toremifene and Neoplasm-Metastasis

In men with metastatic or recurrent prostate cancer, androgen deprivation therapy (ADT) is the standard of care. Although effective in cancer control, ADT is associated with multiple adverse effects of which physicians and patients should be aware herein we review these side-effects and their potential management.. ADT reduces serum levels of testosterone and estrogen, resulting in changes in body composition, increased fracture risk, development of insulin resistance, and an unfavorable lipid profile. A number of studies have investigated the association of ADT with cardiovascular mortality; however, it is unclear whether such an association exists. Recently, two separate clinical trials have found that denosumab, a monoclonal antibody, and toremifene citrate, a selective estrogen receptor modulator, could be used to reduce the incidence of fracture in men on ADT.. By providing clinicians with a greater awareness of the literature on ADT, we may minimize the physical and psychological impact of its side-effects. Physicians should be aware of a recent statement by a multilateral advisory panel, stating that there is no indication for a cardiovascular evaluation before starting ADT. Finally, physicians should be informed of recent developments in the prevention of vertebral fractures in men on ADT.

Topics: Androgen Antagonists; Androgens; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Body Mass Index; Denosumab; Erectile Dysfunction; Gynecomastia; Humans; Insulin Resistance; Libido; Male; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms; RANK Ligand; Risk Assessment; Selective Estrogen Receptor Modulators; Testosterone; Toremifene; United States

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

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

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

The triphenylethylenes tamoxifen and toremifene have been reported to enhance the cytotoxicity of cisplatin by inhibition of protein kinase C (PKC) signal transduction pathways. However, the concentrations of tamoxifen and toremifene required for chemosensitization in preclinical models are generally > or =5 microM, at least tenfold higher than plasma levels observed in patients receiving these agents as antiestrogenic therapy. As part of a translational phase II trial investigating the efficacy and potential molecular mechanism of high-dose toremifene as a cisplatin modulator in metastatic non-small-cell lung cancer, plasma concentrations of toremifene and its active metabolite N-desmethyltoremifene were measured to determine whether targeted levels could be achieved clinically.. Treatment consisted of toremifene, 600 mg orally on days 1-7, and cisplatin, 50 mg/m2 intravenously on days 4 and 11, repeated every 28 days. Toremifene and N-desmethyltoremifene were measured by reverse-phase HPLC assay on days 4 and 11 prior to cisplatin infusion.. In the initial 14 patients, the mean total plasma concentrations of toremifene plus its N-desmethyl metabolite on days 4 and 11 were 14.04 (+/- 8.6) microM and 9.8 (+/- 4.4) microM, respectively. Variability in concentrations achieved did not correlate with renal or hepatic function, gender, or body surface area. Levels of N-desmethyltoremifene were higher on day 11 relative to toremifene concentrations.. We conclude that plasma levels achieved compare favorably with the levels required for cisplatin chemosensitization and PKC modulation in vitro. Targeted toremifene levels can be achieved clinically with 600 mg orally daily in combination with cisplatin and are well tolerated.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Toremifene

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

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

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

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

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

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

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

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

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 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

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 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

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

In this study, we demonstrated that toremifene citrate (TOR) inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVEC) in vitro. Moreover, TOR suppressed angiogenesis in rabbit cornea and lung metastasis of human fibrosarcoma HT-1080 cells in nude mice. The antiangiogenic activity in vitro was apparent at the concentration of 5 microM which is clinically achievable by oral administration of 120 mg/kg of TOR. These results suggest that clinical treatment with 120 mg/day of TOR might be expected to exhibit antiangiogenesis and antimetastasis effects, in addition to inhibition of estrogen-dependent tumor cell growth.

Topics: Angiogenesis Inhibitors; Animals; Corneal Neovascularization; Estrogens; Fibrosarcoma; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Rabbits; Selective Estrogen Receptor Modulators; Toremifene