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。     

中国早期乳腺癌卵巢功能抑制临床应用专家共识（2016年版）

乳腺癌已经成为威胁中国女性健康的第一大恶性肿瘤,发病率呈逐年递增趋势。中国乳腺癌发病率年增幅速度是世界平均水平的2倍,且年轻化趋势显著,约有60%的患者在诊断时仍为绝经前状态［1］。据统计,中国绝经前女性早期乳腺癌患者中50%~60%激素受体为阳性,辅助内分泌治疗是降低这类患者复发风险的重要手段,如采用他莫昔芬治疗5~10年已经成为绝经前激素受体阳性的早期乳腺癌患者的标准内分泌治疗方式［2-5］。     

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。     

戈舍瑞林在绝经前乳腺癌内分泌治疗中对卵巢功能抑制作用的前瞻性临床研究

乳腺癌是一种激素依赖性的疾病,辅助内分泌治疗在预防术后复发和转移中起着重要作用。目前临床研究和应用较多的药物是第三代芳香化酶抑制剂,主要适用于绝经后激素受体阳性的乳腺癌患者。而我国的乳腺癌患者中约有60％～70％处于绝经前期,其中约60％的患者雌激素受体阳性。     

新辅助内分泌治疗在绝经后乳腺癌中的应用

目的 探讨新辅助内分泌治疗在绝经后激素受体阳性的乳腺癌患者的应用.方法 回顾性分析40例绝经后ER和/或PR阳性的乳腺癌患者新辅助内分泌治疗的临床资料.结果 40例患者中完全缓解2例,部分缓解27例,稳定8例,进展3例,总有效率为72.5%;来曲唑的疗效明显高于三苯氧胺,起效时间更短且不受CerbB-2的影响.结论 绝经后激素受体阳性的乳腺癌患者应用新辅助内分泌治疗具有显著疗效,来曲唑疗效优于三苯氧胺.     

来曲唑在老年乳腺癌新辅助内分泌治疗中的疗效观察

目的探讨来曲唑在老年绝经后乳腺癌新辅助内分泌治疗中的近期疗效,耐受性及与临床病理因素的相关性。方法对58例绝经后激素受体阳性的乳腺癌患者进行来曲唑新辅助内分泌治疗,以他莫昔芬新辅助内分泌治疗为对照组。结果来曲唑组临床疗效显著优于他莫昔芬组（P〈0.05）。来曲唑组临床分期晚,ER及PR均阳性的有效率高,与HER-2表达无关。他莫昔芬组HER-2阳性的有效率低。2组治疗前后Ki-67水平均显著下降,有统计学意义（P〈0.05）。2组未出现明显不良反应。结论绝经后、激素受体阳性的乳腺癌选择来曲唑新辅助内分泌治疗安全,有效,尤其适合有合并症的老年体弱者。     

中国早期乳腺癌卵巢功能抑制临床应用专家共识（2021年版）

卵巢功能抑制（ovarian function suppression,OFS）已经应用于乳腺癌治疗数十年,早期辅助治疗研究证实,单独进行OFS能够降低50岁以下乳腺癌患者的复发风险,改善生存情况。鉴于新的循证医学数据不断累积,中国抗癌协会乳腺癌专业委员会遂召集国内乳腺癌专家,在《中国早期乳腺癌卵巢功能抑制临床应用专家共识（2018年版）》的基础上共同商讨制订了《中国早期乳腺癌卵巢功能抑制临床应用专家共识（2021年版） 》。2021年版共识建议,将药物去势[促性腺激素释放激素激动剂（gonadotropin releasing hormone agonist,GnRHa）]作为绝经前激素受体阳性的早期乳腺癌OFS的首选。中高危绝经前激素受体阳性乳腺癌患者推荐接受OFS的内分泌治疗;低危患者推荐选择性雌激素受体调节剂（selective estrogen receptor modulators,SERM）单药治疗;使用芳香化酶抑制剂（aromatase inhibitor,AI）代替SERM治疗的绝经前患者,需要同时接受OFS治疗。关于OFS联合方案,对绝经前激素受体阳性早期乳腺癌的中危和高危患者,或亚群处理效果模式图（subpopulation treatment effect pattern plot,STEPP）分析的较高风险患者推荐OFS联合AI治疗,OFS联合SERM治疗也是合理的选择。对存在SERM禁忌证的任何风险级别患者,推荐OFS联合AI治疗。关于OFS的使用时机,建议根据激素受体阳性乳腺癌患者化疗前的卵巢功能状态,决定辅助内分泌治疗方案。如果考虑卵巢保护,推荐GnRHa同步化疗,不影响患者的生存获益;如果不考虑卵巢保护,推荐GnRHa可以在化疗结束后直接序贯使用。已接受化疗的患者不推荐确认卵巢功能状态后再使用GnRHa。GnRHa辅助内分泌治疗的标准疗程应为5年。完成5年联合OFS的内分泌治疗后,如未绝经且耐受性良好,推荐继续5年联合OFS的内分泌治疗或5年SERM治疗。低危选择OFS替代化疗的患者,可考虑OFS联合内分泌治疗时长为2年。推荐与患者充分沟通可能出现的不良事件,选用合适的药物去势治疗方案。合理的安全管理能够有效地缓解不良反应,增加患者治疗的依从性。对于接受药物去势的患者,不常规推荐在药物去势治疗过程中监测雌激素水平并根据检测报告来决定是否继续药物去势。但在药物去势后,怀疑不完全的卵巢功能抑制时[包括改变用法如注射人员缺乏相关经验、更换剂型或出现某些可能提示卵巢功能恢复的生理变化如月经恢复和（或）更年期症状的周期性波动时],可以进行雌激素水平检测。绝经前乳腺癌患者,无论激素受体阳性或阴性,推荐在（新）辅助化疗前和化疗过程中使用OFS药物保护卵巢功能,降低卵巢功能早衰的发生风险,减少生育能力损害。推荐化疗前2周开始使用GnRHa,每28 d 1次,直至化疗结束后2周给予最后一剂药物。此外共识还建议,激素受体阳性乳腺癌患者抗肿瘤药物的临床试验,应尽可能纳入绝经前女性,在雌激素充分抑制的前提下,探索抗肿瘤药物对肿瘤生物学特性和患者长期生活质量的影响。     

乳腺癌内分泌治疗的进展

内分泌治疗是激素受体阳性乳腺癌综合治疗的重要组成部分,其疗效已得到广泛的认可.随着新的内分泌药物的出现,乳腺癌的内分泌治疗也取得了新的进展.目前,三苯氧胺对绝经前患者仍是内分泌治疗的标准用药,但对绝经后患者应用芳香化酶抑制剂会有更大的效益.芳香化酶抑制剂及药物去势等多个大型的临床研究还正在进行并备受关注.本文概述乳腺癌的内分泌治疗并着重介绍近期的进展.     

乳腺癌的内分泌疗法

乳腺癌是妇女常见的恶性肿瘤之一,发病率占妇女恶性肿瘤的第二位。乳腺癌的发病原因最近认为与内分泌激素有关,因在许多乳腺癌患者的癌组织中有大量雌二醇受体存在,故治疗不单限于手术治疗,须在手术治疗后做雌激素受体(ERS)测定。若测得受体为阳性的患者,手术后还可以继续进行化疗和激素治疗。内分泌疗法包括:①对绝经前妇女行双侧卵巢切除术;②对绝经后妇女行肾上腺切除     

激素受体阳性晚期转移性乳腺癌的内分泌治疗

对于晚期转移性乳腺癌患者,临床治疗的目的是减轻症状、改善生活质量及延长患者生存时间。由于内分泌治疗不良反应小、疗效好,是激素受体阳性没有内脏危象的晚期乳腺癌患者的优先选择。内分泌治疗可能最终会导致耐药,如何延缓耐药,推迟化疗从而减轻患者痛苦是目前临床研究的热点。笔者总结了绝经前、后激素受体阳性晚期转移性乳腺癌患者内分泌治疗相关研究的最新进展以及其与小分子靶向药物联合应用的效果,希望为广大乳腺外科医师提供参考。     

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.     

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.     

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.     

Current status of endocrine therapy for breast cancer

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.     

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.     

Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.     

Chemo/endocrine therapy for breast cancer patients

Standard adjuvant chemo/endocrine therapy for breast cancer patient is based upon St. Gallen's consensus 1998. Recent development in the field of adjuvant chemo/endocrine therapy is an usage of LH-RH analogue with tamoxifen for premenopausal hormone receptor positive women, and also an emerging role of taxans. Orally given 5-FU derivatives may work in adjuvant settings. The third generation aromatase inhibitors have established their role in second line hormone therapy for the advanced or recurrent breast cancer patients. High dose chemotherapy should not be used in outside clinical trials.     

Current status of adjuvant endocrine therapy for hormone responsive breast cancer

Three important meetings on adjuvant hormone therapy for breast cancer were held recently: the 5th EBCTCG Meeting, NIH Consensus Meeting, 7th International Conference on Adjuvant Therapy of Primary Breast Cancer. The conclusions of these meetings are: 1. adjuvant hormone therapy should be indicated only for patients with estrogen/progesterone receptor positive cancer, 2. five years of tamoxifen is the standard care at present, 3. ovarian ablation by any means has been proved effective in premenopausal patients and LH-RH agonist should be given at least two years, and 4. aromatase inhibitors should not be used in clinical practice, because several prospective randomized trials are ongoing at present. The patients treated with LH-RH agonist combined with tamoxifen showed better relapse-free survival compared with LH-RH agonist alone in the INT-0101 trial. This was an important trial because combined hormone therapy had not been proven more effective than individual hormone therapy previously. Combined hormone therapy including LH-RH agonist may be considered in premenopausal patients. There is a growing consensus that chemotherapy is effective through the ovarian suppression. In this sense, hormonal therapy should be considered first for hormone responsive patients. On the contrary, standard chemotherapy has shifted from CMF combination to an anthracycline containing regimen. Chemoendocrine therapy may be considered in high risk patients.     

New period of systemic treatment for breast cancer

The systemic adjuvant treatment for breast cancer is showing remarkable progress with targeted therapy, such as Trastuzumab, in addition to cytotoxic chemotherapy. The timing of adjuvant chemotherapy is also shifting from post surgery to pre surgery. In terms of adjuvant endocrine therapy for hormonal receptor positive breast cancer, Aromatase inhibitor now is established as a standard treatment for postmenopausal patients. LH-RH analog is also standard for premenopausal patients with Tamoxifen. Further, longer survival might be expected with the new combination of cytotoxic chemotherapy and Trastuzumab for locally advanced or metastatic breast cancer patients. Because the trend of systemic treatment for breast cancer patients is to focus on maintaining patients' quality of life, targeted therapy with Trastuzumab and/or new upcoming drugs(e. g., Bevacizumab, Lapatinib, Sunitinib), might be the mainstream systemic therapy. In this section, we discuss standard and new systemic therapy for primary, locally advanced, and metastatic breast cancer patients.