2015年以来，细胞周期蛋白依赖性激酶CDK4和CDK6抑制剂哌柏西利已被广泛用于激素受体阳性晚期乳腺癌的一线治疗。虽然阿贝西利也于2015年被批准用于内分泌治疗耐药的晚期乳腺癌，但是阿贝西利对晚期乳腺癌哌柏西利耐药患者的临床效果尚不明确。
2021年3月24日，美国《国家综合癌症网络杂志》在线发表哈佛大学医学院、麻省总医院癌症中心、达纳法伯癌症研究所、麻省理工学院哈佛布罗德研究所、南佛罗里达大学莫菲特癌症中心、贝勒大学医学中心、圣路易斯华盛顿大学、匹兹堡大学、哥伦比亚大学欧文医学中心的研究报告，探讨了阿贝西利治疗晚期乳腺癌哌柏西利耐药患者的临床结局。
该多中心队列研究对截至2019年5月1日美国6家癌症中心合计87例激素受体阳性晚期乳腺癌哌柏西利耐药后接受阿贝西利治疗患者的临床特征、结局、毒性、生物学预测标志物进行回顾分析。
结果，哌柏西利耐药患者对阿贝西利的耐受性良好，仅少数患者（9.2%）由于毒性反应（并非疾病进展）而停用阿贝西利。
大多数哌柏西利耐药患者（71.3%）接受阿贝西利治疗前间隔至少1个非CDK4/6抑制剂方案。
大多数患者接受了阿贝西利＋抗雌激素药物，氟维司群占47.1%、芳香酶抑制剂占27.6%，其余接受了阿贝西利单药治疗（19.5%）。
阿贝西利治疗后的中位无进展生存5.3个月，中位总生存17.2个月，这与MONARCH-1研究阿贝西利单药治疗难治型激素受体阳性HER2阴性晚期乳腺癌的结果相似。
共计36.8%的患者接受阿贝西利治疗至少6个月。哌柏西利治疗期间临床获益持续时间，对随后阿贝西利治疗持续时间的影响不大。
对于阿贝西利治疗期间疾病快速进展患者，RB1、ERBB2、CCNE1基因突变发生率显著较高。
因此，该多中心小样本回顾研究结果表明，一部分激素受体阳性晚期乳腺癌哌柏西利耐药患者仍可对阿贝西利治疗获益，故有必要进一步开展多中心大样本前瞻研究，确认对CDK4/6抑制剂治疗交叉耐药的分子学预测标志物，并更好地分析哌柏西利耐药患者阿贝西利疗效特征。
J Natl Compr Canc Netw. 2021 Mar 24. Online ahead of print.
Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.
Wander SA, Han HS, Zangardi ML, Niemierko A, Mariotti V, Kim LSL, Xi J, Pandey A, Dunne S, Nasrazadani A, Kambadakone A, Stein C, Lloyd MR, Yuen M, Spring LM, Juric D, Kuter I, Sanidas I, Moy B, Mulvey T, Vidula N, Dyson NJ, Ellisen LW, Isakoff S, Wagle N, Brufsky A, Kalinsky K, Ma CX, O'Shaughnessy J, Bardia A.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Boston, Massachusetts; Moffitt Cancer Center, Tampa, Florida; Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas; Washington University, St. Louis, Missouri; University of Pittsburgh, Pittsburgh, Pennsylvania; Columbia University Irving Medical Center, New York, New York.
BACKGROUND: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i.
PATIENTS AND METHODS: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers.
RESULTS: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naive patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib.
CONCLUSIONS: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.
PMID: 33761455
DOI: 10.6004/jnccn.2020.7662
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