toremifene and Endometrial-Neoplasms

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

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

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

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

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

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

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

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.

Topics: Animals; Antineoplastic Agents, Hormonal; Blotting, Southern; Carcinogens; Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Female; Immunohistochemistry; Interleukin-1; Methylnitrosourea; Mice; Mice, Inbred ICR; Ovary; Polymerase Chain Reaction; Proto-Oncogene Proteins c-fos; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; 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

Topics: Antineoplastic Agents, Hormonal; Cell Division; Endometrial Neoplasms; Endometrium; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Tamoxifen; Toremifene

Topics: Animals; Antineoplastic Agents, Hormonal; Cell Transformation, Neoplastic; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Mice; Neoplasms, Hormone-Dependent; Tamoxifen; Toremifene

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

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

Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the effects of the novel nonsteroidal pure antiestrogen EM-800 and related compounds with those of a series of antiestrogens on the estrogen-sensitive alkaline phosphatase (AP) activity in human endometrial adenocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 nM EM-800 or its active metabolite EM-652 alone failed to affect basal AP activity. In contrast, incubation with 10 nM (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, or raloxifene increased the value of this estrogen-sensitive parameter by 3.3-, 3.5-, 2.2-, and 1.6-fold, respectively, a stimulatory effect that was completely reversed by simultaneous exposure to 30 nM EM-800. Moreover, the stimulation of AP activity induced by 1 nM 17beta-estradiol was completely reversed by EM-800, EM-652, or ICI-182780, at the IC50 value of 1.98 +/- 0.23, 1.01 +/- 0.16, and 5.64 +/- 0.59 nM, respectively, whereas the partial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or raloxifene was observed at IC50 values of 13.5 +/- 3.80, 41.0 +/- 7.2, and 3.74 +/- 0.43 nM, respectively. Thus, as assessed by their activity in the human Ishikawa endometrial carcinoma cells, EM-800 and EM-652 are the most potent known antiestrogens in Ishikawa cells, and, most importantly, they are devoid of the estrogenic activity observed in these human endometrial cancer cells with (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, and raloxifene.

Topics: Adenocarcinoma; Alkaline Phosphatase; Benzopyrans; Endometrial Neoplasms; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Neoplasm Proteins; Piperidines; Propionates; Raloxifene Hydrochloride; Tamoxifen; Toremifene; Tumor Cells, Cultured