Efficacy and tolerability of toremifene and tamoxifen therapy in premenopausal patients with operable breast cancer: a retrospective analysis

Background

Given the use of tamoxifen as standard treatment for hormone receptor–positive breast cancer, the use of toremifene as an adjuvant endocrine therapy has not been widely examined. The present retrospective study compared the efficacy and safety of toremifene and tamoxifen in the treatment of operable hormone receptor–positive breast cancer in premenopausal women.

Methods

Premenopausal patients with hormone receptor– positive operable breast cancer were eligible. Enrolled patients (n = 1847) received either 60 mg toremifene (n = 396) or 20 mg tamoxifen (n = 1451) daily for a minimum of 5 years after surgery. Disease-free survival (dfs) was the primary endpoint. Overall survival (os) and time to distant recurrence were secondary endpoints.

Results

Treatment with toremifene and tamoxifen resulted in no between-group differences in dfs (p = 0.659) or os (p = 0.364). Mean dfs was 10.3 years for both groups. Mean os was 11.2 years for the toremifene group and 11.1 years for tamoxifen group. The 5-year dfs rate was 87.0% in the toremifene group and 85.0% in the tamoxifen group. The 5-year survival rate was 94.3% in the toremifene group and 93.5% in the tamoxifen group. Adverse events rates were similar in the two groups, with the exception of irregular menses, which occurred at a higher rate in the tamoxifen group than in the toremifene group (10.0% vs. 6.3%, p = 0.025).

Conclusions

In this retrospective study, the efficacy and safety profiles of toremifene and tamoxifen for the treatment of operable hormone receptor–positive breast cancer in premenopausal women were similar.     

Variation of estrogen and progesterone receptor status in breast cancer after tamoxifen therapy

In the present paper we have studied the quantitative variations in estrogen (ER) and progesterone receptor (PR) content of breast cancer induced by tamoxifen. In addition to receptors, hormonal levels of estradiol, progesterone, prolactin, FSH, LH and testosterone were also measured. The cases included in our study were consecutively selected among those breast cancers in which an aliquot of the tissue sample sent for analysis of the steroid receptors was positive for cancer and also found to have at least one of the steroid receptors positive, not only in the biopsy but also in the surgical specimen. Following this criterion, we finally collected 14 cases of breast cancer treated daily with 30 mg of tamoxifen during an interval of 3 weeks from the initial biopsy to the final surgery. From our results we can conclude that tamoxifen reduced significantly the ER concentration while no changes were observed in PR values. Concerning hormones, while in premenopausal patients tamoxifen induced a rise in plasma estradiol, in postmenopausal women the only modification observed was a decrease in plasma FSH. The variation in steroid receptor content under tamoxifen therapy may also contribute to the evaluation of the hormone dependency of gynecologic malignancies.     

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive,node positive breast cancer: A randomized study

Summary 370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.     

Effects of toremifene versus tamoxifen on breast cancer patients: a meta-analysis

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

A review of an unfavorable subset of breast cancer: estrogen receptor positive progesterone receptor negative

Estrogen receptor (ER)(+) progesterone receptor (PR)(-) tumors are a distinct subset of breast cancers characterized by aggressive behavior and tamoxifen resistance in spite of being ER(+). They are categorized as luminal B tumors and have greater genomic instability and a higher proliferation rate. High growth factor (GF) signaling and membranous ER activity contribute to the aggressive behavior of these tumors. The absence of PR is attributable to low serum estrogen, low levels of nuclear ER, and features of molecular crosstalk between GFs and membranous ER. PR expression is also downregulated by expression of mutated epidermal growth factor receptor (EGFRvIII). This subset of patients has greater expression of human epidermal growth factor receptor (HER)-1 and HER-2 and active GF signaling mediated by the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin pathway. Currently, aromatase inhibitors, fulvestrant, and chemotherapy may be the favored treatment approaches for this subset of patients. Overcoming tamoxifen resistance with targeted therapies such as gefitinib is being evaluated and strategies involving short courses of tamoxifen have been postulated for prevention of recurrence of this subtype. Understanding the interplay between molecular endocrinology and tumor biology has provided experimental therapeutic insights, and continued work in this area holds the promise of future advances in prognosis.     

High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients.

PURPOSE: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. EXPERIMENTAL DESIGN: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. RESULTS: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival. CONCLUSIONS: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.     

The combined effect of Paclitaxel and toremifene therapy for estrogen receptor positive and aromatase inhibitor resistant metastatic breast cancer

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.     

Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer

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

Recurrence-free survival in breast cancer improved by adjuvant tamoxifen -especially for progesterone receptor positive tumors with a high proliferation

Summary Although the beneficial effect on breast cancer of adjuvant tamoxifen (TAM) is well established, in the series studied by our group this effect seems to have been restricted to patients with steroid receptor (especially progesterone receptor (PgR)) positive tumors. However, as some patients with PgR-positive tumors manifested recurrence despite adjuvant TAM treatment, the question arose whether some other biological factor(s) could be used to identify these non-responding cases. The level of the S-phase fraction (SPF), as measured by flow cytometry, has been shown to be a useful prognostic marker, prognosis being better in cases where the SPF is low than in those where it is high. The aim of the present study was to relate the prognosis after adjuvant TAM to SPF among patients with PgR-positive tumors.In the PgR-positive group as a whole, the effect of TAM on prognosis was more pronounced in the high SPF group than in the low SPF group (p = 0.005) the respective decrease in 3 year recurrence rate was from 19 to 43% and from 17 to 9%. Multivariate analysis of the data for the TAM-treated group showed the level of PgR concentration (low positivevs. high positive), lymph node status, and tumor size to be independent predictive factors, but not the level of SPF (i.e. highvs. low). By contrast, among patients not treated with TAM, the SPF was a strong independent prognostic factor.To sum up, SPF was a strong independent predictor of outcome only for patients receiving no systemic adjuvant therapy, but not in patients receiving adjuvant TAM. Patients with PgR-positive and high S-phase tumors derived more benefit from TAM than patients with PgR-positive and low SPF tumors.     

Cyclin D1 expression and patient outcome after tamoxifen therapy in estrogen receptor positive metastatic breast cancer

Cyclin D1 expression is closely related with ER status in breast cancer. We executed this study to evaluate whether therapeutic response to tamoxifen varies with levels of cyclin D1 expression in 66 ER positive breast cancer patients having solitary bone metastasis. Treatment response to tamoxifen and correlation between cyclin D1 expression and biologic data of the patients were analyzed. Cyclin D1 expression was detected in 46 patients (69.7%) and significantly reduced in poorly differentiated cancer (p=0.023). Patients with cyclin D1-expressing tumors showed better response to tamoxifen but the difference was not statistically significant. Cyclin D1 expression was associated with differentiation of the breast cancer but not useful in discriminating a good responder to tamoxifen treatment.     

卵巢功能抑制治疗雌激素受体阳性早期乳腺癌的短期效应和长期生存的影响因素分析

背景与目的:内分泌治疗已经是激素受体阳性乳腺癌患者手术后辅助治疗的常规手段之一。本研究旨在分析影响可手术乳腺癌患者接受卵巢功能抑制(ovarian function suppression,OFS)治疗后短期效应(雌激素抑制效果)和长期生存(无病生存期)的影响因素。方法:回顾性分析2017年6月—2019年6月于复旦大学附属肿瘤医院行手术且完成术后标准化疗和内分泌治疗(OFS联合他莫昔芬或芳香化酶抑制剂)的435例雌激素受体(estrogen receptor,ER)阳性乳腺癌患者的临床病理学资料和无病生存期(disease-free survival,DFS)。采用单因素和多因素logistic回归分析对雌激素抑制效应有影响的因素,并运用log-rank检验和Cox比例风险回归模型分析对患者DFS有影响的因素。结果:OFS治疗后,年龄≤35岁患者雌激素抑制失败率为8.7%,显著高于35～40岁患者1%的雌激素抑制失败率(P<0.05);不同OFS药物如戈舍瑞林和亮丙瑞林的雌激素抑制作用基本一致(P>0.05)。内分泌治疗方案(HR=0.49,P<0.05)、腋窝淋巴...     

A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer

We randomized 122 premenopausal women to receive tamoxifen or to undergo a surgical oophorectomy. Of 54 evaluable women treated with tamoxifen, 24% had an objective response, as compared with 21% of 53 women having an oophorectomy. The median duration of response for tamoxifen (20 months) was longer than that for surgical oophorectomy (7 months), but this did not achieve statistical significance (P = .056). Overall median survival was 15 months for 58 patients receiving tamoxifen and 25 months for 53 patients undergoing oophorectomy (P = .18). Toxicity was greater in those undergoing oophorectomy, though both treatments were well tolerated. In those premenopausal women for whom hormonal therapy is indicated, tamoxifen is a suitable alternative to surgical oophorectomy.     

绝经前激素受体阳性乳腺癌内分泌治疗现状

内分泌治疗是激素受体阳性乳腺癌患者术后辅助治疗的重要手段之一。在内分泌治疗的背景下,接受5年他莫昔芬治疗一直是绝经前患者的标准治疗方案。近年来,这一标准受到挑战。许多大型随机临床试验结果为绝经前患者辅助内分泌治疗提出了新的选择。本文拟将绝经前激素受体阳性乳腺癌患者的内分泌治疗现状做一综述。     

Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study

Introduction  

Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes.     

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene

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

Cyclical use of tamoxifen and high-dose medroxyprogesterone acetate in advanced estrogen receptor positive breast cancer

Summary One-hundred and seventy patients with estrogen receptor positive (10 pmol/g protein) advanced breast cancer have been treated in a prospective randomized study either with continuous tamoxifen 30 mg × 1 daily (TAM), or with TAM 30 mg × 1 daily for 8 weeks alternating with medroxyprogesterone acetate 500 mg × 2 daily for 8 weeks (TAM/HD-MPA). The response rate was 62% in the group treated with cyclic TAM/HD-MPA versus 41% in the TAM alone group (p = 0.02). There was no significant difference in duration of remissions or survival.     

Effect of screening mammography on breast cancer survival in comparison to other detection methods: A retrospective cohort study

The effectiveness of screening mammography (SMG) on mortality has been established in randomized controlled trials in Western countries, but not in Japan. This study evaluated the effectiveness by comparing the survival based on detection methods. The survivals were estimated by the Kaplan–Meier method. Breast cancer patients diagnosed from 1 January 1989 to 31 December 2000 were determined using the Miyagi Prefectural Cancer Registry and follow-up was performed from the date of the diagnosis until the date of death or the end of follow-up, 31 December 2005. The hazard ratios (HR) and 95% confidence interval (CI) of breast cancer death based on the detection methods were estimated by the Cox proportional-hazard regression model. The mean age of the 7513 patients was 55.7 years (range, 15.0–99.3). The 5-year survival associated with the SMG group, the clinical breast examination (CBE) group, and the self-detection group was 98.3%, 94.3%, and 84.8%, respectively. The HR (95% CI) of deaths from breast cancer was 2.50 (1.10–5.69) for patients in the CBE group and 6.57 (2.94–14.64) for the self-detection group in comparison to the SMG group. In women aged 50–59, the HRs were 1.64 (0.58–4.62) among the CBE group and 3.74 (1.39–10.03) among the self-detection group, and the HRs for the CBE and self-detection groups in women aged 60–69 were 2.96 (0.68–12.83) and 9.51 (2.36–38.26), respectively. After adjusting for stage, the HRs dropped remarkably. Screening mammography may be more effective in the elderly group and be able to reduce the mortality of breast cancer in Japan. ( Cancer Sci 2009)