王者之蝶Ｅ：乳腺癌术后魔戒克星
人类成年以后，正常细胞的有丝分裂周期大多逐渐减缓停滞，这主要受到周期蛋白及其周期蛋白依赖性激酶（CDK）控制。其中，周期蛋白D1及其CDK4和CDK6主要控制细胞有丝分裂周期由DNA合成前期进入DNA合成期。激素受体阳性乳腺癌细胞在雌激素和雌激素受体的刺激下，周期蛋白D1及其CDK4和CDK6结合，将抑癌蛋白Rb磷酸化而失去抑癌作用，细胞有丝分裂周期失控，从而陷入疯狂增殖的恶性循环。对于内分泌治疗耐药的激素受体阳性乳腺癌患者，CDK4和CDK6抑制剂可有效阻断该恶性循环。现有3种CDK4和CDK6抑制剂：哌柏西利、阿贝西利、瑞博西利，都可显著改善激素受体阳性晚期乳腺癌内分泌治疗患者的无进展生存和总生存。不过，目前仅2020年公布的MonarchE研究2年随访报告证实，阿贝西利可显著改善激素受体阳性高风险早期乳腺癌术后内分泌辅助治疗患者的无浸润病变生存和无远处复发生存。
monarchE (NCT03155997): A Randomized, Open-Label, Phase 3 Study of Abemaciclib Combined With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone in Patients With High Risk, Node Positive, Early Stage, Hormone Receptor Positive, Human Epidermal Receptor 2 Negative, Breast Cancer
2021年10月14日，欧洲肿瘤内科学会《肿瘤学报》在线发表德国慕尼黑大学医院、埃尔朗根纽伦堡大学、汉诺威医学院、美国礼来、匹兹堡大学、NSABP基金会、哈佛大学达纳法伯癌症研究所、梅奥医学中心、旧金山加利福尼亚大学、莎拉坎农研究所田纳西肿瘤医院、贝勒大学医学中心德克萨斯肿瘤医院、西班牙马德里康普顿斯大学、巴塞罗那大学肿瘤研究所、马德里欧洲大学、中国复旦大学附属肿瘤医院、中国台湾大学医学院附设医院、墨西哥卡米诺医疗集团、俄罗斯癌症研究中心、波兰格但斯克医科大学、巴西圣保罗临床研究中心、丹麦哥本哈根大学王国医院、日本东京国立癌症中心医院、京都大学医院、意大利热那亚大学圣马蒂诺综合医院、帕多瓦大学威尼托肿瘤研究所、奥地利维也纳医科大学、韩国延世大学癌症中心、英国伦敦大学皇家马斯登医院的monarchE研究3年随访报告，对激素受体阳性高风险早期乳腺癌术后阿贝西利＋内分泌辅助治疗的有效性和安全性进行了更新，并对增殖指数Ki-67进行了分析。
该全球多中心非盲随机对照三期临床研究于2017年7月～2019年8月从全球38个国家地区603家医院入组激素受体阳性且人类表皮生长因子受体HER2阴性高风险早期乳腺癌术后完成放疗和（或）化疗患者5637例，按1∶1随机分为两组，给予内分泌治疗≥5年±阿贝西利2年（每天2次口服150毫克）。其中，队列1入组患者≥4枚腋窝淋巴结阳性或1～3枚腋窝淋巴结阳性且病变组织学分级为3级或肿瘤≥5厘米，队列2入组患者1～3枚腋窝淋巴结阳性且集中确定Ki-67≥20%。主要终点为意向治疗人群（队列1和队列2）无浸润病变生存，次要终点包括Ki-67较高患者（队列2）无浸润病变生存、无远处复发生存、总生存和安全性。
结果，主要结局分析时，中位随访19个月，内分泌治疗±阿贝西利相比：
浸润病变或死亡风减少29%（风险比：0.71，95%置信区间：0.58～0.87，标称P=0.0009）。
次要结局随访分析时，中位随访27个月，90%的患者结束治疗，内分泌治疗±阿贝西利相比：
浸润病变或死亡风险减少30%（风险比：0.70，95%置信区间：0.59～0.82，标称P<0.0001）
远处无复或死亡风险减少31%（风险比：0.69，95%置信区间：0.57～0.83，标称P<0.0001）
3年无浸润病变生存率高5.4%
3年无远处复发生存率高4.2%
虽然Ki-67指数具有预后意义，可结合临床病理特征用于预测复发风险较高的患者，但是无论Ki-67指数如何，阿贝西利的获益一致。
安全性数据与已知的阿贝西利风险特征一致。
因此，该研究最新结果表明，对于激素受体阳性、HER2阴性、淋巴结阳性、高风险早期乳腺癌患者，阿贝西利可显著改善术后内分泌辅助治疗的无浸润病变生存和无远处复发生存，安全性可耐受。Ki-67指数具有预后意义，可结合临床病理特征用于预测复发风险较高的患者，但是无论Ki-67指数如何，都可见阿贝西利获益。总体而言，2年治疗期结束后，阿贝西利的治疗获益仍然显著。
相关链接
Ann Oncol. 2021 Oct 14. Online ahead of print.
Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.
Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, Huang CS, Jaliffe GG, Tryakin A, Goetz MP, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Del Mastro L, Steger GG, Kreipe H, Hegg R, Sohn J, Guarneri V, Cortés J, Hamilton E, André V, Wei R, Barriga S, Sherwood S, Forrester T, Munoz M, Shahir A, San Antonio B, Nabinger SC, Toi M, Johnston SRD, O'Shaughnessy J.
LMU University Hospital, Munich, Germany; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Medizinische Hochschule Hannover, Hannover, Germany; University of Pittsburgh/UPMC, NSABP Foundation, Pittsburgh, USA; Dana-Farber Cancer Institute, Boston, USA; Mayo Clinic, Rochester, USA; University of California San Francisco, San Francisco, USA; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA; Eli Lilly and Company, Indianapolis, USA; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, USA; Universidad Complutense, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Universidad Europea de Madrid, Madrid, Spain; Fudan University Shanghai Cancer Center, Shanghai, China; National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Grupo Medico Camino S.C., Mexico City, Mexico; N.N.Blokhin Russian Cancer Research Center, Moscow, Russia; Medical University of Gdańsk, Gdańsk, Poland; Instituto D'Or de Pesquisa e Ensino, Sao Paulo, Brazil; Clin. Pesq. e Centro Sao Paulo, Sao Paulo, Brazil; Rigshospitalet, Copenhagen, Denmark; National Cancer Center Hospital, Tokyo, Japan; Kyoto University Hospital, Kyoto, Japan; IRCSS Ospedale Policlinico San Martino, Genoa, Italy; Università di Genova, Genoa, Italy; University of Padova, Padua, Italy; Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy; Medical University of Vienna, Vienna, Austria; Yonsei Cancer Center, Seoul, Korea; Royal Marsden NHS Foundation Trust, London, UK.
HIGHLIGHTS
Adjuvant abemaciclib combined with ET improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer.
Abemaciclib benefit extended beyond the 2-year treatment period.
Ki-67 ≥20% was prognostic and may be used with clinicopathological features to identify patients at high risk of recurrence.
Adjuvant abemaciclib + ET benefited patients with high-risk clinicopathologic features regardless of Ki-67 index.
Safety data were consistent with the known abemaciclib risk profile.
BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis.
PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety.
RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile.
CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.
KEYWORDS: abemaciclib, adjuvant, CDK4/6, early breast cancer, Ki-67
DOI: 10.1016/j.annonc.2021.09.015
中国抗癌协会乳腺癌诊治指南与规范（2021年版）