOR) and its metabolite, N-desmethyltoremifene (TOR-1). In both the t.i.d. administration group and the single-dose administration group, plasma TOR and TOR-1 concentrations reached a constant state within 2 weeks after administration was started. Under the constant state, plasma TOR concentrations were 1,493.3 +/- 120.3 ng/ml in the t.i.d. administration group and 1,348 +/- 341.0 ng/ml in the single-dose administration group. Plasma TOR-1 concentrations were 2,378.3 +/- 186.5 ng/ml in the t.i.d. administration group and 2,144 +/- 475.3 ng/ml in the single-dose administration group. In both groups, plasma TOR-1 concentrations were 2 or more times higher than plasma TOR concentrations. These results show there were no differences in plasma concentrations between administration of 120 mg/day of toremifene citrate in divided daily doses (t.i.d.) and in a single daily dose. The two administration methods appear to produce clinically similar actions.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Middle Aged; Postmenopause; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Tamoxifen (TAM) is used for the adjuvant treatment of women with breast cancer and has also been recommended as a chemopreventive agent. Among unwanted side effects, TAM was shown to increase endometrial cancer in treated women by mechanisms that are not yet clearly understood. We studied DNA adducts in lymphocytes of female breast cancer patients treated with TAM or toremifene (TOR), a TAM analogue and compared them with adducts formed by TAM in rat liver, where the drug induces tumours. DNA adducts were measured by TLC-(32)P-post-labelling assays. After TLC, all DNA samples including DNA from untreated healthy women showed a faint radioactive zone, where the positive control DNA adducts isolated from the liver of rats treated with TAM migrated. The relative adduct levels were calculated from the radioactivity present in this zone. Means +/- SD of adduct levels per 10(8) nucleotides (associated with this area) were for untreated volunteers (control) 1.83 +/- 1.41 (n = 13), for TAM treatment 2.17 +/- 3.04 (n = 25) and for TOR treatment 1.18 +/- 1.05 (n = 8). Most of the human samples were further analysed by HPLC after labelling with (32)P in order to compare adducts in human DNA with those in liver DNA isolated from TAM-treated rats. None of the human samples showed any peaks at retention times where putative TAM-DNA adducts were eluted. In conclusion, lymphocyte DNA from female patients treated at therapeutic levels did not show evidence of the formation of TAM- or TOR-DNA adducts.

Topics: Adult; Aged; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; DNA Adducts; Female; Humans; Lymphocytes; Middle Aged; Rats; Tamoxifen; Toremifene

We report a case of far advanced breast cancer showing an excellent response to chemo-endocrine therapy. A 40-year-old female with a huge ulcerated tumor on her left anterior chest visited our hospital. Distant metastases were found in the lymph nodes, liver and bone. Therefore, endocrine therapy (toremifene and medroxyprogesterone acetate) and chemotherapy (cyclophosphamide, Therarubicin and 5-fluorouracil) were started as a combination treatment. As a result, the main tumor and metastatic lesion were remarkably reduced, and extended mastectomy with resection of right axillary lymph nodes was performed. Histologically, cancer cells in the primary lesion mostly disappeared, and only one lymph node in the left axillary lesion showed metastasis. No recurrence was found for 16 months after the surgical treatment. The combined therapy in the present case was extremely effective.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Liver Neoplasms; Lymphatic Metastasis; Neoplasm Staging; Toremifene

Tamoxifen has been used for the treatment of breast cancer since the 1970s, but is considered a carcinogen because it has been linked to liver cancer in rats and an increased risk of endometrial cancer in patients. In rats, DNA adducts appear to be responsible for carcinogenesis, but their contribution to carcinogenesis in humans is not clear. FC-1271a and toremifene are mixed antiestrogens similar to tamoxifen. In order to compare the genotoxicity of these different triphenylethylenes, we treated mice for 28 days with 50 mg/kg of either tamoxifen, toremifene, FC- 1271 a or vehicle control. DNA from liver and uterus was assayed by standard 32P-postlabeling and thin layer chromatography for the presence of DNA adducts. Two methods of drug administration (oral and subcutaneous) and two strains of mice were compared and the plasma and tissue concentrations of the drugs and three metabolites of tamoxifen and toremifene were determined. Regardless of the conditions, only tamoxifen-treated mice showed DNA adducts in the liver. Adduct levels did not correlate with drug or metabolite levels and adducts were present even when drug was not detectable. Mice were also treated orally with either 50, 100, or 200 mg/kg of drug for 7 days. Again, adducts were found only in liver tissue of mice treated with tamoxifen, and adduct levels were dose-dependent. In conclusion, the chlorinated triphenylethylene FC-1271a did not cause DNA adducts under various conditions in mice, suggesting a low carcinogenic potential.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinogens; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; DNA Adducts; Dose-Response Relationship, Drug; Estrogen Antagonists; Female; Humans; Injections, Subcutaneous; Liver; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Spleen; Tamoxifen; Toremifene; Uterus

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Endometrial Neoplasms; Female; Humans; Neoplasm Recurrence, Local; Selective Estrogen Receptor Modulators; Toremifene

During the last decade, several new drugs and classes of drugs have become available for breast cancer treatment. Thus, in addition to tamoxifen we have got several new selective oestrogen receptor modulators (SERMs) with a partially different pharmacological profile. The first generation aromatase inhibitor, aminoglutethimide, has been replaced by more potent and less toxic inhibitors belonging to the triazole class (anastrozole and letrozole) and, more recently, the steroidal aromatase inactivator exemestane [1-3]. These drugs have all revealed a better toxicity profile and, in general, an improved antitumour activity, compared with conventional therapy. Faslodex, the first representative of the so-called 'pure' oestrogen antagonists, has shown beneficial effects in patients resistant to tamoxifen [4].

Topics: Aminoglutethimide; Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Toremifene

We have described fatty liver, diagnosed by computed tomography scanning (CT) in more than 30% of patients with breast cancer who received tamoxifen. Therefore, it is urgent to elucidate the frequency and the degree of fatty liver induced by toremifene, an analogue of tamoxifen, which is also used in breast cancer. We enrolled 52 breast cancer patients who were treated with breast-conservation treatment and administered oral toremifene for 3-5 years as adjuvant endocrine therapy. We evaluated the degree of fatty liver by abdominal CT performed annually. CT demonstrated toremifene-induced fatty liver in four (7.7%) of 52 breast cancer patients. Toremifene-induced fatty liver did not correlate with abnormal levels of AST, ALT, GGT or total cholesterol. One patient who demonstrated moderate fatty liver by CT was histologically diagnosed as non-alcoholic steatohepatitis (NASH) by liver biopsy. The incidence of toremifene-induced fatty liver was significantly lower than that induced by tamoxifen. Accordingly, in terms of fatty liver and NASH, toremifene is considered to be more appropriate agent than tamoxifen. Though toremifene is less likely to induce fatty liver, the possibility remains that toremifene-induced steatohepatitis occurs. Because the diagnosis of fatty liver or NASH can be easily missed if only a blood test is performed, it is necessary to screen fatty liver by annual CT examination for patients who receive an antiestrogen agent.

Topics: Alanine Transaminase; Alcohol Drinking; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bezafibrate; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Chemotherapy, Adjuvant; Cholesterol; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Estrogen Receptor Modulators; Fatty Liver; Female; Fluorouracil; Humans; Mastectomy, Segmental; Middle Aged; Radiotherapy, Adjuvant; Tamoxifen; Tomography, X-Ray Computed; Toremifene

The triphenylethylene antiestrogens, idoxifene (Idox) and toremifene (Tor), are structurally related analogues of tamoxifen (Tam) and were developed to improve the therapeutic index for advanced breast cancer patients. However, the issue of cross-resistance with Tam for these new agents is critical for clinical testing because the majority of breast cancer patients have already received or failed adjuvant Tam. The goal of this study was to determine the effectiveness of Idox as an antitumor agent in three models of Tam-stimulated breast cancer in athymic mice and compare the results with the actions of Tor and ICI 182,780 in a Tam-stimulated MCF-7 tumor model. We first compared the activities of Tam and Idox in the 17beta-estradiol (E2)-stimulated MCF-7 tumor line MT2:E2. Tam and Idox reduced E2-stimulated growth by 65-70% (week 9: P = 0.0009 for Tam, P = 0.0005 for Idox versus E2 alone). However, Tam (1.5 mg daily) and Idox (1.0 mg daily) both produced T47D breast tumors in athymic mice during 23 weeks of treatment (12 tumors/22 sites and 15 tumors/18 sites, respectively). Tam and Idox stimulated tumor growth equally in two different Tam-stimulated MCF-7 models and in a T47D model. Tor was completely cross-resistant with Tam in the MCF-7 tumor model, which implied that neither Idox nor Tor would be effective as a second-line endocrine therapy after Tam failure and may offer no therapeutic advantages over Tam as adjuvant therapies. In contrast, ICI 182,780, a pure antiestrogen currently being tested as a treatment for breast cancer after Tam failure, had no growth-stimulatory effect on the MCF-7 Tam-stimulated breast tumor line. This agent may provide an advantage as an adjuvant therapy and increase the time to treatment failure.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Resistance, Neoplasm; Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Female; Fulvestrant; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Stilbenes; Tamoxifen; Time Factors; Toremifene; Tumor Cells, Cultured

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Risk; Tamoxifen; Toremifene

Vascular endothelial growth factor (VEGF) is a major inducer of tumor angiogenesis and an important prognostic factor in breast cancer. Hypoxia is an important inducer of VEGF expression but less is known of the role of hormones in VEGF regulation. We have studied the regulation of VEGF, VEGF-B, VEGF-C, and VEGF-D mRNAs in human MCF-7 and mouse S115 breast carcinoma cells stimulated by estrogens and androgens, respectively. VEGF, VEGF-B, and VEGF-C were expressed in both cell lines, whereas VEGF-D was expressed only in S115 cells. Addition of estradiol (E2) caused a biphasic increase of VEGF mRNA in MCF-7 cells and led to accumulation of the VEGF protein in the culture medium. The VEGF-B mRNA was not affected, while a decrease occurred in VEGF-C mRNA. Similarly, testosterone upregulated the expression of VEGF mRNA in the S115 cells. Experiments with actinomycin D and cycloheximide suggested that estrogen induction of VEGF mRNA is dependent on the synthesis of new mRNA and increased mRNA half-life. The antiestrogen ICI 182.780 inhibited E2 stimulation of VEGF, suggesting that the effect was mediated by the estrogen receptor. In contrast, the antiestrogens tamoxifen and toremifene which inhibit MCF-7 cell growth in vivo and in vitro did not inhibit estrogen effect but induced VEGF mRNA expression when used alone. The antiandrogen cyprosterone acetate inhibited T induction of VEGF mRNA in S115 cells, thus suggesting that activation of androgen receptor must be involved in the increase of VEGF mRNA. Our results suggest that both estrogen and androgen stimulate the expression of VEGF by increasing gene transcription and mRNA stability. In addition, the antiestrogens tamoxifen and toremifene also increased VEGF expression. Estrogen and androgen induction of VEGF expression and promotion of new vessel formation may be an important paracrine mechanism by which these hormones contribute to the early phase of tumor growth of hormonal cancer.

Topics: Animals; Breast Neoplasms; Cycloheximide; Cyproterone Acetate; Endothelial Growth Factors; Estradiol; Estrogen Antagonists; Female; Humans; Lymphokines; Mammary Neoplasms, Experimental; Mice; Neoplasms, Hormone-Dependent; Protein Synthesis Inhibitors; RNA, Messenger; RNA, Neoplasm; Steroids; Tamoxifen; Testosterone; Toremifene; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

A 68-year-old woman complained of obstructive jaundice 9 years after a radical mastectomy. CT scan demonstrated multiple metastasis of the liver and two coin lesions of the right lung. The biliary tract was completely obstructed at the portal fissure. Multiple liver and lung metastasis of breast cancer were diagnosed because of high CA 15/3 serum levels and normal gastrointestinal study. Following unsuccessful treatment with tamoxifen (TAM), we used toremifene (TORE) and 5'-deoxy-5-fluorouridine (5'-DFUR) followed by percutaneous transhepatic cholangiodrainage (PTCD). The biliary tract was reopening and jaundice disappeared with improvement of the general condition. Then endocrine therapy with medroxy progesterone acetate and UFT and chemotherapy with CAF (Cyclophosphamide, Adriamycin, 5-FU) were begun. A partial response (PR) was obtained with the disappearance of liver metastasis and two coin lesions of the lung 5 months after the first treatment. The effect of chemo-endocrine combination therapy continued for 5 months. Survival time from recurrence was 13 months. In our case, PR was obtained by using chemo-endocrine combination therapy, although a poor prognosis has been reported in patients with obstructive jaundice caused by multiple liver metastasis of recurrent breast cancer.

Topics: Aged; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cholestasis; Cyclophosphamide; Doxorubicin; Drainage; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Mastectomy, Radical; Medroxyprogesterone Acetate; Tamoxifen; Tegafur; Toremifene; Uracil

Two cases of metastatic breast cancer are reported in which endocrine chemotherapy with Toremifene + 5'-DFUR proved markedly effective. Case 1: A 69-year-old female. After CAF therapy as a adjuvant chemotherapy, Tamoxifen and Tegafur had been administered. At the 5th postoperative year, multiple metastases to lung and a rise in the tumor marker were found. Since the patient was not desirous of intensive chemotherapy, administration of Toremifene 120 mg/day and 5'-DFUR 800 mg/day was initiated. The patient showed PR 9 months after and achieved CR 14 months later. Case 2: A 48-year-old female. CAF therapy for a total of 6 cycles was performed as adjuvant chemotherapy. The patient was administered Tamoxifen and followed. On bone scintigrams 3.5 years after surgery, an abnormal accumulation appeared in the left sternoclavicular joint, and an infiltrative tumor mass was formed in the skin of that region. Administration of Toremifene + 5'-DFUR was initiated. After 6 months, the infiltrative mass disappeared. These findings are suggestive of the effectiveness of this combined chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Female; Floxuridine; Humans; Lung Neoplasms; Middle Aged; Remission Induction; Toremifene

A 43-year-old female underwent muscle preserving mastectomy with 6 cycles of adjuvant CMF chemotherapy for breast cancer. She developed multiple lung metastases 16 months later. The metastases were refractory to 3 cycles of CAF administration, and worsened (PD). We therefore added high-dose toremifene to her treatment. This combination therapy brought a marked decrease in the lung metastases. After 9 cycles of CAF with high-dose toremifene therapy, lung metastatic findings had almost disappeared from her chest X-ray. Following this treatment, UFT and toremifene were orally administered for maintenance therapy. Thirty-two months later at present, no increase in these lesions has been observed. High-dose antiestrogen drugs have the potential to inhibit P-glycoprotein. The combination of high-dose toremifene with CAF is potentially effective against ADM-resistant breast cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Estrogen Antagonists; Female; Fluorouracil; Humans; Lung Neoplasms; Mastectomy; Toremifene

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Consumer Product Safety; Estrogen Antagonists; Female; Humans; Research Personnel; Toremifene

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Drug Interactions; Enzyme Inhibitors; Estrogen Antagonists; Female; Hot Flashes; Humans; Letrozole; Middle Aged; Nausea; Nitriles; Postmenopause; Toremifene; Triazoles

A experimental study was reported here to clarify the chemosensitizing effect of Toremifene (Tor) on human breast cancer cell lines. MCF7, estrogen dependent adriamycin (ADM) resistant cell, and MDA-MB231, estrogen independent cell, were preincubated for 8 hours with Tor 0, 4 or 10 microM, then with ADM 0-10 micrograms/ml for one hour. After that, cells were cultured for 24 hours, and their cell cycle and growth were analyzed with flow-cytometry and MTT assay, respectively. Furthermore, the ADM concentrations of these cells were measured by high-performance liquid chromatographic assay (HPLC). Although flowcytometric analysis showed the enhancement of Gz block only in MCF7 at the ADM concentration with 5 micrograms/ml, the sensitizing effect was revealed by MTT assay, and the elevation of ADM concentration was found in HPLC assay in both cells. The chemosensitizing effect of Toremifene was observed in estrogen dependent and independent cell lines.

Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Estrogen Antagonists; Female; Humans; Neoplasms, Hormone-Dependent; Toremifene; Tumor Cells, Cultured

Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective.. In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996.. Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen.. Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Estrogen Antagonists; Female; Fluorouracil; Humans; Middle Aged; Neoplasm Recurrence, Local; Toremifene

To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial.. In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward.. The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders.. According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Ovary; Postmenopause; Sex Hormone-Binding Globulin; Thyrotropin-Releasing Hormone; Toremifene

The new antiestrogen toremifene (TOR) is currently on the market for the treatment of advanced breast cancer in postmenopausal women. TOR is known to exhibit a similar efficacy profile as tamoxifen (TAM) in the treatment of advanced breast cancer and there are studies to suggest that the beneficial side effects of TAM on bone and blood lipids are also achieved with TOR. However, the data concerning the action of TOR on the endometrium is sorely lacking. In light of the estrogenic effect of TAM on the uterus and the 2-3-fold increased incidence in endometrial carcinoma detected in patients receiving TAM therapy, it is imperative to investigate the effect of TOR on endometrial carcinoma. We compared the actions of TAM and TOR on the EnCa101 human endometrial tumor model and find that both antiestrogens have similar growth stimulatory effects. To investigate a potential mechanism of antiestrogen-stimulated endometrial tumor growth, we have examined known activators of the AP-1 signal transduction pathway, the protein kinase C (PKC) family of isozymes, in the EnCa101 human endometrial tumor model. We find that increased PKC isozyme expression correlates with hormone-independent breast cancer as well as antiestrogen-stimulated endometrial cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Carcinoma; Cell Division; Endometrial Neoplasms; Estrogen Antagonists; Female; Humans; Protein Kinase C; Tamoxifen; Toremifene; Tumor Cells, Cultured

Previous studies have suggested that multiple myeloma (MM) cells express estrogen receptors (ER). In the present study, we characterized the effects of estrogen agonists and antagonists (anti-estrogens [AE]) on growth of MM cell lines and MM patient cells. In addition to antagonizing estrogen binding to ER, AE can trigger apoptosis. Hence, we also determined whether estrogens or AE altered MM cell survival. Immunoblotting showed that ER-alpha is expressed in 4 of 5 MM cell lines (ARH-77, RPMI 8226, S6B45, and U266, but not OCI-My-5 cells), as well as in freshly isolated MM cells from 3 of 3 patients. 17beta-estradiol (E2) did not significantly alter proliferation of MM cell lines or MM patient cells. In contrast, two structurally distinct AE, tamoxifen (TAM) and ICI 182,780 (ICI), significantly inhibited the proliferation of all 5 MM cell lines and MM cells from 2 of 2 patients (IC50, 2 to 4 micromol/L). Proliferation of these cell lines was also inhibited by the hydroxylated TAM derivative, 4-hydroxytamoxifen (4HTAM), although this derivative was less potent than TAM (IC50, 3 to 25 micromol/L). In contrast, the dehalogenated TAM derivative toremifene (TOR) did not inhibit MM cell proliferation. We next examined the effects of these agents on MM cell survival. TAM, ICI, and, to a lesser extent, 4HTAM and TOR triggered apoptosis in both ER-alpha-positive as well as ER-alpha-negative MM cell lines and patient MM cells, evidenced both by fluorescence-activated cell sorting (FACS) analysis using propidium iodide staining and the TUNEL assay. TAM-induced growth inhibition and apoptosis of ER-alpha-positive S6B45 MM cells was not blocked by coculture with excess E2. TAM-induced apoptosis of S6B45 MM cells was also unaffected by addition of exogenous interleukin-6. Importantly, both the inhibition of MM cell proliferation and the induction of MM cell apoptosis were achieved at concentrations of TAM (0.5 and 5.0 micromol/L) that did not significantly alter in vitro growth of normal hematopoietic progenitor cells. Similar plasma levels of TAM have been achieved using high-dose oral TAM therapy, with an acceptable toxicity profile. These studies therefore provide the rationale for trials to define the utility of AE therapy in MM.

Topics: Apoptosis; Breast Neoplasms; Cell Division; Cell Survival; Coloring Agents; Estradiol; Estrogen Antagonists; Flow Cytometry; Fulvestrant; Hematopoietic Stem Cells; Humans; Immunoblotting; Multiple Myeloma; Propidium; Receptors, Estrogen; Tamoxifen; Toremifene; Tumor Cells, Cultured

Toremifene (TOR) is a new antiestrogenic agent, a triphenylethylene derivative that was developed as an alternative to tamoxifene (TAM). TOR has been observed to be more effective than TAM with milder toxicity at high doses. We examined the in vitro combination-effect of TOR with cyclophosphamide, adriamycin, 5-fluorouracil and three drug mixture (CAF) on the growth of various human mammary carcinomas. The combination shows a semi-additive or additive growth inhibitory effect on all estrogen positive cells used here except one cell line. In particular, the additive or synergic combination-effect was observed on TAM resistant cells. Furthermore, TOR exhibits a chemosensitizing activity in ADR-resistant cells by expressing P-glycoprotein coded by MDR-1 (multidrug resistance gene). The chemosensitizing activity is dose-dependent of TOR. As described above, the combination of TOR with CAF shows more than a semi-additive effect in this experiment. In conclusion, the addition of high-dose TOR to CAF therapy might be useful for advanced/recurrent breast cancer.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Division; Cyclophosphamide; Doxorubicin; Drug Synergism; Estrogen Antagonists; Female; Fluorouracil; Humans; Toremifene; Tumor Cells, Cultured

Previous studies have revealed that protein kinase C (PKC) is responsible for malignant progression. In the present study, we investigated the potent inhibitory effects of an antiestrogen, toremifene, on PKC-mediated cellular adhesion. A phorbol ester, phorbol 12-myristate 13-acetate (PMA), significantly enhanced alpha2beta1 integrin-dependent adhesion of MCF-7 breast carcinoma cells. This PMA-induced adhesion was partially inhibited by incubating cells with toremifene prior to PMA exposure in a time- and dose-dependent manner. FACS analysis demonstrated that the PMA-induced alpha2beta1-dependent cellular adhesion was accompanied with elevated expression of alpha2beta1+integrin subunit on the cell surface. However, toremifene did not affect the elevated expression levels of these integrins but rather the avidity of alpha2beta1 integrin. We concluded that toremifene inhibited cellular adhesion activated by PMA, probably through mechanism which inhibits PKC.

Topics: Breast Neoplasms; Carcinogens; Carcinoma; Cell Adhesion; Enzyme Repression; Estrogen Antagonists; Humans; Protein Kinase C; Tetradecanoylphorbol Acetate; Toremifene; Tumor Cells, Cultured

Tamoxifen has been shown to promote the growth of human endometrial tumors implanted in athymic mice, and it has been associated with a twofold to threefold increase in endometrial cancer. Toremifene, a chlorinated derivative of tamoxifen, and ICI 182,780, a pure antiestrogen, are two new antiestrogens being developed for the treatment of breast cancer. The effects of these drugs on endometrial cancer are currently unknown. Our objective was to evaluate the effects of toremifene and ICI 182,780 on the growth of human endometrial cancer in athymic mice.. Athymic, ovariectomized mice were implanted with human endometrial tumors and treated with estrogen, tamoxifen, or the new antiestrogens.. The effects of tamoxifen and toremifene on the growth of either tamoxifen-stimulated or tamoxifen-naive endometrial tumors in athymic mice were not substantially different. ICI 182,780 inhibited the growth of tamoxifen-stimulated endometrial cancer, in both the presence and the absence of estrogen.. Toremifene and tamoxifen produce identical effects in our endometrial cancer models. Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer. In contrast, ICI 182,780 inhibited tamoxifen-stimulated endometrial cancer, both in the presence and in the absence of estrogen, suggesting that this drug may be safe with regard to the endometrium, even if it is used following tamoxifen, and that it may not result in an increased incidence of endometrial cancer. Indeed, it is even possible that ICI 182,780 may prove useful as an adjuvant agent in early stage endometrial cancer.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Disease Models, Animal; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Mice; Mice, Nude; Ovariectomy; Tamoxifen; Toremifene

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Receptors, Estrogen; Toremifene

The antiestrogen tamoxifen is known to cause liver cancer in rats. This may be due to the formation of abundant DNA adducts in rat liver. A likely precursor to some of the tamoxifen adducts in rats is alpha-hydroxytamoxifen. It is not clear whether the rat data are relevant to human exposure. In the present study, we show that one of the major metabolites in humans reacts with double-stranded DNA in vitro in the absence of any metabolizing enzymes or activating chemicals. At least two distinct adduct spots resulting from 4-hydroxy-N-desmethyltamoxifen (metabolite Bx) were detected by 32P postlabeling and thin layer chromatography. The adduct level increases dramatically when metabolite Bx is irradiated with UV light to fuse into a phenanthrene ring system. 4-hydroxy-N-desmethyltoremifene, which differs from Bx by a single chlorine atom, forms fewer DNA adducts without irradiation but similar amounts after irradiation. These results suggest that the chlorine atom may interfere with drug-DNA interactions which facilitate adduct formation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chromatography, Liquid; DNA Adducts; Female; Humans; In Vitro Techniques; Liver Neoplasms; Tamoxifen; Toremifene; Ultraviolet Rays

Topics: Antineoplastic Agents, Hormonal; Breast; Breast Diseases; Breast Neoplasms; Bromocriptine; Contraceptive Agents, Female; Diagnosis, Differential; Drug Therapy, Combination; Female; Hormone Antagonists; Humans; Mammography; Plant Extracts; Toremifene; Treatment Outcome

Two cases of recurrent breast cancer, for which combined therapy using toremifene and oral chemotherapeutic agents were effective, are reported. In case 1, high-dose toremifene (120 mg/day) and 5'-DFUR were administered to a forty-seven-year-old woman with lung metastasis of estrogen-receptor positive breast cancer, who had been previously treated with polychemotherapy and tamoxifen. A complete response was obtained after six months of treatment and this condition has remained for longer than one year. In case 2, a fifty-year-old woman developed liver and lung matastasis of breast cancer with increased tumor marker levels. Forty mg/day of toremifene and oral cyclophosphamide was started and transarterial embolization of the hepatic artery using lipiodol, adriamycin and mitomycin C was performed. Both hepatic and pulmonary metastasis disappeared, and the tumor maker level was normalized one month later. No regrowth of the tumors has been observed for more than six months. The chemosensitizing effect of toremifene might be responsible for the favorable effects on these matastases of breast cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Female; Floxuridine; Humans; Lung Neoplasms; Middle Aged; Mitomycin; Remission Induction; Tamoxifen; Toremifene

Oestrogen has previously been shown to downregulate the expression of ERBB2 oncogene in human breast cancer cells, which contain a normal non-amplified ERBB2 gene. However, amplified ERBB2 seems to escape from hormonal regulation. We studied shedding of the extracellular domain (ectodomain, ECD) of the ERBB2 encoded protein in BT-474 human breast cancer cells treated with oestrogen or anti-oestrogen. Oestrogen-responsiveness of these cells has been previously demonstrated by stimulation of cell growth and expression of pS2, a marker gene known to be regulated by oestrogen receptor at transcriptional level. The concentration of the soluble ECD in the culture medium was increased by the anti-oestrogen toremifene as a function of time. In contrast, the level of ERBB2 mRNA and protein in cell lysates was not stimulated, but was transiently suppressed by toremifene. In the presence of oestrogen, the level of ECD remained low. The increased shedding of ECD in the presence of toremifene, without parallel change in ERBB2 transcripts (4.8 and 2.3 kb) and in cellular ERBB2 protein level, suggests that toremifene specifically contributes to the shedding of the ERBB2 ectodomain. These results show that shedding of ECD is an additional level of regulation of ERBB2 by the anti-oestrogen toremifene. This may contribute to resistance to growth inhibition by anti-oestrogens of breast cancers which overexpress ERBB2.

Topics: Blotting, Northern; Breast Neoplasms; Cell Division; Culture Media, Conditioned; Estrogen Antagonists; Extracellular Space; Female; Gene Expression; Humans; Immunoblotting; Receptor, ErbB-2; RNA, Messenger; RNA, Neoplasm; Toremifene; Tumor Cells, Cultured

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Drugs, Investigational; Estrogen Antagonists; Female; Humans; Lavandula; Male; Neoplasms; Oils, Volatile; Ovarian Neoplasms; Piperidines; Plant Oils; Plants, Medicinal; Prostatic Neoplasms; Raloxifene Hydrochloride; Retinoids; Tamoxifen; Toremifene

To explore the mechanism(s) by which antiestrogens may protect against the development of cardiovascular disorders, we measured the production of vasodilatory, antiaggregatory prostacyclin (PGI2) and that of vasoconstrictive, proaggregatory thromboxane A2 (TxA2) before and after 6 months' use of antiestrogens in postmenopausal patients after operation for stage II breast cancer (n = 38). Urine samples were assayed by high performance liquid chromatography and radio-immunoassays for 2,3-dinor-6-ketoprostaglandin F1 alpha (= metabolite of PGI2, dinor-6-keto) and for 2,3-dinor-thromboxane B2 (= metabolite of TxA2, dinor-TxB2). In addition, in 35 of these 38 patients we assayed the capacity of platelets to produce thromboxane A2 during standardized blood clotting. The 4 patients using low-dose aspirin had low thromboxane production, and were excluded from further analysis of the data. An antiestrogen regimen consisting either of tamoxifen (n = 15) or of toremifene (n = 19) caused no changes in production of PGI2 or TxA2, or in their ratio, and in this regard, these antiestrogens behaved similarly. Hypertensive patients (n = 7) using different anti-hypertensive agents were characterized by reduced urinary out-put of dinor-6-keto (18.5 +/- 6.1 vs 35.5 +/- 18.5 ng/mmol, mean +/- SD, p < 0.05) and reduced platelet capacity to produce TxA2 (62.6 +/- 67.8 vs 134.6 +/- 75.6 ng/mL, p < 0.05). The patients (n = 15) who had used estrogen replacement therapy (ERT) up until diagnosis of breast cancer showed reduced dinor-TxB2 excretion (15.5 +/- 12.7 vs 29.9 +/- 20.9 ng/mmol, p < 0.05) before initiation of antiestrogens, and elevated dinor-6-keto output during the antiestrogen regimen (32.4 +/- 21.2 vs 22.7 +/- 8.7 ng/mmol, p = 0.07). Smokers (n = 6) had elevated dinor-TxB2 output before and during antiestrogen use. Thus we conclude that the cardiovascular protection provided by an antiestrogen regimen is unlikely to be mediated through vaso- and platelet active PGI2 and TxA2.

Topics: Aged; Breast Neoplasms; Epoprostenol; Estrogen Antagonists; Estrogens; Female; Humans; Hypertension; Menopause; Middle Aged; Molecular Structure; Smoking; Tamoxifen; Thromboxane A2; Toremifene

Acquired tamoxifen (TAM) resistance is supposed to be the major cause of hormone therapy failure in estrogen receptor (ER)-positive breast cancer patients. Toremifene (TOR), a chlorinated TAM-related compound, has been found to be more effective and less toxic than TAM. Moreover 4-hydroxy-toremifene (OH-TOR), like 4-hydroxy-tamoxifen (OH-TAM), is the most effective metabolite in human. To better understand the relative role of TAM, TOR, OH-TAM, and OH-TOR, singly or in combination, we studied their effect on MCF7, ZR-75.1, and T47D cell lines, which, despite their positive receptor status, have a different responsiveness to estradiol and antiestrogenic compounds. The results may be summarized as follows; in MCF7 cells, all compounds, singly or in association, showed an inhibitory effect; ZR75.1 cells were resistance to TAM and OH-TAM, but partially sensitive to TOR and OH-TOR; in T47D cells, all compounds displayed their estrogenic activity and induced cell growth. These result suggest the inefficacy of these triphenylethylene derivatives as a hormone treatment even when given in a simultaneous or sequential combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Division; Estrogen Antagonists; Female; Humans; Receptors, Estrogen; Tamoxifen; Toremifene; Tumor Cells, Cultured

The author established three variant cell lines which were proliferative in the serum-free medium. These three cell lines were derived from MCF-7, a human breast cancer cell line. These 3 variants (MCF-S1, MCF-S2 and MCF-S3) proliferate estrogen (E2)-dependently, but the amounts of E2 receptor and progesterone receptor in the cells are different from each other among the variants. The author compared the effects of hormonal therapeutic agents, tamoxifen (TAM), 3-hydroxytamoxifen (3-OH-TAM), toremifene (TORE), and medroxyprogesterone acetate (MPA) on MCF-7 and the established variant cells. Although TAM showed little effect on the growth of any cell lines in the absence of E2, it considerably inhibited the growth of MCF-S2 cells and MCF-7 cells in the presence of 10(-10)M E2. TORE also provided no inhibitory effect at less than 10(-7)M concentration on any cells in the absence of E2, but it dose-dependently inhibited DNA synthesis of MCF-S2 cells in the presence of E2. On the other hand, although 3-OH-TAM markedly inhibited the growth of any cell lines at a concentration of less than 10(-6)M in the presence of E2, it dose-dependently inhibited the DNA synthesis of any cell lines in the absence of E2, and the effect was remarkable in the case of MCF-S2 or MCF-S3. MPA showed a tendency to increase the proliferation of any cells in the absence of E2, conversely in the presence of E2, and it slightly inhibited DNA synthesis at concentrations of over 10(-8)M. These results suggest that the effect of hormonal agents on breast cancer cells may depend on either hormonal levels or the characteristics of the cancer cells. The effect of the hormonal agents are diverse, and a hormonal agent which does not work well on one cancer cell population may work well on another population.

Topics: Breast Neoplasms; Cell Division; Female; Humans; Medroxyprogesterone Acetate; Mutation; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Toremifene; Tumor Cells, Cultured

Fifty patients with advanced breast cancer refractory to prior tamoxifen therapy were assigned to investigational treatment with high-dose toremifene administered 120 mg orally twice a day. Treatment was generally well tolerated. The majority (80%) of the patients had no side effects, and among the remaining 10 patients reported side effects were mostly mild and/or transient. Two objective tumor responses were observed: one complete response (CR), duration 6.2 months, and one partial response (PR), duration 8 months. The response rate was thus 4% (95% CI: 0.5 to 14%). In addition 3 patients experienced a mixed response, some metastatic sites responding, while at other sites disease progressed; 22 patients had disease stabilization for > 2 months. A subset analysis disclosed that a small subgroup of patients, including 7 patients in this study, who had achieved CR at some of the sites during preceding tamoxifen therapy, experienced a long progression-free time during high dose toremifene treatment. The median time to progression in this subgroup of patients was 9.4 months (95% CI: 3.8 to 9.4) as opposed to 2.1 months (95% CI: 2.0 to 2.8) for all the remaining 43 patients, which is a significant decrease in disease progression (p < 0.03). Such results reveal that although this kind of second-line hormonal treatment with high dose toremifene cannot be recommended for all tamoxifen failures, there might be a subset of patients, i.e. those who achieve CR in some lesion during tamoxifen therapy, who benefit from this type of treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Resistance; Feasibility Studies; Female; Humans; Middle Aged; Recurrence; Tamoxifen; Toremifene; Treatment Outcome

The ability of the anti-oestrogens tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites to modify doxorubicin (dox) toxicity to intrinsically resistant and multidrug resistant cell lines was compared, using human breast and lung cancer, and Chinese hamster ovary cell lines. The anti-oestrogens significantly enhanced dox toxicity to multidrug resistant, P-glycoprotein-positive cell lines, but did not affect toxicity to intrinsically resistant, P-glycoprotein-negative cells. Modification was observed at clinically achievable anti-oestrogen concentrations. Toremifene and tamoxifen would therefore appear to be good candidates for in vivo studies as MDR modulating agents in selected patients with P-glycoprotein-positive tumours.

Topics: Animals; Antibodies, Monoclonal; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Carrier Proteins; Cell Division; CHO Cells; Cricetinae; Doxorubicin; Drug Interactions; Drug Resistance; Drug Screening Assays, Antitumor; Epitopes; Estrogen Antagonists; Humans; Lung Neoplasms; Membrane Glycoproteins; Tamoxifen; Toremifene; Tumor Cells, Cultured

The clinical study of compounds that modulate multidrug resistance has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at the level of the tumor cell. Previously, toremifene has been shown to be well tolerated clinically and to sensitize multidrug resistant cells to the effects of cytotoxic chemotherapeutic agents. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-MB-A1 human breast cancer cells were studied using flow cytometric analysis and growth inhibition assays. Cell cycle kinetics of MDA-MB-A1 cells were not significantly affected by treatment with either toremifene, N-desmethyltoremifene, Toremifene IV or vinblastine alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene or one of its metabolites for 72 hours followed by treatment for one hour with vinblastine caused a marked shift of cells to G2/M, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of vinblastine alone on vinblastine-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-MB-A1 cells to vinblastine. This chemosensitizing effect of toremifene was accompanied by an enhanced inhibition of cell growth by vinblastine. The chemosensitizing effects of toremifene or one of its metabolites in combination with cytotoxic chemotherapy can be effectively monitored by flow cytometry, an easily accessible technique.

Topics: Breast Neoplasms; Cell Cycle; Cell Division; Drug Resistance; Drug Synergism; Female; Flow Cytometry; Humans; Toremifene; Tumor Cells, Cultured; Vinblastine

Antiestrogens inhibit the stimulative effects of estrogens on breast cancer growth, but the mechanism(s) by which they trigger tumor regression are not completely understood. Growth retardation and tumor regression can be achieved by enhanced cell death and/or arrested cell proliferation.. Our aim was to investigate the effect of a new antiestrogen, toremifene, on human breast cancer cells grown either in culture or as tumors in nude mice.. The growth and morphology of in vitro cultured cells of the human breast cancer cell line MCF-7 were monitored by time-lapse video. MCF-7 cells and ZR-75-1 human breast cancer cells were grown as tumors in nude mice and subsequently examined by electron microscopy. The integrity of DNA isolated from these cells was determined by standard gel electrophoretic techniques. Northern blot hybridization analysis was used to determine the steady-state levels of the mRNAs for testosterone-repressed prostatic message-2 (TRPM-2), tumor growth factor beta-1 (TGF beta 1), and pS2 (a small, cysteine-rich protein of unknown function).. Time-lapse video microscopy of the cell cultures indicated that treatment with 7.5 microM toremifene for 3 days caused approximately 60% of the cells to exhibit morphologic characteristics typical of cells undergoing programmed death, or apoptosis. The number of mitoses gradually decreased to zero over a 3- to 4-day period. Estrogen withdrawal for the same length of time resulted in an approximately equal number of apoptoses and mitoses. These changes were not associated with the pattern of DNA fragmentation, detectable as ladders in agarose gels, that is characteristic of the DNA of cells undergoing apoptosis. Elevated levels of TRPM-2 and TGF beta 1 mRNAs were observed in in vitro or in vivo grown tumor cells treated with 5-10 microM toremifene. Elevated levels of TRPM-2, but not TGF beta 1, mRNA were observed in the tumor cells after estrogen withdrawal. The steady-state level of pS2 mRNA in the tumor cells dropped in response to either toremifene treatment or estrogen withdrawal.. Toremifene causes growth inhibition of estrogen-sensitive breast cancer cells by inducing some cells to undergo apoptosis and by inhibiting other cells from entering mitosis. The higher than normal amounts of TRPM-2 and TGF beta 1 protein that would likely result from the elevated levels of TRPM-2 and TGF beta 1 mRNAs measured in these cells after toremifene treatment may have an important role in the growth inhibition process.. Apoptosis as an active, targeted process provides a potential new therapeutic approach for treating breast cancer.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Division; Clusterin; Female; Gene Expression; Glycoproteins; Humans; Mice; Mice, Nude; Molecular Chaperones; Neoplasm Proteins; Neoplasm Transplantation; RNA, Messenger; RNA, Neoplasm; Toremifene; Transforming Growth Factor beta; Tumor Cells, Cultured

Toremifene is currently being evaluated as a chemosensitizing agent in doxorubicin-resistant patients. Although concentrations of > 2 microM reverse resistance in vitro, target concentrations required to reverse multidrug resistance (MDR) in vivo may be highly influenced by variables such as protein binding in serum. We examined the effects of high serum concentrations on the cellular accumulation of toremifene in an MDR MDA-MB-A-1 human breast-cancer cell line. We then examined the cellular accumulation of doxorubicin at various toremifene concentrations in 5% - 100% serum. We also measured the concentrations of toremifene and its major metabolites in plasma specimens obtained from two patients receiving 360 mg/day for 5 days in a phase I study. Our results show that (1) high serum concentrations decrease toremifene accumulation, (2) toremifene concentrations of < or = 2.5 microM enhance doxorubicin accumulation, and (3) patients achieve plasma toremifene concentrations of 10-15 microM following doses of 360 mg/day x 5 days. Our findings suggest that in vivo toremifene concentrations well above those used to reverse resistance in vitro are required to overcome the effect of high serum-protein binding.

Topics: Blood Proteins; Breast Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Female; Humans; Protein Binding; Tamoxifen; Toremifene; Tumor Cells, Cultured

NK622, a novel tamoxifen(TAM) analog with nonsteroidal structure is an antiestrogenic drug with less toxicity compared with that of TAM. We studied the in vivo antitumor activity against human breast cancer xenografts in nude mice. NK 622 significantly inhibited the growth of estrogen-dependent Br-10 breast cancer but not inhibited the growth of estrogen-independent MC-2-JCK and MC-5-JCK when orally administered once daily for 14 days at the maximum tolerated dose (200mg/kg/day). The dose of NK622 in animal studies was calculated by measuring plasma level in patients receiving 40 mg/body/day oral treatment and clinically equivalent dose (CED) was determined. At the calculated CED, NK622 significantly inhibited the growth of Br-10. These results indicate that NK622 is a promising drug comparable to TAM because of the growth inhibition of estrogen-dependent breast cancers.

Topics: Animals; Breast Neoplasms; Cell Division; Estrogens; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Toremifene

In this study we describe the effects of tamoxifen, toremifene and their 4-hydroxy and N-desmethyl metabolites on the toxicity of a range of drugs to human breast and lung cancer and to Chinese hamster ovary cell lines, determined using a tetrazolium-based semi-automated colorimetric assay. Vinblastine resistance was completely abolished in an mdr1-transfected lung cancer cell line (S1/1.1), indicating that P-glycoprotein-mediated multidrug resistance can be fully reversed by anti-oestrogens. A substantial (14- to 39-fold) enhancement of vinblastine toxicity to highly multidrug-resistant (MCF-7Adr) cells expressing P-glycoprotein was also observed in the presence of tamoxifen, toremifene and their metabolites, while m-amsacrine, cisplatin and melphalan toxicity was unaffected.

Topics: Amsacrine; Animals; Breast Neoplasms; Cell Survival; CHO Cells; Cisplatin; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance; Humans; Lung Neoplasms; Melphalan; Tamoxifen; Toremifene; Tumor Cells, Cultured; Vinblastine

The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50 = less than 0.1 microgram/ml MDA 231; IC 50 = 100 micrograms/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Breast Neoplasms; Chromatography, High Pressure Liquid; Doxorubicin; Drug Interactions; Drug Resistance; Female; Flow Cytometry; Humans; Receptors, Estrogen; Tamoxifen; Toremifene; Tumor Cells, Cultured

Monitoring effective antiestrogenic activity of the triphenylethylenes in patients with breast cancer is usually determined by the duration of response. The pharmacokinetics of toremifene and tamoxifen have been shown to be highly variable but patient specific. In the present study, we developed a method to accurately assess the antiestrogenic activity of these agents using plasma specimens, cell culture, and cell cycle measurements. Plasma specimens (4-5mls) obtained from patients receiving toremifene (360mg/day for 5 days in a phase I trial) or tamoxifen (20mg/day) were extracted and reconstituted in tissue culture media (4-5mls), and growth inhibition was determined in estrogen responsive MCF-7 cells. Additionally, plasma specimens were quantified for toremifene or tamoxifen concentrations using HPLC. Growth inhibition of plasma specimens containing either toremifene or tamoxifen and their metabolites was also examined. Cell cycle measurements were determined following in vitro exposure with flow cytometric techniques. Our results show that a dose-response relationship exists between cell growth inhibition and cell cycle measurements for human plasma with added toremifene or tamoxifen, and also for human plasma specimens containing drug and its metabolites after treatment. Our antiestrogenic bioassay can address clinical research problems such as patient-specific pharmacokinetics, dosing compliance, and acquired antiestrogen resistance.

Topics: Breast Neoplasms; Cell Division; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Estrogen Antagonists; Female; Flow Cytometry; Humans; Tamoxifen; Toremifene; Tumor Cells, Cultured

The clinical study of compounds that modulate multidrug resistance in cancer cells has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at a cellular level. The non-steroidal triphenylethylene toremifene is well tolerated clinically and can sensitize multidrug resistant cells to the effects of doxorubicin in vitro. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-A1 human breast cancer cells were studied using flow cytometric analysis. Cell cycle kinetics of MDA-A1 cells were not significantly affected by treatment with either toremifene or doxorubicin alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene for 70 hours followed by treatment with doxorubicin caused a marked shift of cells to G2, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of doxorubicin alone on doxorubicin-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-A1 cells to doxorubicin. This chemosensitizing effect of toremifene was accompanied by an enhanced accumulation of doxorubicin in MDA-A1 cells (+110% after 70 hours pre-incubation with toremifene), and by a depression in protein kinase C activity in MDA-A1 cells that was maximal following 70 hours incubation with toremifene. Flow cytometry is a widely available technique that might be applied clinically to monitor at the cellular level the chemosensitizing effects of toremifene and other modulators of multidrug resistance.

Topics: Breast Neoplasms; Cell Cycle; Doxorubicin; Drug Resistance; Flow Cytometry; Humans; Protein Kinase C; Receptors, Estrogen; Toremifene; Tumor Cells, Cultured

Amplification and enhanced expression of the erbB2/HER-2/neu gene has been associated with an increased growth rate and poor prognosis of human breast cancer. We have studied the relationship between erbB2 expression and the regulation of cell growth by estrogen and anti-estrogens in the human breast cancer cell line ZR-75-1 in vitro and in athymic nude mice, pS2 being used as a marker gene for estrogen-stimulated gene expression. Only low amounts of erbB2 mRNA were seen in the cells grown in vitro in the presence of estrogen which stimulated the cells to proliferate rapidly and induced the expression of pS2 mRNA. Upon hormone withdrawal, erbB2 mRNA and protein increased, while pS2 mRNA declined to an undetectable level and cell proliferation slowed down. Opposite but more rapid changes were observed upon estrogen addition. The anti-estrogens toremifene and tamoxifen inhibited estrogen induction of pS2 expression, down-regulation of erbB2 expression and proliferation of the ZR-75-I cells in a concentration-dependent manner. Similar results were obtained in nude mice. ZR-75-I cells formed tumors only in mice carrying estrogen pellets. In these tumors little erbB2 mRNA was seen. Concomitant administration of toremifene or tamoxifen increased erbB2 mRNA and abolished pS2 mRNA. Our results show that enhanced expression of erbB2 is associated with hormone deprivation and growth arrest of the estrogen-dependent breast cancer cell line ZR-75-I. Thus, in mammary epithelial cells, erbB2 may have important estrogen-regulated functions which are not related to cell proliferation.

Topics: Animals; Breast Neoplasms; Cell Division; Cell Line; Estradiol; Estrogen Antagonists; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogenes; Receptor, ErbB-2; RNA, Messenger; Tamoxifen; Toremifene; Transplantation, Heterologous

The effects of anti-estrogen therapy (tamoxifen or toremifene) on in vitro lymphocyte functions were investigated in breast cancer patients. We found that the amount of DNA synthesis, with or without PWM stimulation, was decreased in all cancer patient groups compared to normal controls. The number of Ig-secreting cells was enhanced in unstimulated peripheral blood lymphocyte cultures but decreased in PWM-stimulated cultures. This occurred in all cancer patient groups investigated, with or without anti-estrogen therapy, as compared to healthy controls. On the other hand, subsequent samples with two-month intervals showed that anti-estrogens can increase PFC responses and inhibit DNA synthesis of peripheral blood lymphocytes in more than half of the patients. Interestingly, the enhancing dexamethasone effect, which usually causes an increase in the number of Ig-secreting cells in PWM-stimulated cultures, was also seen more often in anti-estrogen-treated patients. These results suggest that anti-estrogens may have immunoregulatory effects in vivo.

Topics: Breast Neoplasms; Dexamethasone; DNA; Estrogen Antagonists; Female; Humans; Immunoglobulins; Lymphocytes; Pokeweed Mitogens; Tamoxifen; Toremifene

The effects of toremifene, a new antiestrogenic drug, were investigated in vitro on the exponentially growing human mammary carcinoma cell line MCF-7. The drug effects were monitored by serial cell counts and DNA flow cytometry. The inhibitory effect of toremifene on MCF-7 became greater as the drug concentration was increased from 1 microM to 10 microM. At 5 microM toremifene induced a large decrease in the relative percentages of S- and G2/M-phase cells, and an increase in the amount of cell debris, indicating increased cell death. After withdrawal of the drug the mammary cancer cells resumed logarithmic growth similar to that of control cells. The effects caused by toremifene were similar to those caused by tamoxifen both in quality and quantity.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Count; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Tamoxifen; Toremifene; Tumor Cells, Cultured

Estrogens and anti-estrogens enhance the number of immunoglobulin (Ig)-secreting cells in pokeweed mitogen (PWM)-stimulated lymphocyte cultures. Lymphocytes from patients who have received anti-estrogen therapy show similar enhancement of Ig-secreting cells after PWM stimulation. In this study the effect of anti-estrogen (toremifene) therapy on serum immunoglobulin (IgA, IgM, IgG) levels in breast cancer patients was investigated. Serum Ig levels were followed up to two years after or during the therapy. An unexpected finding was that the Ig levels decreased during the follow-up period. This decrease was seen in patients who responded to the therapy as well as in those who did not.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Lymphocyte Activation; Lymphocytes; Pokeweed Mitogens; Receptors, Estrogen; Tamoxifen; Toremifene

We have previously shown that transforming growth factor beta (TGF beta) is a hormonally regulated negative growth factor in estrogen responsive MCF-7 human breast cancer cells. We have now compared the antiestrogens tamoxifen, droloxifene (3-hydroxytamoxifen), and toremifene in their ability to induce the secretion of autoinhibitory TGF beta by MCF-7 cells. The main results are as follows: induction of TGF beta secretion by droloxifene is about two to three times higher than by identical concentrations of tamoxifen or toremifene. A 5-10 times higher concentration of tamoxifen or toremifene than droloxifene is necessary to reach a similar induction of TGF beta secretion. In contrast to tamoxifen, intermittent application of droloxifene is as effective as continuous treatment in inducing TGF beta secretion. We conclude from these data that TGF beta proteins represent markers of antiestrogen action and might also play a pivotal role in their mechanism of action. Droloxifene is a more effective inducer of TGF beta and a more potent growth inhibitor for estrogen responsive human breast cancer cells than tamoxifen and toremifene in vitro. Therefore, droloxifene might also possess a higher antiestrogenic potential in treatment of human breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Estrogen Antagonists; Female; Humans; Tamoxifen; Toremifene; Transforming Growth Factor beta; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Tamoxifen; Toremifene

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Estrogen Antagonists; Humans; Tamoxifen; Toremifene

Topics: Animals; Breast Neoplasms; Cholesterol; Estrogen Antagonists; Female; Humans; Tamoxifen; Toremifene

The antiproliferative action of the antiestrogen toremifene and recombinant human interferon-alpha 2a (IFN-alpha 2a) were examined on human breast cancer cell lines grown in culture and in the athymic mouse. Solid tumors grew from an inoculation of a 99:1 ratio of hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells without estrogen administration. However, estradiol supplementation significantly increased the rate of tumor growth. The daily administration of 1.35 x 10(6) U of recombinant human IFN-alpha 2a resulted in a marked rduction of tumor growth in both estradiol-treated and non-treated mice. Toremifene administration (130 micrograms/day from a sustained release preparation) markedly inhibited estradiol stimulation of mouse uterine weight and partially reduced estradiol-stimulated tumor growth. The combination of IFN-alpha 2a (1.35 x 10(6) u/day) with toremifene (130 micrograms/day) reduced estradiol-stimulated growth much below that of toremifene alone but not below that seen with interferon alone. Toremifene (10(-10)-10(-6) M) did not inhibit the growth of hormone-independent MDA-MB-231 breast cancer cells in vitro whereas it did inhibit the growth of hormone-dependent MCF-7 cells in phenol red containing media. IFN-alpha 2a (1-10,000 u) inhibited the growth of both MCF-7 and MDA-MB-231 cells in culture; however, MCF-7 cells were approximately 10-fold more sensitive to interferon inhibition. This was consistent with the MCF-7 cells showing a greater sensitivity to interferon than MDA-MB-231 cells in the induction of 2'5'-oligoadenylate synthetase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Breast Neoplasms; Combined Modality Therapy; Drug Screening Assays, Antitumor; Estrogen Antagonists; Estrogens; Humans; Interferon alpha-2; Interferon Type I; Interferon-alpha; Mice; Mice, Nude; Neoplasms, Hormone-Dependent; Recombinant Proteins; Tamoxifen; Toremifene; Tumor Cells, Cultured

Fourteen postmenopausal women with estrogen-receptor positive advanced breast cancer and no prior cytostatic treatment received 20 mg toremifene daily as a single dose after a loading dose (120----60----60 mg) for the first 3 days. All were evaluable and had undergone at least 6 weeks' treatment. Results were: no complete remissions (CR), 3 partial remissions (PR), 8 no change (NC) and 3 cases of progressive disease (PD). Three patients had mild side effects: nausea, insomnia, sweating and arm pain.

Topics: Aged; Blood Sedimentation; Breast Neoplasms; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Female; Humans; Middle Aged; Tamoxifen; Toremifene

Toremifene, an antiestrogenic drug administered at three dose levels (60, 120, and 300 mg/day) was investigated in 17 postmenopausal patients with advanced breast cancer previously treated with hormonal and/or cytostatic therapy. The drug proved to be well tolerated at all dose levels without any serious side effects even on prolonged administration. Neither response nor side effects have shown any dose dependency in this small group of patients.

Topics: Adult; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Estrogen Antagonists; Estrogens; Female; Humans; Middle Aged; Neoplasms, Hormone-Dependent; Receptors, Estrogen; Tamoxifen; Toremifene

Toremifene is a new antiestrogenic compound. Toremifene has definite antitumor effect in advanced breast cancer. The response rate in the present phase II study among postmenopausal women, mostly not pretreated with systemic therapy and with ER positive or not determined ER status in tumor tissue, was 11/23 (48%; 95% confidence interval 37-59%) including 6 complete responses. The toxicity profile was similar to that of tamoxifen. It is concluded that toremifene is at least as active as tamoxifen in advanced breast cancer and that a randomized study between these two antiestrogens is indicated.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Humans; Middle Aged; Tamoxifen; Toremifene

Twelve postmenopausal women with inoperable or metastatic breast cancer were given toremifene at a daily dose of 60 mg. The patients had no prior endocrine or cytotoxic therapy and further inclusion criteria were bidimensionally measurable disease, performance status above 50, expected survival of more than 3 months and estrogen receptor status positive or undetermined. Objective response [complete remission (CR) + partial remission (PR)] was achieved in 6 patients (50%) and stable disease was obtained in 5 patients. No side effects of the treatment were noted.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Humans; Middle Aged; Tamoxifen; Toremifene

MFC-7 cells were exposed to toremifene, human alpha and gamma interferons and combinations of them in vitro. Growth of the cells was followed by ATP bioluminescence method. Rats bearing DMBA-induced tumors were treated with toremifene, rat gamma interferon and their combination daily for five weeks. The growth of the tumors was followed by palpation weekly. Toremifene and interferons inhibited the growth of MCF-7 cells. Interferons alpha and gamma were additive; toremifene and interferons were additive or at the best synergistic. Toremifene inhibited the growth of DMBA-induced tumors. Rat gamma interferon alone had no clear effect on the tumor growth. Combination of toremifene and gamma interferone was the most effective treatment and did not show any detectable toxicity. Toremifene and interferons have interesting interactions. Clinical studies using the combination might be warranted.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Breast Neoplasms; Drug Interactions; Drug Synergism; Estrogen Antagonists; Female; Humans; Interferon Type I; Interferon-gamma; Mammary Neoplasms, Animal; Rats; Tamoxifen; Time Factors; Toremifene; Tumor Cells, Cultured

Breast cancer cell lines (MCF-7, T47D, BT-20 and STT-11) and fresh cells from malignant effusions of eight breast cancer patients were examined for their in vitro sensitivity to 17 beta-estradiol (E2), tamoxifen and toremifene in a miniaturized, improved nucleic acid precursor incorporation assay (MINI assay). Seven of the eight patients received either tamoxifen or toremifene following a MINI assay and the correlation was examined between in vitro sensitivity and clinical responses to the hormonal agents. In cell lines, E2 stimulated thymidine incorporation by estrogen receptor (ER)-rich cells, MCF-7 and T47D, but not by ER-poor cells, BT-20 and STT-11. Tamoxifen induced both ER-mediated and -unmediated effects in ER-rich cells. The latter effect was also observed in ER-poor cells. Toremifene had less ER-unmediated effect in all of the cells tested than tamoxifen did. The ER-mediated effect of toremifene was weaker than that of tamoxifen in cell lines but was equipotent to tamoxifen in fresh cells. E2 affected thymidine incorporation by cells withdrawn from patients who showed a partial response to the anti-estrogens. No clear correlation was demonstrated between in vitro sensitivity to anti-estrogens of fresh cells and clinical response to these agents. The present results suggest that 1) the MINI assay is a useful system to investigate hormonal effects on breast cancer cell lines; 2) clinical responses to anti-estrogens are not predicted by in vitro response to the agents but might be predicted by the in vitro response to E2; and 3) toremifene has a smaller non-specific effect on breast cancer cells than tamoxifen and is equipotent to tamoxifen in the ER-mediated effect in vitro.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Drug Screening Assays, Antitumor; Estradiol; Female; Humans; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Thymidine; Toremifene

The immune status of breast cancer patients was followed during antiestrogen treatment for at least 1 year or until progression of the disease. Twelve post-menopausal women with advanced estrogen-receptor-positive breast cancer were treated with a novel antiestrogen, toremifene. Immune functions were determined before the start of the treatment and at 3, 6, and 12 months. For NK cell cytotoxicity testing there were 74 healthy controls and for T cell subset measurements 28 healthy controls. No statistically significant changes in the T cell subsets or NK cell cytotoxicity were observed during treatment. However, throughout toremifene treatment patients had fewer CD4 cells (T helper lymphocytes) than did the controls. Cancer patients had higher pretreatment B cell values than the controls, P = 0.01, but during the first months of toremifene treatment B cell values decreased and remained within the normal range thereafter. A positive effect on mitogen-stimulation tests with phytohemagglutinin (PHA) and concanavalin A (ConA) was observed during the first months of treatment (P = 0.01 for PHA and 0.03 for log [ConA] and a stabilization at the higher level thereafter. These results indicate that toremifene has a stimulatory effect on cell-mediated immunity in breast cancer patients.

Topics: B-Lymphocytes; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Killer Cells, Natural; Lymphocyte Activation; T-Lymphocytes; Tamoxifen; Toremifene

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Humans; Menopause; Middle Aged; Tamoxifen; Toremifene

Topics: Breast Neoplasms; Drug Design; Drug Evaluation; Estrogen Antagonists; Female; Humans; Tamoxifen; Time Factors; Toremifene

A liquid chromatographic-atmospheric pressure ionization mass spectrometric method has been developed for the analysis of toremifene metabolites in human urine after oral administration. This ionization source is a useful device for studying metabolites of toremifene because the total effluent from high-performance liquid chromatography is fed through an interface with a direct heating nebulizer and vaporizer at atmospheric pressure. To obtain good sensitivity the use of the right mobile phase is very important: ammonium acetate in methanol in the case of toremifene and its metabolites. Four unconjugated and three glucuronide-conjugated metabolites were detected in human urine. The majority of these were new and distinguishable from known metabolites.

Topics: Antineoplastic Agents; Atmospheric Pressure; Breast Neoplasms; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Mass Spectrometry; Spectrophotometry, Ultraviolet; Tamoxifen; Toremifene

Forty-six postmenopausal women with estrogen receptor positive advanced breast cancer were treated with the novel antiestrogen toremifene in this phase II study. The patients had no prior or concurrent hormonal or cytostatic treatment. Sixty milligrams of toremifene was given as a single daily dose for a minimum treatment period of 6 weeks. Eight patients (17%) achieved complete response, 17 (37%) partial response and 12 (26%) showed no change. The median durations of responses were 93, 66 and 24 weeks, respectively. Three patients still continue the treatment in complete response, four patients in partial response. No significant differences in response rates could be seen when related to different estrogen receptor concentrations. The treatment was well tolerated, only two patients had remarkable side-effects; one of the patients interrupted the treatment mainly because of tremor. Our conclusion is that toremifene is an effective, safe and in clinical practice easily applied choice of treatment in estrogen receptor positive advanced breast cancer.

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Drug Evaluation; Estrogen Antagonists; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Middle Aged; Receptors, Estrogen; Tamoxifen; Time Factors; Toremifene

Topics: Breast Neoplasms; Estrogen Antagonists; Female; Humans; Menopause; Prolactin; Sex Hormone-Binding Globulin; Tamoxifen; Thyrotropin-Releasing Hormone; Toremifene

Topics: Breast Neoplasms; DNA, Neoplasm; Estrogen Antagonists; Humans; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Toremifene; Tumor Cells, Cultured

Estrogen receptor (ER) concentration of breast cancer tissue is important in predicting the response of each patient to hormonal, especially antiestrogen treatment. About half of the patients with ER rich tumours respond and only about 10% of the patients with ER poor tumours respond to antioestrogen treatment. Tamoxifen is a well known and widely used drug. Toremifene is a new antioestrogen, developed in Finland. At standard doses both compounds have comparable hormonal and antitumour effects, and there is no clear difference between the compounds in the affinity to ER. The value of ER in predicting the response to tamoxifen and toremifene therapy in ER positive breast cancer is significant. It is not known, however, if the role of ER remains the same with high dose toremifene. Although ERs are an important predictive factor, the antioestrogens evidently act through them only in part. As the prediction is correct in about half of the patients, other mechanisms must influence tumour growth regulation, such as the expression of oncogenes and the synthesis and activity of growth factors.

Topics: Breast Neoplasms; Estrogen Antagonists; Female; Humans; Receptors, Estrogen; Tamoxifen; Toremifene

Topics: Aged; Aged, 80 and over; Breast Neoplasms; Estrogen Antagonists; Female; Humans; Middle Aged; Receptors, Estrogen; Tamoxifen; Toremifene

The effect of human interferons alpha and gamma alone and in combination with a novel antiestrogen toremifene were studied in vitro using MCF-7 cell line, an estrogen receptor positive and antiestrogen sensitive cell line. The effects were evaluated by a simple bioluminescence method with which the number of living cells was obtained as cellular adenosine triphosphate (ATP) content. The growth of MCF-7 cells was inhibited both by interferon alpha and interferon gamma. At least additive effect was evident when the cells were exposed to combination of interferons and toremifene: the combination was additive with interferon gamma + toremifene and synergistic with interferon alpha + toremifene. The combination of toremifene and interferons may have clinical importance.

Topics: Adenosine Triphosphate; Breast Neoplasms; Cell Division; Cell Line; Drug Interactions; Drug Synergism; Estrogen Antagonists; Humans; In Vitro Techniques; Interferon Type I; Interferon-gamma; Interferons; Receptors, Estrogen; Tamoxifen; Time Factors; Toremifene