Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer

Purpose

The benefits of adding ovarian suppression to either tamoxifen or aromatase inhibitors as adjuvant breast cancer therapy in premenopausal women are controversial. Therefore, we performed a systematic literature review and meta-analysis of relevant randomized trials.

Methods

We identified and combined four qualifying trials reporting disease-free survival (DFS) and overall survival (OS) using meta-analysis.

Results

Combining ABCSG-12, SOFT, and TEXT studies, there were 65 fewer DFS events (HR 0.89, 95% CI 0.57–1.39) but 30 more deaths for ovarian suppression plus aromatase inhibitor compared to ovarian suppression plus tamoxifen (HR 1.31, 95% CI 0.93–1.84, P = 0.12, τ = 0.03, heterogeneity, P = 0.18). DFS and OS were more concordant for combined SOFT and E-3193 findings; for ovarian suppression plus tamoxifen compared to tamoxifen alone, there were 24 fewer DFS events (HR 0.83, 95% CI 0.67–1.07, P = 0.09, τ ² = 0) and 14 fewer deaths (HR 0.76, 95% CI 0.53–1.07). The SOFT Estrogen Substudy demonstrated inconsistent estrogen suppression with combined ovarian suppression and aromatase inhibitor.

Conclusion

Given the discordance between DFS and OS and inconsistent estrogen suppression with ovarian suppression plus aromatase inhibitor, adding aromatase inhibitor to ovarian suppression as adjuvant therapy in premenopausal women is premature.

     

Ovarian function after ovarian transposition and additional pelvic radiotherapy: A systematic review

ObjectiveTo investigate the ovarian survival (OS) after ovarian transposition (OT) and pelvic radiation.DesignSystematic review.Electronic databases were searched to identify studies on OT prior to external beam radiation therapy (EBRT, to the pelvic). Primary outcome was the ovarian function after radiotherapy and ovarian transposition. Secondary outcomes were complication-rate. Only studies in English, German or French were included.SettingNot applicable.PatientsFertile women undergoing ovarian transposition prior to pelvic radiation therapy.InterventionsWe included all studies, containing >5 patients, treated with OT prior to radiation therapy.Main outcome measureOvarian function.ResultsOur search yielded a total of 1130 studies of which 38 were eligible with a total of 765 patients. All studies were cohort studies or case-series. Heterogeneity among studies could not be rejected hence meta-analysis could not be performed.OS after OT and EBRT ranged from 20% to 100%. The median follow-up ranged from 7 to 102 months. OS was higher after OT and brachytherapy (OS 63.6–100%) when compared to OT and EBRT (20–100%) and OT concomitant chemoradiotherapy (0–69.2%).Only 22 studies (with 112 patients) reported on complications: among these studies the complication-rate was 0%–28.6%.ConclusionFrom our systematic review of literature we conclude that the preservation of ovarian function after OT prior to EBRT is successful in 20–100% of patients. Most favorable outcome with regard to preservation of ovarian function is seen in patients after OT and BT, followed by OT and EBRT and OT and RT combined with chemotherapy.     

Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer

BackgroundEndocrine therapy is the preferred treatment for hormone-receptor (HR) positive metastatic breast cancer. In premenopausal patients, ovarian function suppression with goserelin in combination with anastrozole yielded promising results in phase II studies. Fulvestrant, a pure antioestrogen, yields high rates of disease stabilisation in postmenopausal women. Therefore, we investigated the feasibility and safety of fulvestrant plus goserelin in premenopausal women with HR-positive metastatic breast cancer.MethodsPremenopausal patients with metastatic breast cancer eligible for endocrine treatment received fulvestrant 250 mg and goserelin 3.6 mg every four weeks as first- to fourth-line therapy. Clinical benefit rate (CBR; response rate plus disease stabilisation ⩾6 months) was defined as the primary study end-point. Time to progression (TTP) and overall survival (OS) were estimated using the Kaplan–Meier product limit method.FindingsTwenty-six patients received treatment as scheduled. 81% were pre-treated with tamoxifen and 69% had received prior aromatase inhibitors in combination with goserelin. The majority of patients (69%) presented with visceral metastases.Complete response was observed in a single patient, partial response in three and disease stabilisation ⩾6 months in eleven patients, resulting in a CBR of 58%. Median TTP was 6 months (95% confidence interval (CI), 2.4–9.6) and OS 32 months (95% CI, 14.28–49.72), respectively.InterpretationResults suggest that the combination of fulvestrant and goserelin offers promising activity in premenopausal patients and further investigation is warranted.     

Extended Therapy With Letrozole and Ovarian Suppression in Premenopausal Patients With Breast Cancer After Tamoxifen

IntroductionIn premenopausal women with breast cancer, standard adjuvant endocrine therapy has been 5 years of tamoxifen. This study sought to investigate the safety and feasibility of treating patients who remain premenopausal after adjuvant tamoxifen with gonadotropin-releasing hormone agonist (GnRH-a) concurrent with an aromatase inhibitor, mimicking the strategy that has proven effective in postmenopausal patients.Patients and MethodsThis phase II single-arm clinical trial aimed to enroll 50 premenopausal women who had completed > 4.5 years of adjuvant tamoxifen for a 2-year course of leuprolide (7.5 mg intramuscularly monthly or 22.5 mg intramuscularly every 3 months) and letrozole (2.5 mg orally daily). Zoledronic acid (4 mg intravenously every 6 months) was offered optionally to help prevent bone loss.ResultsDespite aggressive recruitment strategies at the 3 participating sites (including Dana-Farber Cancer Institute), poor accrual over 3.5 years ultimately led to early study closure after only 16 patients began therapy. Of the 16, 4 stopped treatment before 1 year, owing to toxicity; 5 completed 2 years of protocol-directed therapy; and 7 remained on treatment as of September 1, 2013, for an average of 53.5 weeks (SD, 17.2 weeks). Hot flashes, vaginal dryness, and pain were common toxicities.ConclusionExtended therapy with GnRH-a and an aromatase inhibitor (plus optional bisphosphonate) is associated with substantial side effects in premenopausal women who have already completed > 4.5 years of adjuvant tamoxifen. This study's poor accrual suggests that young women may not be highly motivated to pursue lengthier courses of endocrine therapy and that future studies of this approach may be challenging.     

A European,Observational, Prospective Trial of Trabectedin Plus Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Ovarian Cancer

PurposeThe noninterventional, prospective NIMES‐ROC phase IV study ({"type":"clinical-trial","attrs":{"text":"NCT02825420","term_id":"NCT02825420"}}NCT02825420) evaluated trabectedin plus pegylated liposomal doxorubicin (PLD) in real‐life clinical practice.Patients and MethodsEligible participants included adults with platinum‐sensitive recurrent ovarian cancer (PS‐ROC) who had received one or more cycles of trabectedin/PLD before inclusion according to the marketing authorization. The primary endpoint was progression‐free survival (PFS) according to investigator criteria.ResultsTwo hundred eighteen patients from five European countries were evaluated, 72.5% of whom were pretreated with at least two prior chemotherapy lines and received a median of six cycles of trabectedin/PLD (range: 1–24). Median PFS was 9.46 months (95% confidence interval [CI], 7.9–10.9), and median overall survival (OS) was 23.56 months (95% CI, 18.1–34.1). Patients not pretreated with an antiangiogenic drug obtained larger median PFS (p < .007) and OS (p < .048), largely owning to differences between the two populations. Twenty‐four patients (11.0%) had a complete response, and 57 patients (26.1%) achieved a partial response for an objective response rate (ORR) of 37.2%. Fifty‐nine patients (27.1%) had disease stabilization for a disease control rate of 64.2%. No statistically significant difference in PFS, OS, or ORR was observed by BRCA1/2 status and platinum sensitivity. Most common grade 3/4 adverse events (AEs) were neutropenia (30.3%), anemia (6.4%), thrombocytopenia (5.5%), and asthenia (5.0%). No deaths attributed to treatment‐related AEs or unexpected AEs occurred.ConclusionThe combination of trabectedin/PLD represents a clinically meaningful and safe option for patients with PS‐ROC regardless of prior treatment with an antiangiogenic drug, being comparable with previously observed outcomes in selected and less pretreated patients from clinical trials.Implications for PracticeThis noninterventional, prospective study, conducted in 57 reference sites across Europe, consistently confirmed that trabectedin plus pegylated liposomal doxorubicin (PLD) in routine clinical practice represents a clinically meaningful and safe option for women with platinum‐sensitive recurrent ovarian cancer. Although the study population represented a heterogeneous, older, and more pretreated population than those in prospective clinical trials, the combination of trabectedin plus PLD induced comparable clinical benefits, with a similar and manageable safety profile. Overall, these findings show that trabectedin in combination with PLD maintains antitumor activity when administered to heavily pretreated patients in real‐life clinical practice.     

New insights on the role of luteinizing hormone releasing hormone agonists in premenopausal early breast cancer patients

Luteinising hormone releasing hormone agonists (LH-RHa) are effective in the treatment of advanced endocrine-sensitive breast cancer in premenopausal patients, but their role in the adjuvant setting has remained controversial for a long time.Tamoxifen for 5 years has been traditionally considered the standard endocrine therapy for premenopausal patients and this is still valid for many patients. However, the recently reported SOFT trial has suggested that adding ovarian function suppression (OFS) to tamoxifen could improve DFS in women at sufficient risk to warrant adjuvant chemotherapy and who remained premenopausal after this therapy. The administration of an aromatase inhibitor plus OFS represents an additional therapeutic option for hormone-receptor positive premenopausal breast cancer patients, according to the combined analysis of the SOFT and TEXT trials. Temporary ovarian suppression induced by LH-RHa has been recognized as an effective strategy to preserve ovarian function from the toxic effects of chemotherapy and is now recommended in young breast cancer patients with endocrine-insensitive tumors.In this review, we discuss recent data on the role of LH-RHa in combination with tamoxifen or with an aromatase inhibitor, and we comment on its role as a strategy to preserve ovarian function in young patients candidates for adjuvant or neo-adjuvant chemotherapy.     

Predicting Ovarian Activity in Women Affected by Early Breast Cancer: A Meta‐Analysis‐Based Nomogram

Background.

The assessment of ovarian reserve in premenopausal women requiring anticancer gonadotoxic therapy can help clinicians address some challenging issues, including the probability of future pregnancies after the end of treatment. Anti-Müllerian hormone (AMH) and age can reliably estimate ovarian reserve. A limited number of studies have evaluated AMH and age as predictors of residual ovarian reserve following cytotoxic chemotherapy in breast cancer patients.

Materials and Methods.

To conduct a meta-analysis of published data on this topic, we searched the medical literature using the key MeSH terms “amenorrhea/chemically induced,” “ovarian reserve,” “anti-Mullerian hormone/blood,” and “breast neoplasms/drug therapy.” Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements guided the search strategy. U.K. National Health Service guidelines were used in abstracting data and assessing data quality and validity. Area under the receiver operating characteristic curve (ROC/AUC) analysis was used to evaluate the predictive utility of baseline AMH and age model.

Results.

The meta-analysis of data pooled from the selected studies showed that both age and serum AMH are reliable predictors of post-treatment ovarian activity in breast cancer patients. Importantly, ROC/AUC analysis indicated AMH was a more reliable predictor of post-treatment ovarian activity in patients aged younger than 40 years (0.753; 95% confidence interval [CI]: 0.602–0.904) compared with those older than 40 years (0.678; 95% CI: 0.491–0.866). We generated a nomogram describing the correlations among age, pretreatment AMH serum levels, and ovarian activity at 1 year from the end of chemotherapy.

Conclusion.

After the ongoing validation process, the proposed nomogram may help clinicians discern premenopausal women requiring cytotoxic chemotherapy who should be considered high priority for fertility preservation counseling and procedures.

Implications for Practice:

In general, a nomogram helps clinicians better visualize a specific risk for a single patient. In premenopausal women affected by early breast cancer who need adjuvant cytotoxic regimens, the proposed nomogram—based on the assessment of pretreatment age and anti-Müllerian hormone serum levels—can assess the personal probability of maintaining ovarian activity at 1 year from the end of chemotherapy. The ongoing validation process is also evaluating other key factors contributing to post-treatment ovarian activity (i.e., type of cytotoxic regimen) and will confirm the nomogram’s reliability and clinical utility.     

Expanding role of bisphosphonates in the management of early breast cancer

Evaluation of: Gnant M, Mlineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360(7), 679–691 (2009)

Current expert guidelines support tamoxifen alone or tamoxifen plus ovarian suppression as adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer. Aromatase inhibitors have succeeded tamoxifen as the endocrine manipulation of choice in the treatment of postmenopausal patients. However, their use as monotherapy has traditionally been contraindicated in premenopausal women because the suppression of peripheral aromatase results in reduced feedback to the hypothalamus, and an increase in ovarian stimulation. The Austrian Breast and Colorectal Cancer Study Group trial 12 randomized premenopausal women with endocrine-responsive early breast cancer receiving the luteinizing hormone-releasing hormone agonist goserelin to tamoxifen or anastrozole without finding a significant efficacy advantage for either arm. A further randomization within the study assigned patients to receive zoledronic acid or not. Intriguingly, the addition of the bisphosphonate to adjuvant endocrine therapy significantly improved disease-free survival in the trial population. These data support the hypothesis that bisphosphonates can reduce rates of distant metastases by manipulation of the bone microenvironment, or potentially, by a direct anti-tumor effect. We discuss the potential impact of this study on clinical practice and the important issue of bone health in young women with breast cancer.     

Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.     

Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study

BackgroundOvarian function suppression (OFS) with tamoxifen or aromatase inhibitors (AIs) improves disease-free survival in premenopausal women with breast cancer, mostly in those at higher risk of recurrence. However, its real-world use and impact remain poorly understood.Patients and MethodsThis is a multicenter retrospective cohort study of premenopausal women with stage I to III hormone receptor-positive breast cancer diagnosed from 2006 to 2015 that aimed to look at the uptake and effectiveness of the addition of OFS to backbone endocrine therapy (tamoxifen or AI). To deal with confounding, we used both multivariate modeling and propensity score matching.ResultsOf 1717 eligible patients, 17.1% were treated with OFS. There was a substantial increase of use of OFS over time, especially from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). In a multivariate model, only younger age and year of diagnosis ≥ 2014 were associated with OFS utilization (both P < .001). With a median follow-up of 38 months (P25-P75, 19.6-66.4 months), patients receiving OFS had a better overall survival than those not receiving OFS (adjusted hazard ratio, 0.44; 95% confidence interval, 0.19-0.96; absolute benefit at 5 years, 2.1% [95.3% vs. 93.2% in those not receiving OFS]). A similar benefit was identified using propensity score matching.ConclusionsIn the real-world setting, there was an increase in the use of OFS after 2014. After 2014, one-quarter of premenopausal women received adjuvant OFS, of which more than 30% received it in combination with an AI. In this study, the use of adjuvant OFS was associated with an overall survival benefit.     

卵巢功能去势联合芳香化酶抑制剂治疗绝经前转移性乳腺癌的临床研究

目的 评价卵巢功能去势联合芳香化酶抑制剂（AI）治疗绝经前转移性乳腺癌患者的临床疗效及预后。方法 140例绝经前激素受体阳性的晚期乳腺癌患者,接受卵巢功能去势（包括双侧卵巢切除手术和戈舍瑞林）联合AI（包括阿那曲唑、来曲唑和依西美坦）的治疗。评价疗效并分析影响预后的因素。结果 全组患者的中位无进展生存时间（PFS）为8.0个月,临床获益率（CBR）为56.3％。接受一线内分泌治疗患者的中位PFS为9.0个月（95％CI：6.3～11.7个月）,接受二线及以上内分泌治疗患者的中位PFS为6.0个月（95％CI：4.1～7.9个月）,两者差异有统计学意义（P=0.002）;两组患者的临床获益时间分别为13.1个月（95％CI：10.9～16.3个月）和9.3个月（95％CI：6.8～11.8个月）,CBR分别为66.7％和35.6％,差异均有统计学意义（P＜0.05）。全组患者的亚组分析显示,单个部位转移、无内脏转移、既往未接受过解救化疗者治疗后获得更长的中位PFS和更好的CBR。Cox多因素生存分析显示,转移灶数目是影响患者PFS的独立预后因素。结论 卵巢功能去势联合AI治疗绝经前激素受体阳性的转移性乳腺癌患者临床疗效肯定,耐受性好,可作为一线治疗的选择。     

Prediction of Postchemotherapy Ovarian Function Using Markers of Ovarian Reserve

Background.

Reproductive-aged women frequently receive both chemotherapy and endocrine therapy as part of their treatment regimen for early stage hormone receptor-positive breast cancer. Chemotherapy results in transient or permanent ovarian failure in the majority of women. The difficulty in determining which patients will recover ovarian function has implications for adjuvant endocrine therapy decision making. We hypothesized that pretreatment serum anti-Müllerian hormone (AMH) and inhibin B concentrations would predict for ovarian function following chemotherapy.

Methods.

Pre- and perimenopausal women aged 25–50 years with newly diagnosed breast cancer were enrolled. Subjects underwent phlebotomy for assessment of serum AMH, inhibin B, follicle-stimulating hormone, and estradiol prior to chemotherapy and 1 month and 1 year following completion of treatment. Associations among hormone concentrations, clinical factors, and biochemically assessed ovarian function were assessed.

Results.

Twenty-seven subjects were evaluable for the primary endpoint. Median age was 41. Twenty subjects (74.1%) experienced recovery of ovarian function within 18 months. Of the 26 evaluable subjects assessed prior to chemotherapy, 19 (73.1%) had detectable serum concentrations of AMH. The positive predictive value of a detectable baseline serum AMH concentration for recovery of ovarian function was 94.7%, and the negative predictive value was 85.7%. On univariate analysis, younger age and detectable serum AMH concentration at chemotherapy initiation were predictive of increased likelihood of recovery of ovarian function.

Conclusion.

Prechemotherapy assessment of serum AMH may be useful for predicting postchemotherapy ovarian function. This finding has implications for decision making about adjuvant endocrine therapy in premenopausal women treated with chemotherapy.     

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three‐Weekly Schedule in First‐Line Treatment of Ovarian Cancer

BackgroundConventional first‐line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5‐6) with paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC‐3W with a modified protocol of weekly paclitaxel 80 mg/m² and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28‐day cycle (i.e., with 1 week off‐treatment [PC‐W]).Materials and MethodsMedical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity.ResultsPC‐3W was administered to 402 patients (median age, 60.5 years) and PC‐W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III–IV. Notwithstanding a higher proportion of residual disease and older patients in the PC‐W group, median progression‐free survival was 21.4 months and 13.2 months for PC‐W and PC‐3W, respectively; median overall survival was 75.2 and 54.0 months for PC‐W and PC‐3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC‐W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC‐W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia.ConclusionPC‐W is as active and better tolerated than the standard PC‐3W regimen. PC‐W may serve as an alternative option for elderly or frail patients.Implications for PracticeWeekly scheduling of paclitaxel 80 mg/m² and carboplatin AUC2, administered on days 1, 8, and 15 in a 28‐day cycle (PC‐W) for first‐line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). It is possible that the weekly holiday on day 21 in the PC‐W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC‐3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.     

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first‐line maintenance treatment of BRCA‐mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first‐line maintenance treatment of homologous recombination deficient (HRD)–positive advanced ovarian cancer. Both these approvals were based on randomized, double‐blind, placebo‐controlled trials. Approval for olaparib monotherapy was based on the SOLO‐1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first‐line platinum‐based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA‐1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high‐grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first‐line platinum‐based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD‐positive status. Both trials demonstrated clinically meaningful improvements in progression‐free survival and favorable benefit‐risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting.Implications for PracticeThese approvals represent the first poly (ADP‐ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first‐line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA‐mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient–positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum‐based chemotherapy.     

Adjuvant endocrine therapy for premenopausal women with early breast cancer

Adjuvant endocrine therapy is a pivotal component of treatment for premenopausal women with early-stage hormone receptor-positive breast cancer. Currently, the standard endocrine therapy for premenopausal women is tamoxifen; a role for ovarian suppression or ablation has also been identified. Uncertainty remains about the optimal use of endocrine therapy in this setting. The role of ovarian suppression with tamoxifen or aromatase inhibitor, the optimal duration of adjuvant endocrine therapy and the utility of biomarkers and pharmacogenetic studies to select therapy are questions worthy of further investigation.     

Adjuvant endocrine treatment of early breast cancer

Endocrine therapy plays a pivotal role in the early treatment of estrogen receptor (ER)-positive breast cancer. Although evidence suggests that chemotherapy may work partly through ovarian ablation in young women who have ER-positive tumors, combined chemotherapy and endocrine therapy are generally advocated. In postmenopausal women, aromatase inhibition has become the new "gold standard" of treatment. More research is needed to define optimal regimens (aromatase inhibitor monotherapy versus tamoxifen sequential application), optimal duration of therapy and potential advantages of particular compounds. The optimal use of estrogen suppression (ovarian ablation with or without aromatase inhibition) and tamoxifen (administered sequentially or in concert with ovarian ablation) in premenopausal women has yet to be defined.     

戈舍瑞林联合阿那曲唑作为一线内分泌方案治疗绝经前伴中、高危复发转移因素乳腺癌的临床研究

背景与目的:现已证实治疗绝经前乳腺癌患者,阿那曲唑疗效优于他莫昔芬,并有研究表明戈舍瑞林为安全有效的卵巢去势药物,然而两者联用作为乳腺癌内分泌治疗一线方案则鲜有报道.本研究旨在观察分析戈舍瑞林联合阿那曲唑作为绝经前伴中、高危复发转移因素的乳腺癌一线内分泌治疗临床疗效和预后.方法:分析本中心2002年至今应用戈舍瑞林联合阿那曲唑作为绝经前伴中、高危复发转移因素的68例乳腺癌患者一线内分泌治疗方案的疗效和预后:应用戈舍瑞林3.6 mg,每28 d皮下注射1次;阿那曲唑1 mg口服,每天1次;28 d为1个周期.所有患者按期评价疗效和不良反应.结果:68例患者中2例出现肿瘤复发转移,其余66例患者随访至今未出现肿瘤复发转移;中位治疗时间为3.6年,中位随访时间为48个月,无病生存率(disease-free survival,DFS)为97.1%,总生存率(overall survival,OS)为98.5%.结论:戈舍瑞林联合阿那曲唑治疗绝经前伴有中、高危复发转移因素乳腺癌疗效肯定,不良反应较轻,是一种有效的一线内分泌治疗药物.     

What is the current status of ovarian suppression/ablation in women with premenopausal early-stage breast cancer?

The role of ovarian suppression/ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer has been evolving for more than a century. It is clear that OS/OA is an effective adjuvant therapy for these women, but despite numerous studies enrolling thousands of women, many unanswered questions remain. In particular, a major question is whether additional benefit is gained with combination treatment comprising luteinizing hormone-releasing hormone (LH-RH) agonists and tamoxifen over tamoxifen alone. Ongoing trials also are assessing the coupling of aromatase inhibitors (traditionally contraindicated in these patients because of paradoxic stimulation of estrogen production) and LH-RH agonists. Any potential disease-free or overall survival advantage of combination treatment must be balanced against a possible increase in adverse effects and impairment of quality of life. This review focuses on new data regarding how to incorporate OS/OA into the rational treatment of this challenging patient population.     

What is the current status of ovarian suppression/ablation in women with premenopausal early-stage breast cancer?

The role of ovarian suppression/ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer has been evolving for more than a century. It is clear that OS/OA is an effective adjuvant therapy for these women, but despite numerous studies enrolling thousands of women, many unanswered questions remain. In particular, a major question is whether additional benefit is gained with combination treatment comprising luteinizing hormone-releasing hormone (LH-RH) agonists and tamoxifen over tamoxifen alone. Ongoing trials also are assessing the coupling of aromatase inhibitors (traditionally contraindicated in these patients because of paradoxic stimulation of estrogen production) and LH-RH agonists. Any potential disease-free or overall survival advantage of combination treatment must be balanced against a possible increase in adverse effects and impairment of quality of life. This review focuses on new data on how to incorporate OS/OA into the rational treatment of this challenging patient population.     

Ovarian ablation for premenopausal breast cancer: A review of treatment considerations and the impact of premature menopause

Historically, ovarian ablation (OA) was used as therapy for women with recurrent hormone-receptor-positive (HRP) premenopausal breast cancer. With the publication of the SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) randomized trials, there is considerable interest in OA as an adjuvant treatment, either in combination with tamoxifen or an aromatase inhibitor (AI). Thus, we have reviewed current guidelines and key studies on this important topic and have highlighted the relevant biological and pharmacological aspects of the various endocrine therapies. The results of two key randomized trials addressing the use and controversies of OA in premenopausal breast cancer are discussed and recent research emphasizing the detrimental consequences of premature menopause and the cost-effectiveness of OA is presented. In low-risk patients with HRP premenopausal breast cancer, OA is not beneficial and tamoxifen remains the anti-hormone treatment of choice. In high-risk women (previous chemotherapy or women younger than 35), OA in combination with AI is more effective but is arguably not cost-effective, particularly when OA is achieved medically using a GnRH agonist/antagonist. Compared to tamoxifen alone, the SOFT trial showed a 4.5–7.7% reduction in breast cancer relapse using OA (in combination with either tamoxifen or AI) in high-risk women, though the 5-year overall survival benefit was limited (1.4–3.6%). Premature menopause is associated with long-term mortality risks and women often experience significant menopausal symptoms that impact on quality of life. These considerations should play a role in the treatment selection of those patients who may benefit from adjuvant OA.