2015年以來，細(xì)胞周期蛋白依賴性激酶CDK4和CDK6抑制劑哌柏西利已被廣泛用于激素受體陽性晚期乳腺癌的一線治療。雖然阿貝西利也于2015年被批準(zhǔn)用于內(nèi)分泌治療耐藥的晚期乳腺癌，但是阿貝西利對晚期乳腺癌哌柏西利耐藥患者的臨床效果尚不明確。

　　2021年3月24日，美國《國家綜合癌癥網(wǎng)絡(luò)雜志》在線發(fā)表哈佛大學(xué)醫(yī)學(xué)院、麻省總醫(yī)院癌癥中心、達(dá)納法伯癌癥研究所、麻省理工學(xué)院哈佛布羅德研究所、南佛羅里達(dá)大學(xué)莫菲特癌癥中心、貝勒大學(xué)醫(yī)學(xué)中心、圣路易斯華盛頓大學(xué)、匹茲堡大學(xué)、哥倫比亞大學(xué)歐文醫(yī)學(xué)中心的研究報(bào)告，探討了阿貝西利治療晚期乳腺癌哌柏西利耐藥患者的臨床結(jié)局。

　　該多中心隊(duì)列研究對截至2019年5月1日美國6家癌癥中心合計(jì)87例激素受體陽性晚期乳腺癌哌柏西利耐藥后接受阿貝西利治療患者的臨床特征、結(jié)局、毒性、生物學(xué)預(yù)測標(biāo)志物進(jìn)行回顧分析。

　　結(jié)果，哌柏西利耐藥患者對阿貝西利的耐受性良好，僅少數(shù)患者（9.2%）由于毒性反應(yīng)（并非疾病進(jìn)展）而停用阿貝西利。

　　大多數(shù)哌柏西利耐藥患者（71.3%）接受阿貝西利治療前間隔至少1個(gè)非CDK4/6抑制劑方案。

　　大多數(shù)患者接受了阿貝西利＋抗雌激素藥物，氟維司群占47.1%、芳香酶抑制劑占27.6%，其余接受了阿貝西利單藥治療（19.5%）。

　　阿貝西利治療后的中位無進(jìn)展生存5.3個(gè)月，中位總生存17.2個(gè)月，這與MONARCH-1研究阿貝西利單藥治療難治型激素受體陽性HER2陰性晚期乳腺癌的結(jié)果相似。

　　共計(jì)36.8%的患者接受阿貝西利治療至少6個(gè)月。哌柏西利治療期間臨床獲益持續(xù)時(shí)間，對隨后阿貝西利治療持續(xù)時(shí)間的影響不大。

　　對于阿貝西利治療期間疾病快速進(jìn)展患者，RB1、ERBB2、CCNE1基因突變發(fā)生率顯著較高。

　　因此，該多中心小樣本回顧研究結(jié)果表明，一部分激素受體陽性晚期乳腺癌哌柏西利耐藥患者仍可對阿貝西利治療獲益，故有必要進(jìn)一步開展多中心大樣本前瞻研究，確認(rèn)對CDK4/6抑制劑治療交叉耐藥的分子學(xué)預(yù)測標(biāo)志物，并更好地分析哌柏西利耐藥患者阿貝西利療效特征。

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