Comparison of effects of tamoxifen and Toremifene on hepatic function and serum lipids in breast cancer patients during adjuvant endocrine therapy.

To investigate the effects of tamoxifen (TAM) and toremifene (TOR) on hepatic function and serum lipid levels in breast cancer patients receiving adjuvant endocrine therapy. The clinical data of 597 early breast cancer patients treated at the First Affiliated Hospital of Nanjing Medical University between January 2016 and December 2022 were collected. All the patients received standard adjuvant endocrine therapy with TAM or TOR after chemotherapy. Hepatic function and serum lipid data of all patients before and at 6 months and 1, 2, and 3 years after the treatment were collected retrospectively and analyzed statistically. There: no negative effect on hepatic function was observed in patients treated with either TAM or TOR. The triglyceride levels in both groups increased during treatment, and the effect of TAM on improving total cholesterol levels was stronger. Total cholesterol levels were not affected by time or treatment regimen. The low-density lipoprotein cholesterol levels decreased in both groups, and the effect was similar between groups. TAM can decrease the high-density lipoprotein cholesterol levels, whereas TOR can increase the high-density lipoprotein cholesterol levels, and there was a significant difference between groups. In the postoperative adjuvant endocrine therapy, TOR and TAM will not negatively impact the hepatic function of breast cancer patients, and TOR is better than TAM in the management of serum lipids; therefore, it may be a better choice for clinical medication.

Effects of Tamoxifen vs. Toremifene on fatty liver development and lipid profiles in breast Cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

Toremifene, rather than tamoxifen, might be a better option for the adjuvant endocrine therapy in CYP2D6*10T/T genotype breast cancer patients in China.

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.

Bone Health and Bone-Targeted Therapies for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Bone health is a significant concern in men with prostate cancer. PURPOSE: To evaluate the effectiveness of drug, supplement, and lifestyle interventions aimed at preventing fracture, improving bone mineral density (BMD), or preventing or delaying osteoporosis in men with nonmetastatic prostate cancer. DATA SOURCES: Ovid MEDLINE (1946 to 19 January 2017), EMBASE (1980 to 18 January 2017), and the Cochrane Database of Systematic Reviews (19 January 2017). STUDY SELECTION: Randomized trials and systematic reviews of trials that were published in English; involved men with nonmetastatic prostate cancer; and compared bone-targeted therapies with placebo, usual care, or other active treatments. DATA EXTRACTION: Two reviewers independently extracted study characteristics and assessed study risk of bias for each outcome. DATA SYNTHESIS: Two systematic reviews and 28 reports of 27 trials met inclusion criteria. All trials focused on men with nonmetastatic prostate cancer who were initiating or continuing androgen deprivation therapy (ADT). Bisphosphonates were effective in increasing BMD, but no trial was sufficiently powered to detect reduction in fractures. Denosumab improved BMD and reduced the incidence of new radiographic vertebral fractures in 1 high-quality trial. No trials compared calcium or vitamin D versus placebo. Three lifestyle intervention trials did not show a statistically significant difference in change in BMD between exercise and usual care. LIMITATIONS: Most trials were of moderate quality. Only 2 randomized controlled trials were designed to examine fracture outcomes. Potential harms of treatments were not evaluated. CONCLUSION: Both bisphosphonates and denosumab improve BMD in men with nonmetastatic prostate cancer who are receiving ADT. Denosumab also reduces risk for radiographic vertebral fractures, based on 1 trial. More trials studying fracture outcomes are needed in this population. PRIMARY FUNDING SOURCE: Program in Evidence-Based Care.

[Follicle-Stimulating Hormone and Estradiol Levels in Japanese Women Treated with Toremifene and Anastrozole for Two Years - A Retrospective Analysis of Data from a Prospective Randomized Trial].

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.

The effect analysis of CYP2D6 gene polymorphism in the toremifene and tamoxifen treatment in patient with breast cancer.

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.

Nano-Targeted Delivery of Toremifene, an Estrogen Receptor-α Blocker in Prostate Cancer.

PURPOSE: Estrogen Receptor-α (ERα) expression is increased in prostate cancer and acts as an oncogene. We propose that blocking of estrogen hormone binding to ERα using the ERα blocker toremifene will reduce the tumorigenicity of prostate cancer, and nano-targeted delivery of toremifene will improve anticancer efficacy. We report the synthesis and use in an orthotopic mouse model of PLGA-PEG nanoparticles encapsulating toremifene and nanoparticles encapsulating toremifene that are also conjugated to anti-PSMA for targeted prostate tumor delivery. METHODS: Human prostate cancer cell line PC3M and a nude mouse model were used to test efficacy of nano-targeted and nano-encapsulated toremifene versus free toremifene on the growth and differentiation of tumor cells. RESULTS: Treatment with free toremifene resulted in a significant reduction in growth of prostate tumor and proliferation, and its nano-targeting resulted in greater reduction of prostate tumor growth, greater toremifene tumor uptake, and enhanced tumor necrosis. Tumors from animals treated with nano-encapsulated toremifene conjugated with anti-PSMA showed about a 15-fold increase of toremifene compared to free toremifene. CONCLUSIONS: Our data provide evidence that blocking ERα by toremifene and targeting prostate cancer tissues with anti-PSMA antibody on the nanoparticles' surface repressed the tumorigenicity of prostate cancer cells in this mouse model.

[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.

VAV3 mediates resistance to breast cancer endocrine therapy.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Indoleamine 2,3-dioxygenase activity during toremifene therapy for aromatase inhibitor-resistant metastatic breast cancer].

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.

Efficacy of high-dose toremifene therapy in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors:a retrospective, single-institution study.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: HD-TOR is an effective endocrine therapy for patients with MBC who have failed AIs.

Prognostic factors and benefit populations of ovarian function suppression in premenopausal HR+/HER2+ early-stage breast cancer patients who received trastuzumab: Evidence from a real-world study with long-term follow-up.

BACKGROUND: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. METHODS: Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). RESULTS: After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. CONCLUSIONS: For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes.

PURPOSE: Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)-positive breast cancer patients under different genotypes. MATERIALS AND METHODS: CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. RESULTS: A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). CONCLUSION: Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

Endometrial Adenofibroma in a Patient Receiving Toremifene: A Case Report

INTRODUCTION: 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. CASE PRESENTATION: 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. CONCLUSION: 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.

Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93.

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.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS: In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS: The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS: Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. TRIAL REGISTRATION NUMBER: UMIN000001841.

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.

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.