Thrombosis of acute superior mesenteric artery in a patient with breast cancer receiving toremifene therapy: a case report and literature review.

It is widely recognized that cancer itself is related to increased risk of thromembolism. Venous thromboembolism is relatively common in breast cancer patients, but arterial thrombosis, especially acute superior mesenteric artery thrombosis (SMAT) associated with chemotherapy or endocrinotherapy, rarely occurs in breast cancer patients. There were few reports about acute SMAT in cancer patients who underwent chemotherapy, but no reports of acute SMAT caused by endocrine-therapy. We reported a 54-year-old patient with acute SMAT during toremifene treatment after breast cancer surgery. She underwent 4 cycles chemotherapy of TC regimen, then accepted toremifen endocrinotherapy because of positive estrogen receptor. She suffered from acute SMAT after 2 months toremifen treatment. Therefore, we consider that this case of acute SMAT may be a rare adverse event of toremifen. In view of the high risk and rarity of acute SMAT caused by toremifene, we suggest that except for venous thrombosis, arterial thrombosis in special position (ATSP) should be kept in mind during use of toremifene. Once a thrombotic event occurs, toremifene should be stopped immediately.

Comparison of adverse drug reactions between tamoxifen and toremifene in breast cancer patients with different CYP2D6 genotypes: A propensity-score matched cohort study.

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.

A prospective, randomized study of Toremifene vs. tamoxifen for the treatment of premenopausal breast cancer: safety and genital symptom analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: TOR and TAM have similar side effects on the female genital system and quality of life in premenopausal early breast cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02344940. Registered 26 January 2015 (retrospectively registered).

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

Improvements in visual acuity and macular morphology following cessation of anti-estrogen drugs in a patient with anti-estrogen maculopathy resembling macular telangiectasia type 2: a pathogenic hypothesis.

BACKGROUND: 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. CASE PRESENTATION: 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. CONCLUSIONS: 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.

Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study.

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.

Clinical significance of fatty liver disease induced by tamoxifen and toremifene in breast cancer patients.

BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Hormonal manipulation with toremifene in sporadic desmoid-type fibromatosis.

INTRODUCTION: Many patients affected by desmoid-type fibromatosis (DF) are treated with a course of hormonal therapy as front line. So far, tamoxifene has been the preferred choice. Toremifene is an anti-oestrogen agent, but possible further mechanisms of action in desmoids are related to its role in regulation of transforming growth factor-beta and ß-catenin pathways. MATERIAL AND METHODS: We retrospectively reviewed all patients treated with toremifene between 2005 and 2012 at a reference institution. Indication to toremifene was radiologically progressive disease and/or symptomatic deterioration. Progression-free survival (PFS), clinical benefit (CB) and safety profile were analysed. RESULTS: Forty-four patients were treated with toremifene 180 mg daily, 20 for radiological progression, 16 for pain and 8 for both. In 28 patients, toremifene was offered as front-line therapy, while in 11 after tamoxifen failure. PFS was 89.6% at 2 years. According to Response Evaluation Criteria in Solid Tumours, partial response, stable disease and disease progression were observed in 25%, 65% and 10% of the patients, respectively. Symptomatic relief was obtained in 75% of patients. Median time to response was 4 months. Overall CB was 86%. Adverse events G≥2 according to National Cancer Institute Common Toxicity Criteria were recorded in ten patients. DISCUSSION: Present series provides evidence to make toremifene an option in patients with DF, even after failure on different hormonal agents. A prospective trial is ongoing to confirm these results.

Selective Estrogen Receptor Modulator-Associated Nonalcoholic Fatty Liver Disease Improved Survival in Patients With Breast Cancer: A Retrospective Cohort Analysis.

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.

[A Case of Liver Failure Induced by Toremifene in a Patient with Metastatic Breast Cancer].

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.

Toremifene for breast cancer: a review of 20 years of data.

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.

Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Phase II clinical trial of high-dose toremifene as primary hormone therapy in aromatase inhibitor-resistant breast cancer.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: TOR-120 monotherapy was effective and safe as a primary hormone therapy for recurrent breast cancer unresponsive to AIs.

Low-grade endometrial stromal sarcoma developing in a postmenopausal woman under toremifene treatment for breast cancer.

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.

[Osteoporosis in men receiving androgen deprivation therapy for non-metastatic prostate cancer]. / Osteoporose beim Mann mit hormonablativer Therapie bei nicht-metastasiertem Prostatakarzinom.

Osteoporosis is defined as a continuous loss of bone mineral density accompanied by an increased fracture risk in females and males. A fall of estrogen concentrations at the menopause and the consecutive rapid bone loss are an established pathogenic mechanism in female osteoporosis. Males do not have a menopause equivalent during which significant amounts of bone are lost. Several diseases, therapeutic strategies and nutritional deficiencies may also result in bone loss and reduced bone mineral density. Prostate cancer is the most common visceral malignancy in men. Suppression of endogenous androgen production as a therapeutic tool is commonly used in patients with non-metastatic prostate cancer and is associated with significant bone loss and an increased fracture risk. Androgen deprivation therapy is prescribed both for men with locally advanced or high-risk non-metastatic prostate cancer. Osteoclast inhibition with any of several bisphosphonates improves bone mineral density and reduces fracture risk. Denosumab (a monoclonal antibody against RANK ligand) and toremifene (a selective estrogen receptor modulator) recently have been shown to be effective to reduce vertebral fractures in patients with non-metastatic prostate cancer receiving androgen-deprivation therapy. This overview focuses on cancer-treatment-induced bone loss in patients with non-metastatic prostate cancer.

Toremifene versus tamoxifen for advanced breast cancer.

BACKGROUND: Toremifene (TOR) and tamoxifen (TAM) can both be used as treatments for advanced breast cancer. OBJECTIVES: To compare the efficacy and safety of TOR with TAM in patients with advanced breast cancer. SEARCH METHODS: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: 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. AUTHORS' CONCLUSIONS: 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.

[Efficacy of high-dose toremifene as a second-line hormone therapy in patients with advanced or metastatic breast cancer resistant to aromatase inhibitor].

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: HD-TOR as a second-line therapy is optimal for advanced or metastatic AI resistance postmenopausal breast cancer.

A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer.

Granulosa cell tumor of the ovary after long-term use of tamoxifen and toremifene.

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.

Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis.

INTRODUCTION: 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. AREAS COVERED: 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.' EXPERT OPINION: 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.