第41届美国圣安东尼奥乳腺癌研讨会重要研究进展解析

第41届美国圣安东尼奥乳腺癌研讨会于2018年12月4～8日在美国得克萨斯州圣安东尼奥如期召开。笔者选取本次大会公布的乳腺癌外科手术治疗、化疗、靶向治疗、免疫治疗及内分泌治疗领域重要的研究数据分别进行解读和分享,以期为临床医师治疗和研究乳腺癌提供思路和参考。EORTC AMAROS研究10年随访数据提示,对于前哨淋巴结活组织检查阳性的原发性乳腺癌患者,采用腋窝放射治疗替代腋窝淋巴结清扫术是安全可行的。3期GEICAM/CIBOMA研究结果显示,早期三阴性乳腺癌患者完成手术和标准化疗后使用卡培他滨辅助治疗,并未显著改善生存。哈佛大学Meta分析结果提示,行新辅助化疗后达到pCR的患者,术后可豁免常规辅助化疗,不影响生存获益。中国邵志敏教授主持的多中心PEONY研究结果显示,在早期或局部晚期的HER-2阳性乳腺癌患者新辅助治疗中,帕妥珠单克隆抗体＋曲妥珠单克隆抗体＋多西他赛双靶向治疗组术后总体pCR率显著高于曲妥珠单克隆抗体＋多西他赛单靶向治疗组。KATHERINE研究表明,曲妥珠单克隆抗体-美坦新偶联物对早期HER-2阳性乳腺癌辅助治疗具有重要价值。IMpassion 130研究中,有关免疫学生物标志物亚组疗效评估的探索性分析显示,免疫细胞程序性死亡配体-1阳性表达者接受阿替利珠单克隆抗体联合白蛋白紫杉醇治疗后显著获益。PALLET研究结果显示,对绝经后早期的ER阳性、HER-2阴性乳腺癌患者使用新辅助内分泌治疗,来曲唑联合细胞周期蛋白依赖性激酶4/6抑制剂可显著提高Ki67抑制率,但未提高患者的临床缓解率。AERAS研究10年数据显示,阿那曲唑辅助内分泌治疗延长至10年组患者显著获益。EBCTCG Meta分析显示,延长内分泌治疗可显著降低绝经后的激素受体阳性乳腺癌患者的肿瘤复发风险。TAM-01研究结果提示,对于乳腺导管内廇变患者而言,低剂量他莫昔芬可能更具减毒、增效的优势。临床医师应积极推动新型药物的临床研究和生物预测标志物的探索性分析,充分发挥国内的优势,积极学习先进技术和理念,在临床治疗中使乳腺癌患者最大限度获益。     

乳腺癌新辅助内分泌治疗与靶向治疗联合应用研究进展北大核心

新辅助内分泌治疗是雌激素受体(estrogen receptor,ER)阳性乳腺癌患者的一种潜在的治疗选择,但由于缺乏与新辅助化疗疗效的对比和治疗持续时间的可靠数据,且病理完全缓解率(pathological complete response,pCR)低,目前仅在年老体弱的患者中使用。然而,靶向药物如细胞周期蛋白依赖激酶(Cyclin-dependent kinase,CDK)4/6抑制剂、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)抑制剂等结合内分泌治疗,已经在晚期乳腺癌的治疗中取得了成功,为患者带来了显著的获益。在早期乳腺癌的新辅助治疗中,内分泌治疗联合靶向治疗仍处于研究阶段,最近的数据展现出了有希望的应用前景。本文旨在评估新辅助内分泌治疗联合靶向治疗在ER阳性乳腺癌治疗中的现状,希望为后续的临床研究及应用提供参考。     

乳腺肿瘤专业医生决策的辅助工具——辅助在线

早期乳腺癌病人术后合理选择辅助化疗和内分泌治疗,需要权衡利弊。辅助在线可以帮助医生评估病人术后复发死亡的风险和接受辅助治疗可能带来获益的数值,对于早期乳腺癌病人术后辅助治疗的选择具有指导价值。     

乳腺癌新辅助内分泌治疗进展

 针对局部晚期乳腺癌患者,尤其是绝经后内分泌反应型且不能耐受化疗的群体,新辅助内分泌治疗不失为一种选择方案。第三代芳香化酶抑制剂为绝经后患者首选药物,因其疗效显著优于他莫昔芬。同比新辅助化疗,在病例选择得当的前提下,新辅助内分泌治疗可获得相似的短期获益,由于长时间随访结果较少,总体预后尚不清楚。     

再议乳腺癌内分泌治疗10项热点问题

近年来,乳腺癌的内分泌治疗数据更新较多,使临床工作中产生了新的问题,带来了新的思考。该文就绝经前乳腺癌患者内分泌治疗中卵巢功能抑制的适宜患者的选择,卵巢功能抑制联合口服内分泌药物方案的选择,内分泌治疗过程中不良反应管理,乳腺癌患者的生育问题和延长内分泌治疗等10项早期乳腺癌内分泌治疗中的热点问题,结合数据和笔者的临床经验进行再次阐述。     

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。     

三阳性乳腺癌内分泌治疗联合靶向治疗的研究进展

三阳性乳腺癌(triple-positive breast cancer,TPBC)是指雌激素受体、孕激素受体和人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达均为阳性的乳腺癌,占所有乳腺癌病理学类型的5%～10%。TPBC是Luminal B型乳腺癌亚型的一种特殊类型,既可以接受内分泌治疗,又可以接受靶向治疗。目前国内外指南推荐TPBC的治疗首选抗HER2靶向治疗联合化疗,但TPBC新辅助治疗的病理学完全缓解率却低于激素受体阴性/HER2阳性乳腺癌,且雌激素受体表达>30%的患者从抗HER2靶向治疗联合化疗中获益较小。目前随着多种抗HER2靶向药物不断问世,以及细胞周期蛋白依赖性激酶4和6抑制剂的临床应用,使得临床上对于高选择的患者首选靶向治疗联合内分泌治疗成为可能。本文就TPBC内分泌治疗联合靶向治疗的最新研究进展进行综述。     

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。     

mTOR表达与雌激素受体阳性乳腺癌辅助内分泌治疗预后的关系

目的探讨雌激素受体（estrogen receptor,ER）阳性乳腺癌中mTOR蛋白的表达与乳腺癌辅助内分泌治疗预后间的关系。方法采用免疫组化方法检测60例ER阳性且接受内分泌辅助治疗患者的原发乳腺癌组织中p-mTOR蛋白的表达情况,观察mTOR蛋白的表达特点.并分析其与临床特征间的关系及对无病生存的影响。结果 mTOR蛋白强阳性表达的乳腺癌细胞具有更多的组织学恶性特征,mTOR阴性组中位无病生存（56.4个月）显著优于阳性组（33.5个月）（P=0.015）,多因素回归分析中mTOR为阳性者发生肿瘤复发转移的风险比例（HR）是mTOR阴性者的3.212倍,其95%CI为1.291～7.992。结论 mTOR表达状态为ER阳性是乳腺癌复发转移的独立预后因素,提示辅助内分泌治疗联合mTOR抑制剂可为ER阳性乳腺癌患者带来生存获益。     

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。     

Systemic therapy of metastatic breast cancer

Recent research has produced several new options for endocrine treatment of metastatic breast cancer. Among these, tamoxifen has become the most commonly used endocrine therapy for metastatic breast cancer due to its few side effects and an overall response rate of 35%. Despite an obvious clinical rationale for combined endocrine therapy, most trials have failed to show any benefit. Although data from trials combining tamoxifen with prednisolone or androgens seem promising, the use of combined endocrine therapy still has to be considered experimental. In patients with metastatic breast cancer, a combination of cytotoxic and endocrine therapy generally leads to a higher rate of remission than in patients treated with either modality alone. The increase in rate of response, however, is not followed by an increase in survival. The combined approach should therefore be explored further in randomized trials, preferably based upon a better understanding of tumor cell kinetics.     

Emerging gene-based prognostic tools in early breast cancer: First steps to personalised medicine

Breast cancer remains a major cause of neoplastic disease in much of the developed world. The majority of cases are diagnosed with oestrogen receptor (ER)-positive and human epidermal growth factor receptor-2 negative invasive ductal carcinoma and are treated predominantly by surgery which includes sentinel node biopsy and adjuvant endocrine therapy ± adjuvant radiotherapy. It is believed that an indeterminate subset of the patient population is needlessly incurring chemotherapy related morbidity without attaining any increase in survival due to therapy. Furthermore in the era of extended adjuvant endocrine therapy it is important to identify those patients who can be safely treated with 5 years rather than 10 years of endocrine therapy thus optimising the benefit-risk balance. This perception has propelled the development of more personalised prognostic tools for newly diagnosed cases of ER-positive breast cancer. In this article, we shall review the evidence regarding the currently available gene assays for human breast cancer.     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

Extended Endocrine Therapy: Is 5 Years Enough?

Purpose of Review

Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy.

Recent Findings

Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5 years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment.

Summary

Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

     

The use of endocrine therapy

Endocrine therapy is still a mainstay in the treatment of metastatic breast cancer. It has been observed that about one third of women with metastatic breast cancer will respond to endocrine therapy. This response rate is surprisingly consistent for a wide variety of endocrine approaches, with a few exceptions, such as the use of corticosteroids, androgens, or danazol for which the response rate appears lower. Endocrine therapy is, in general, considerably less toxic than single or combination chemotherapy, but toxicities within the endocrine therapies may vary considerably. Thus, the choice and optimal sequencing of endocrine maneuvers relate largely to minimizing toxicity and optimizing total duration of benefit. A number of newer endocrine approaches including the antiestrogens and aminoglutethimide have recently provided a variety of less toxic choices. Even more recently, compounds such as the LHRH agonists and antiandrogens are being tested, although their use remains experimental. Combinations of two or more endocrine therapies or of chemotherapy and endocrine therapy are currently, also a subject of considerable interest. No studies to date, however, have shown a clear advantage to concurrent chemotherapy endocrine combinations or to the use of two or more concurrent hormonal maneuvers, with the possible exception of the combination of prednisolone with tamoxifen or with oophorectomy, which has improved overall survival in two trials.     

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant therapy has four goals in breast cancer: decrease tumor volume to operate tumors that initially were inoperable, increase the number of conservative surgeries, evaluate the chemosensitivity in vivo and analyze the management of micrometastases. Neoadjuvant treatment provides a unique setting in which we can monitor clinical, pathological, proliferative and molecular responses. Combining different strategies such us surgery, radiation therapy, chemotherapy, and endocrine therapy has contributed substantially to the survival improvement in breast cancer. Third-generation aromatase inhibitors have proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. The need to define how to select the patients that will benefit the most from these therapies, the optimal duration of treatment, the best method to evaluate the treatment response, the identification of predictive factors for response, and the superiority of certain endocrine agents over others have been reviewed. We have carried out a critical analysis of the current literature on the utilization of endocrine therapy in the neoadjuvant setting for breast cancer. This review discusses the current evidence regarding primary endocrine therapy and the current opinions on length of treatment and measurement of response prior to surgery.     

Exemestane: a potent irreversible aromatase inactivator and a promising advance in breast cancer treatment

With the introduction of orally-active, potent and selective third-generation aromatase inhibitors and inactivators – anastrozole, letrozole and exemestane – approaches to the treatment of advanced breast cancer are undergoing re-evaluation. In advanced breast cancer, aromatase inhibitors and inactivators are likely to become established as the primary choice over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated in the first-line setting. The current evaluation of exemestane, an oral steroidal irreversible aromatase inactivator, for primary and adjuvant therapy and the potential role of potent estrogen-deprivation therapy in prevention of postmenopausal breast cancer may extend the use of antiaromatase therapy as an increasingly valuable palliative treatment option, conferring survival benefit and possible preventive outcomes across several treatment settings in the management of breast cancer.     

Exclusive endocrine therapy or partial breast irradiation for women aged ≥70 years with luminal A-like early stage breast cancer (NCT04134598 – EUROPA): Proof of concept of a randomized controlled trial comparing health related quality of life by patient reported outcome measures

BackgroundPostoperative radiation therapy after breast conserving surgery in the older adult population is a matter of debate; although radiation therapy was shown to benefit these patients concerning local disease control, the absolute benefit was small and potentially negligible. Partial breast irradiation has been introduced as an alternative treatment approach for low-risk patients. Older adult patients with early breast cancer constitute a unique population with regards to prognosis and potential comorbidities, thus minimizing treatment to maintain health-related quality of life (HRQoL) without compromising survival is extremely important. Estimates of the patient's risk of benefit and/or harm with treatment should be performed together with an assessment of baseline comorbidities, life expectancy, and care preferences. Published data suggest that radiation therapy or endocrine therapy alone resulted in excellent disease control in older women with early breast cancer, and that the combination of both treatments has less incremental benefit than expected. Conversely, the toxicity profile of endocrine therapy is well known, often significantly impacting long term HRQoL of these potentially frail patients.MethodsPatients older than 70 years receiving breast conserving surgery with T1N0, Luminal A-like tumors will be randomized to receive partial breast irradiation-alone or endocrine therapy-alone. The main objectives are to determine patient reported outcome measures in terms of HRQoL, as assessed by the EORTC QLQ-C30 using the global health status of patients, and to demonstrate a non-inferior local control rate between arms. Secondary endpoints are represented by individual scales from QLQ-C30 and module QLQ-BR45 scores; ELD14 questionnaire; geriatric COre DatasEt assessment; distant control rate, adverse events rates, breast cancer specific, and overall survival.DiscussionThe EUROPA trial is a new randomized trial focused on older adults (≥70 years) affected by good prognosis primary breast cancer. Our assumption is that postoperative radiation therapy-alone avoids the long-term toxicity of endocrine therapy and favorably impacts on HRQoL in this population. In the current report we present the trial's background and methods, focusing on perspectives in the field of precision medicine.Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04134598 / EUROPA trial.     

Current status of adjuvant chemotherapy for breast cancer

Breast cancer is one of the most common malignancies among Japanese women. Approximately 40,000 new patients are diagnosed annually. In the USA, however,the mortality from breast cancer has recently been declining. A nationwide screening promotion using mammography, and recent advances in the treatment for early breast cancer have been the main reasons. It was widely accepted that for breast cancer as a systemic disease, appropriate systemic treatment of either chemotherapy and endocrine therapy improved the survival. We describe here the contributions of new agents to the improvement in survival for breast cancer patients and introduced the concept of dose density.     

Controversies in the therapy of early stage breast cancer

Breast cancer is the most common malignancy among U.S. women, with more than 200,000 new cases diagnosed annually. In the U.S., mortality from breast cancer has declined in recent years as a result of more widespread screening, leading to earlier detection, as well as advances in the adjuvant treatment of early-stage disease. It is widely accepted that the appropriate use of adjuvant chemotherapy and endocrine therapy improves the disease-free and overall survival of patients with early-stage breast cancer. It is, therefore, standard clinical practice to administer adjuvant systemic therapy to patients with node-positive and high-risk, node-negative breast cancer. There remain, however, many controversies in the primary systemic therapy of breast cancer, which are discussed in this review.