绝经前女性乳腺癌辅助内分泌治疗选择策略

0 引言 我国女性乳腺癌患者50％以上属于绝经前,因为国人乳腺癌发病年龄高峰在45～49岁.虽然绝经前乳腺癌患者激素受体阳性的比例略低(大约60％),但适合选择内分泌治疗病例的绝对数则多于绝经后患者.绝经前女性乳腺癌患者内分泌治疗的主要手段包括雌激素受体选择性调节剂三苯氧胺( tamoxifen,TAM)、卵巢功能抑制(包括手术、放射或药物去势)及卵巢功能抑制联合三苯氧胺,芳香化酶抑制剂(AI)必须联合卵巢去势.     

中国早期乳腺癌卵巢功能抑制临床应用专家共识（2024年版）

中国乳腺癌患者发病年龄较轻,60%的女性患者在诊断时为绝经前。与绝经后相比,未绝经女性卵巢功能旺盛,可持续大量分泌雌激素、促进乳腺癌细胞增殖。卵巢功能抑制（ovarian function suppression,OFS）已用于乳腺癌临床治疗数十年,大量循证证据表明,单用OFS和加用OFS均可降低未绝经女性乳腺癌的复发风险并改善生存。部分OFS研究的长期随访数据（SOFT/TEXT研究12和13年随访、STO-5研究20年随访、亚裔人群的ASTRRA研究8年随访）近期陆续公布,进一步证实对于早期乳腺癌患者加用OFS可显著降低10年以上的复发风险,提高治愈可能。monarchE和NATALEE研究显示,部分CDK4/6抑制剂叠加在绝经前早期乳腺癌患者含有药物去势[促性腺激素释放激素类似物（gonadotropin releasing hormone analog,GnRHa）]的辅助内分泌治疗方案时仍可进一步增加生存获益。中国抗癌协会乳腺癌专业委员会召集了国内乳腺癌治疗领域的临床专家,在2021年版的基础上共同商讨编制了《中国早期乳腺癌卵巢功能抑制临床应用专家共识（2024年版）》。本共...     

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。     

中国早期乳腺癌术后辅助治疗开展现状——一项基于110家医院的横断面调查研究

背景与目的：乳腺癌术后辅助治疗是乳腺癌综合治疗的重要组成部分之一。对中国乳腺癌诊疗现状进行基线调查,掌握早期乳腺癌术后辅助治疗的开展情况。方法：选取全国范围内110家乳腺癌年手术量超过200例的医疗机构,以问卷调查形式开展研究,调查内容包括手术医师及其所在科室和医院的基本情况、2017年乳腺癌手术开展情况,以及对乳腺癌术后辅助治疗相关热点问题的具体决策。结果：80.9%的受访医院使用常规病理学指标作为预后评价工具,多基因检测工具的使用比例不到20%。对于T 1a 期患者,48.2%的医院对人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性型患者采用靶向治疗,77.3%的医院对三阴性乳腺癌（triple-negative breast cancer,TNBC）采用辅助化疗,蒽环类药物序贯紫杉类药物方案是最常用的化疗方案。对于高复发风险的患者,70.9%的受访医院主张密集化疗,但大部分医院的实际实施比例不到20%。对于激素受体阳性的患者,主张延长内分泌治疗时长至10年的医院占一半以上。绝经后患者联合应用双膦酸盐的比例在40%以内,绝经前患者使用卵巢功能抑制（ovarian function suppression,OFS）的比例总体也在40%以下,芳香化酶抑制剂（aromatase inhibitor,AI）是OFS的公认联合药物。结论：目前国内医院使用多基因预后预测工具的比例较低,对早期乳腺癌患者的辅助治疗决策较为保守,密集化疗、OFS和双膦酸盐等治疗方法和药物的应用比例较低。蒽环序贯紫杉方案和AI的临床应用已形成共识,延长内分泌治疗时长也成为新的趋势。     

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）、腋窝淋巴结状态（HR = 4.21,P<0.05）和肿瘤直径（HR = 2.00,P<0.05）均是患者DFS的独立预后因素;虽然雌激素抑制失败患者倾向预后较差（P = 0.10）,但不同OFS药物对降低复发转移的疗效也一致。结论： 年龄是乳腺癌患者采用OFS治疗后短期雌激素抑制失败的独立危险因素;内分泌药物、腋窝淋巴结状态以及肿瘤直径会影响ER阳性可手术乳腺癌患者的长期预后;无论是戈舍瑞林还是亮丙瑞林对患者降低雌激素水平和长期无病生存期差异无统计学意义。     

绝经后乳腺癌患者内分泌治疗研究进展

激素受体阳性的浸润性乳腺癌患者,雌激素受体（estrogen receptor,ER）的调节是全身治疗的重要组成部分。大约3/4的浸润性乳腺癌患者激素受体阳性,而雌激素受体通路是肿瘤细胞生长的关键,对于所有ER阳性的患者,选择性雌激素受体调节剂他莫西芬（tamoxifen,TAM）是绝经前及绝经后乳腺癌患者传统的内分泌辅助治疗,但最近的试验研究显示芳香化酶抑制剂（aromatase inhibitors,AIs）对绝经后乳腺癌患者的治疗颇具优势。本文综述了绝经后乳腺癌患者内分泌治疗进展。     

绝经前激素受体阳性乳腺癌辅助内分泌治疗的研究进展

内分泌治疗是激素受体阳性乳腺癌术后辅助治疗的主要手段之一。对于绝经前患者,术后五年的他莫昔芬（TAM）一直是辅助内分泌治疗的金标准,然而,随着诸多旨在提高辅助内分泌治疗疗效研究的发表与更新,辅助内分泌治疗取得较多的进展。本文围绕绝经前乳腺癌阐述当前辅助内分泌治疗的情况,主要分析他莫昔芬（TAM）、芳香化酶抑制剂（AI）、药物性卵巢功能抑制的地位、它们之间联合的优势人群、药物使用的时限等,探讨绝经前早期乳腺癌辅助内分泌治疗的研究进展。     

戈合瑞林用于乳腺癌治疗的研究进展

综述戈舍瑞林的抗肿瘤机制、临床前研究以及临床研究的现状。研究证明戈舍瑞林是一种安全、有效、可逆的卵巢功能抑制药物。对绝经前晚期乳腺癌患者，戈舍瑞林单药或戈舍瑞林和三苯氧胺联用至少能达到同卵巢去势或CMF化疗相同的疗效；用作绝经前乳腺癌患者术后辅助治疗，对雌激素受体阳性腋淋巴结有转移的患者，戈舍瑞林可获得和CMF化疗方案同样的疗效，但戈舍瑞林副作用少于卵巢去势或CMF化疗。     

绝经前乳腺癌辅助内分泌治疗的现状和展望

三苯氧胺(TAM)服用5年是绝经前受体阳性乳腺癌术后辅助内分泌治疗的标准治疗。卵巢去势可用于对TAM有使用禁忌的患者。药物卵巢去势其有效性等同于手术去势,治疗结束后卵巢功能可能恢复。卵巢去势联合TAM可用于年轻的中高危复发患者、化疗不能诱导去势的高危复发患者。卵巢去势联合芳香化酶抑制剂作为临床常规辅助治疗有待于足够的临床研究证据,医生在临床实践中,可讨论用于部分不适合TAM治疗和/或有高危复发因素的患者。绝经前乳腺癌术后辅助内分泌治疗还有很多未解决的问题。更多的临床试验结果将为我们的临床实践提供充分的证据。     

乳腺癌药物卵巢去势新进展

内分泌治疗在激素受体阳性乳腺癌治疗中的地位已受到广泛认可。芳香化酶抑制剂（ Aro-matase inhibitors,AIs）在疗效、耐受性等方面均优于他莫昔芬（Tamoxifen,TAM）。但AIs只可应用于处于绝经状态的乳腺癌患者,因此,对于三苯氧胺耐药或存在禁忌症以及存在高危因素的绝经前患者,卵巢去势无疑为她们打开了一道通往更多、更优选择的大门。手术及放疗去势因其在可逆性、可控性及副作用方面的劣势,而逐渐被药物去势所取代。本文就乳腺癌的药物卵巢去势治疗在内分泌治疗、与化疗比较等方面的新进展做一综述。     

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.     

The aromatase inhibitors (plus ovarian function suppression) in premenopausal breast cancer patients: Ready for prime time?

Tamoxifen alone or the combination of ovarian function suppression (OFS) and tamoxifen are the mainstay of hormonal therapy in premenopausal women with endocrine-responsive breast cancer. The results of large trials conducted with the third generation of aromatase inhibitors (AIs) in the metastatic, neoadjuvant and adjuvant setting, indicated better outcomes among postmenopausal breast cancer patients with endocrine responsive disease given AIs than among those given tamoxifen. These results supported the investigation of AIs in combination with OFS in premenopausal women with hormone receptor positive breast cancer. In this article we reviewed the efficacy and toxicity data on the use of AIs combined with OFS in premenopausal breast cancer patients in metastatic, neoadjuvant and adjuvant setting.     

Endocrine therapy in premenopausal women with breast cancer: a critical appraisal of current evidence

Nearly 60% of all breast cancer premenopausal women are diagnosed with a hormone receptor positive tumor and, therefore, are candidates for adjuvant hormonal therapy. Treatment with tamoxifen for at least 5 years has been for a long time the standard of care, as it is associated with overall positive clinical outcomes. However, in the last decade, a number of studies on adjuvant endocrine therapy in premenopausal women with hormone receptor positive breast cancer have been published, adding a bulk of evidence to existing knowledge in this field. A critical appraisal of their results appears necessary in order to put the recently collected data into the current framework of treatment, and to discuss the several issues that remain open. Here, we review the most recent evidence on the following: the optimal duration of tamoxifen treatment, results of the studies comparing tamoxifen alone to tamoxifen plus ovarian function suppression (OFS), results of the studies comparing tamoxifen plus OFS to aromatase inhibitors plus OFS.     

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

BackgroundRecent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation.Design and methodsWe analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.ResultsDistributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.ConclusionBased on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.Clinicaltrials.govNCT00066690 and NCT00066703.     

Adjuvant therapy of breast cancer

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.     

Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.     

Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93

Introduction International Breast Cancer Study Group (IBCSG) Trial 11-93 is the largest trial evaluating the role of the addition of chemotherapy to ovarian function suppression/ablation (OFS) and tamoxifen in premenopausal patients with endocrine-responsive early breast cancer. Methods IBCSG Trial 11-93 is a randomized trial comparing four cycles of adjuvant chemotherapy (AC: doxorubicin or epirubicin, plus cyclophosphamide) added to OFS and 5 years of tamoxifen versus OFS and tamoxifen without chemotherapy in premenopausal patients with node-positive, endocrine-responsive early breast cancer. There were 174 patients randomized from May 1993 to November 1998. The trial was closed before the target accrual was reached due to low accrual rate. Results Patients randomized tended to have lower risk node-positive disease and the median age was 45. After 10 years median follow up, there remains no difference between the two randomized treatment groups for disease-free (hazard ratio = 1.02 (0.57–1.83); P = 0.94) or overall survival (hazard ratio = 0.97 (0.44–2.16); P = 0.94). Conclusion This trial, although small, offers no evidence that AC chemotherapy provides additional disease control for premenopausal patients with lower-risk node-positive endocrine-responsive breast cancer who receive adequate adjuvant endocrine therapy. A large trial is needed to determine whether chemotherapy adds benefit to endocrine therapy for this population.     

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.     

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.