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.     

绝经后晚期乳腺癌新辅助内分泌治疗的疗效观察

目的探讨新辅助内分泌治疗对于绝经后晚期乳腺癌治疗的可行性,比较三苯氧胺与来曲唑的疗效。方法 51例绝经后乳腺癌晚期患者随机分为2组,三苯氧胺组26例采用三苯氧胺治疗,来曲唑组25例采用来曲唑治疗,比较并且分析2组的临床效果和毒副反应。结果来曲唑组的总有效率为68.0%,明显高于三苯氧胺组的30.7%,差异有统计学意义（P〈0.05）。2组毒副反应均较轻。结论新辅助内分泌治疗对于绝经后晚期乳腺癌治疗安全有效,而且来曲唑治疗效果优于三苯氧胺。     

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。     

来曲唑显著降低激素受体阳性绝经后乳腺癌患者的死亡和复发风险

《Journalof Clinical Oncology》于2011年2月14日发表了乳腺癌国际研究组BIG1-98研究的最新结果：与他莫昔芬相比,来曲唑辅助治疗激素受体阳性的绝经后乳腺癌患者,可显著降低死亡、疾病复发和远处转移风险。     

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。     

激素受体阳性晚期乳腺癌内分泌治疗选择

激素受体阳性乳腺癌占所有乳腺癌的70%。内分泌治疗是这个亚型乳腺癌的主要治疗手段,最常见药物有他莫昔芬和芳香酶抑制剂如阿拉曲唑、来曲唑和依西美坦。全文重点总结新型内分泌治疗药物,如雌激素受体降解剂(Fulvestrant),以及新的靶向药物如mTOR抑制剂(Everolimus)、CDK4/6抑制剂(Palbociclib、Ribociclib和Abemaciclib)和PI3K抑制剂(Alpelisib、Buparlisib和Pictilisib)等。新的靶向药物联合内分泌治疗已经改变了临床实践,延长激素受体阳性晚期乳腺癌患者的生存期。     

延长辅助内分泌治疗在激素受体阳性早期乳腺癌治疗中的价值

雌激素受体（estrogen receptor,ER）阳性早期乳腺癌的复发风险一直存在。MA.17试验证明,在淋巴结阳性、雌激素受体阳性的乳腺癌患者中,常规应用5年来曲唑治疗后继续应用他莫昔芬治疗,其无病生存期（disease-free survival,DFS）和整体生存期（overall survival,OS）都得到了明显改善。MA.17R试验证明,完成5年芳香化酶抑制剂治疗的患者,继续随机应用来曲唑或安慰剂,来曲唑组的DFS明显改善。在这些研究中,延长内分泌治疗能减少远期复发的绝对益处是适度的,然而其耐受性和依从性的挑战依然存在。对于完成5年常规内分泌治疗的患者,最终是选择他莫昔芬还是来曲唑来延长治疗,主要应该考虑患者的绝经状态、淋巴结情况、耐受性和潜在的利益大小这些因素。     

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。     

乳腺癌内分泌治疗对髓系抑制性细胞的影响

目的分析乳腺癌内分泌治疗药物他莫昔芬和来曲唑对髓系抑制性细胞(MDSC)数量及功能的影响。方法采用简单随机化分组法将53例接受术后辅助治疗的乳腺癌患者随机分为他莫昔芬组(接受他莫昔芬治疗)22例和来曲唑组(接受来曲唑治疗)31例。采用流式细胞术检测两组患者内分泌治疗前及治疗后6个月的外周血MDSC的相对数和绝对数;应用体外培养体系分析并比较两组MDSC对T细胞增殖水平的影响。结果内分泌治疗前,他莫昔芬组与来曲唑组患者的MDSC相对数、绝对数比较,差异均无统计学意义(P﹥0.05);治疗6个月后,来曲唑组患者的MDSC相对数、绝对数分别为(3.09±1.91)%、(1.73±0.35)×106/ml,均明显低于他莫昔芬组的(9.65±3.50)%、(2.92±1.18)×106/ml,差异均有统计学意义(P﹤0.01)。来曲唑组患者的外周血经MDSC处理后CD3+T细胞的增殖水平为(65.93±17.48)%,明显高于他莫昔芬组的(30.25±4.94)%,差异有统计学意义(P﹤0.01)。结论与他莫昔芬比较,乳腺癌患者术后接受来曲唑治疗,可降低MDSC的数量并抑制其功能。     

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］。     

Letrozole in the neoadjuvant setting: the P024 trial

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR- cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P<0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P=0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P=0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2- cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P=0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.     

Letrozole in the neoadjuvant setting: the P024 trial

Neoadjuvant chemotherapy trials have consistently reported lower response rates in hormone receptor-positive (HR+) breast cancer when compared with HR? cases. Preoperative endocrine therapy has therefore become a logical alternative and has gained considerable momentum from the finding that aromatase inhibitors (AIs) are more effective than tamoxifen for HR+ breast cancer in both the neoadjuvant and adjuvant settings. The most convincing neoadjuvant trial to demonstrate the superiority of an AI versus tamoxifen was the P024 study, a large multinational double-blind trial in postmenopausal women with HR+ breast cancer ineligible for breast-conserving surgery. The overall response rate (ORR) was 55% for letrozole and 36% for tamoxifen (P < 0.001). Significantly more letrozole-treated patients underwent breast-conserving surgery (45 vs. 35%, respectively; P = 0.022). In addition, ORR was significantly higher with letrozole than tamoxifen in the human epidermal growth factor receptor HER1/HER2+ subgroup (P = 0.0004). The clinical efficacy of letrozole in HER2+ breast cancer was confirmed by fluorescent in situ hybridization analysis and was found to be comparable to that of HER2? cases (ORR 71% in both subsets). Biomarker studies confirmed the superiority of letrozole in centrally assessed estrogen receptor-positive (ER+) tumors and found a strong relationship with the degree of ER positivity for both agents. Interestingly, letrozole was effective even in marginally ER+ tumors and, unlike tamoxifen, consistently reduced the expression from estrogen-regulated genes (progesterone receptor and trefoil factor 1). Furthermore, when analyzed by Ki67 immunohistochemistry, letrozole was significantly more effective than tamoxifen in reducing tumor proliferation (P = 0.0009). Thus, neoadjuvant letrozole is safe and superior to tamoxifen in the treatment of postmenopausal women with HR+ locally advanced breast cancer.     

Neoadjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive early breast cancer: a new concept

Patients with resectable, nonmetastatic (stage I–IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer.     

Letrozole for the management of breast cancer

Letrozole, a third-generation aromatase inhibitor, has been the only aromatase inhibitor to date to show unequivocal superiority to tamoxifen as first-line treatment of metastatic postmenopausal breast cancer. The superiority of letrozole compared with tamoxifen was also reflected in the neoadjuvant setting, in both estrogen receptor-positive and estrogen receptor-unknown patients with differing HER-2 status. Currently, studies are being performed in the adjuvant setting, which will provide important data on the long-term safety of letrozole and help determine its suitability as a chemopreventive agent in healthy women at risk of developing breast cancer. Nevertheless, the superior clinical efficacy and survival data of letrozole suggest that it has the potential to displace tamoxifen as the gold standard in breast cancer treatment in the coming years.     

Letrozole for the management of breast cancer

Letrozole, a third-generation aromatase inhibitor, has been the only aromatase inhibitor to date to show unequivocal superiority to tamoxifen as first-line treatment of metastatic postmenopausal breast cancer. The superiority of letrozole compared with tamoxifen was also reflected in the neoadjuvant setting, in both estrogen receptor-positive and estrogen receptor-unknown patients with differing HER-2 status. Currently, studies are being performed in the adjuvant setting, which will provide important data on the long-term safety of letrozole and help determine its suitability as a chemopreventive agent in healthy women at risk of developing breast cancer. Nevertheless, the superior clinical efficacy and survival data of letrozole suggest that it has the potential to displace tamoxifen as the gold standard in breast cancer treatment in the coming years.     

Anti-tumor effects of letrozole

The use of drugs, which inhibit estrogen biosynthesis, is an attractive treatment for postmenopausal women with hormone-dependent breast cancer. Estrogen deprivation is most specifically achieved using inhibitors which block the last stage in the biosynthetic sequence, i.e., the conversion of androgens to estrogens by the aromatase enzyme. Recently, a new generation of aromatase inhibitors has been developed. Among these, letrozole (Femara) appears to be the most potent. When given orally in milligram amounts per day to postmenopausal women, the drug almost totally inhibits peripheral aromatase and causes a marked reduction in circulating estrogens to levels that are often undetectable in conventional assays. Similarly, neoadjuvant studies demonstrate that letrozole substantially inhibits aromatase activity in both malignant and nonmalignant breast tissues, and markedly suppresses endogenous estrogens within the breast cancers. These studies also illustrate anti-estrogenic and anti-proliferative effects of letrozole in estrogen receptor (ER)-rich tumors. Thus, tumor expression of progesterone receptors and the cell-cycle marker Ki67 is significantly and consistently reduced with treatment. Additionally, clear pathological responses as evidenced by decreased cellularity and increased fibrosis are seen in the majority of cases. These results translated into clinical benefit in a series of 24 breast cancers treated neoadjuvantly with letrozole (either 2.5 or 10 mg): tumor volume reductions > 25% were observed in 23 women, and > 50% reductions in 18 patients. Pathological and clinical effects are seen much more consistently than with tamoxifen. Thus, in a multicenter randomized trial of letrozole vs. tamoxifen (PE 024), clinical study outcomes were superior for letrozole in comparison with tamoxifen with regard to overall tumor response and an increase in the proportion of patients treated by breast conserving surgery. Letrozole has also been used in advanced breast cancer, both as second-line hormone treatment following tamoxifen failure, and more recently as first-line therapy. Trials of second-line treatment in which letrozole has been compared with either older aromatase inhibitors or progestins have shown equivalent or superior clinical activity and improved tolerability favoring letrozole. In first-line comparison with tamoxifen in metastatic disease, a phase III trial of over 900 postmenopausal women showed letrozole to be significantly better than tamoxifen in terms of overall tumor response rates, clinical benefit, and time to treatment failure. In summary, letrozole is an exceptionally potent and specific endocrine agent. In patients with ER-rich tumors, high rates of pathological and clinical response have been documented, and large phase III trials against established treatments such as tamoxifen and progestin suggest superior (or at least equivalent) clinical efficacy. Letrozole is a drug of immense potential and in the future is likely to occupy a central role in the management of postmenopausal women with hormone-dependent breast cancer.     

The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors.

There are now a number of highly effective options for the treatment of hormone-receptor-positive breast cancer. Although tamoxifen was the standard hormonal treatment for many years, we now have another option for postmenopausal women: the third-generation aromatase inhibitors (AIs) anastrozole, exemestane and letrozole. A number of trials have investigated the use of third-generation AIs compared with tamoxifen throughout the continuum of treatment settings for postmenopausal women with breast cancer. In the neoadjuvant setting, letrozole, given for 4 months, resulted in better overall clinical response and breast-conserving surgery rates than tamoxifen. The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen trial gave anastrozole for 3 months with no difference in clinical response but significantly improved breast-conserving surgery rates. Compared with tamoxifen, anastrozole and letrozole significantly improved disease-free survival as early adjuvant treatment for hormone-receptor-positive disease. Switching to anastrozole or exemestane after 2 to 3 years of adjuvant tamoxifen for a total of 5 years of therapy was also more effective than continued tamoxifen. All three agents are approved in the early adjuvant or switching setting in the USA. Letrozole following 5 years of tamoxifen as extended adjuvant treatment improved disease-free survival and, in the node-positive subgroup, overall survival when compared with placebo. Anastrozole and letrozole are both approved for the first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women; letrozole showed an improved response rate compared with tamoxifen. Anastrozole, letrozole and exemestane are all indicated for the second-line treatment of advanced breast cancer. In summary, third-generation AIs have been shown to have superior efficacy over tamoxifen in the metastatic, neoadjuvant and adjuvant settings and to improve outcome as extended adjuvant therapy following 5 years of tamoxifen. Ongoing studies will further define the role of sequential adjuvant treatment. Appropriate duration of treatment is another important area of investigation. This review will cover hormonal therapy for postmenopausal women with breast cancer and will not address the treatment of premenopausal women.     

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

来曲唑与三苯氧胺在绝经后期乳腺癌新辅助内分泌治疗中的疗效对比

目的 比较来曲唑与三苯氧胺用于绝经后期乳腺癌新辅助内分泌治疗的近期疗效和毒副反应.方法将收治的绝经后期、ER阳性、有合并症的55例乳腺癌随机分为两组,并行新辅助内分泌治疗.来曲唑组25例:2.5 mg/次,1次/d,连续60 ～90 d;三苯氧胺组30例:10mg/次,2次/d,连续60～90 d.比较两组的近期疗效和...     

Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.

PURPOSE: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: This multicenter phase III trial randomly assigned 916 patients with hormone receptor-positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician's discretion. This report updates efficacy at a median follow-up of 32 months. RESULTS: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P <.0001), time to treatment failure (median, 9 v 5.7 months, respectively; P <.0001), overall objective response rate (32% v 21%, respectively; P =.0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy ("time to chemotherapy") was significantly longer (P =.005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P =.001). CONCLUSION: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.