绝经前耐药乳腺癌：依维莫司有效
对于激素受体阳性HER2阴性晚期乳腺癌，首选内分泌治疗。不幸的是，部分患者对内分泌治疗无效（原发耐药），即使近期有效，远期也将复发（继发耐药），耐药的重要原因之一为哺乳动物雷帕霉素靶蛋白（mTOR）信号通路激活。2012年，美国《新英格兰医学杂志》发表的BOLERO-2研究结果表明，对于内分泌治疗耐药的激素受体阳性HER2阴性晚期乳腺癌绝经后女性，mTOR抑制剂依维莫司仍然有效，可显著延长内分泌治疗的无进展生存时间。不过，与西方国家相比，中国等东方国家的乳腺癌女性超过半数为绝经前，依维莫司是否仍然有效？2019年，韩国LEO研究结果未能证实依维莫司对晚期乳腺癌内分泌治疗耐药绝经前女性有效，仅对其中已发生内脏或骨转移患者有效。
2021年8月26日，《美国医学会杂志》肿瘤学分册在线发表中国医学科学院肿瘤医院樊英、罗扬、王佳玉、马飞、李青、张频、徐兵河、辽宁省肿瘤医院孙涛、复旦大学附属肿瘤医院邵志敏、哈尔滨医科大学附属肿瘤医院张清媛、湖南省肿瘤医院欧阳取长、天津医科大学肿瘤医院佟仲生、中山大学附属肿瘤医院王树森、中国医科大学附属第一医院滕月娥、浙江省肿瘤医院王晓稼、北京大学人民医院王殊、中山大学孙逸仙纪念医院刘强、江苏省肿瘤医院冯继峰、上海交通大学医学院附属瑞金医院沈坤炜、吉林大学白求恩第一医院宋艳秋等学者的MIRACLE（CBCSG 016）研究报告，首次证实依维莫司对激素受体阳性HER2阴性晚期乳腺癌内分泌治疗耐药绝经前女性有效。
MIRACLE (CBCSG016): Everolimus Trial for Advanced Premenopausal Breast Cancer: A Multicenter, Randomized Phase ll Study of Letrozole Versus Letrozole Plus Everolimus for Hormone Receptor-Positive Premenopausal Women With Recurrent or Metastatic Breast Cancer on Goserelin Treatment After Progression on Tamoxifen (NCT02313051)
该全国多中心非盲随机对照二期临床研究2014年12月8日～2018年9月26日从全国19家医院入组激素受体阳性HER2阴性晚期乳腺癌他莫昔芬耐药绝经前女性199例（平均年龄44.3±6.3岁）按1∶1的比例随机分为两组：
依维莫司＋内分泌治疗组101例：依维莫司每天口服10毫克＋来曲唑每天口服2.5毫克＋戈舍瑞林每28天皮下注射3.6毫克
内分泌治疗组98例：来曲唑每天口服2.5毫克＋戈舍瑞林每28天皮下注射3.6毫克
若内分泌治疗组患者发生疾病进展，则允许交叉接受依维莫司。2015年1月5日～2019年12月30日对意向治疗患者进行分析。主要终点为无进展生存，定义为随机分组至确认疾病进展或任何原因所致死亡的时间。
结果，依维莫司＋内分泌治疗组与内分泌治疗组的患者相比：
中位无进展生存：19.4个月比12.9个月（95%置信区间：16.3～22.0、7.6～15.7）
进展或死亡风险：减少36%（风险比：0.64，95%置信区间：0.46～0.89，P=0.008）
内分泌治疗组56例患者（57.1%）交叉接受依维莫司，交叉后中位无进展生存5.5个月（95%置信区间：3.8～8.2个月）。
因此，该多中心小样本非盲随机对照二期临床研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌他莫昔芬耐药绝经前女性，来曲唑＋戈舍瑞林±依维莫司相比，无进展生存显著较长，故有必要进一步开展大样本双盲安慰剂随机对照三期临床研究进行验证。
相关链接
JAMA Oncol. 2021 Aug 26. Online ahead of print.
Effectiveness of Adding Everolimus to the First-line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial.
Fan Y, Sun T, Shao Z, Zhang Q, Ouyang Q, Tong Z, Wang S, Luo Y, Teng Y, Wang X, Wang S, Liu Q, Feng J, Shen K, Song Y, Wang J, Ma F, Li Q, Zhang P, Xu B.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Liaoning Cancer Hospital & Institute, Shenyang, China; Fudan University Shanghai Cancer Center, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China; Hunan Cancer Hospital, Changsha, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Sun Yat-sen University Cancer Center, Guangzhou, China; The First Hospital of China Medical University, Shenyang, China; Zhejiang Cancer Hospital, Hangzhou, China; Peking University People's Hospital, Beijing, China; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Jiangsu Cancer Hospital, Nanjing, China; Ruijin Hospital of Shanghai Jiaotong University, Shanghai, China; The First Hospital of Jilin University, Changchun, China.
This randomized clinical trial compares the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with hormone receptor-positive, ERBB2-negative advanced breast cancer who experienced disease progression during selective estrogen receptor modulator treatment.
QUESTION: Is the addition of everolimus to endocrine therapy effective in the first-line treatment of hormone receptor (HR)-positive, ERBB2-negative premenopausal advanced breast cancer after disease progression during selective estrogen receptor modulator (SERM) treatment?
FINDINGS: In this randomized clinical trial of 199 premenopausal women with SERM-resistant, HR-positive, ERBB2-negative advanced breast cancer, those who received everolimus plus endocrine therapy (letrozole) had longer progression-free survival compared with those who received letrozole alone. The addition of everolimus to the same endocrine agent was effective even after disease progression.
MEANING: Everolimus plus letrozole is effective in the first-line treatment of premenopausal patients with SERM-resistant, HR-positive, ERBB2-negative advanced breast cancer.
IMPORTANCE: The effectiveness of the mammalian target of rapamycin (mTOR) inhibitor everolimus in premenopausal women with hormone receptor (HR)-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving selective estrogen receptor modulators (SERMs) is unknown.
OBJECTIVE: To compare the effectiveness of everolimus plus letrozole vs letrozole alone in premenopausal women with HR-positive/ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs.
DESIGN, SETTING, AND PARTICIPANTS: The Everolimus Trial for Advanced Premenopausal Breast Cancer (MIRACLE) was a multicenter, open-label phase 2 randomized clinical trial of everolimus plus letrozole vs letrozole alone as first-line treatment conducted from December 8, 2014, to September 26, 2018. Participants included premenopausal women with HR-positive, ERBB2-negative advanced breast cancer who experienced disease progression while receiving SERMs. Analysis was performed on an intent-to-treat basis from January 5, 2015, to December 30, 2019.
EXPOSURES: Patients were randomly assigned in a 1:1 ratio to receive everolimus (10 mg orally once daily) plus letrozole (2.5 mg orally once daily) (n = 101) or letrozole alone (2.5 mg orally once daily) (n = 98). Both groups received goserelin, 3.6 mg, subcutaneously on day 1 of each 28-day cycle. Patients in the letrozole group were permitted to cross over to receive everolimus with letrozole if disease progression occurred.
MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS), defined as the time from randomization to confirmed disease progression or death due to any cause.
RESULTS: A total of 199 women (mean [SD] age, 44.3 [6.3] years) were randomized. Patients receiving everolimus plus letrozole achieved a significantly longer median PFS compared with those receiving letrozole alone (19.4 months [95% CI, 16.3-22.0 months] vs 12.9 months [95% CI, 7.6-15.7 months]; hazard ratio, 0.64 [95% CI, 0.46-0.89]; P = .008). A total of 56 of the 98 patients in the letrozole group (57.1%) were crossed over to also receive everolimus. The median PFS after crossover was 5.5 months (95% CI, 3.8-8.2 months).
CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, PFS was significantly longer among premenopausal patients with HR-positive/ERBB2-negative advanced breast cancer who received everolimus plus letrozole than among those who received letrozole alone. The results revealed that everolimus was effective even among patients receiving treatment with the same endocrine agent after disease progression.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02313051
PMID: 34436536
DOI: 10.1001/jamaoncol.2021.3428