细胞游离DNA雌激素受体α突变发生率与转移性乳腺癌结局：BOLERO-2临床试验二次分析
2016年8月11日，《美国医学会杂志·肿瘤学》在线发表纽约纪念斯隆-凯特林癌症中心、诺华制药、维也纳医科大学、德克萨斯大学MD安德森癌症中心的研究报告，发现雌激素受体α（ESR1）突变与雌激素受体阳性转移性乳腺癌患者预后较差有相关性。
该研究对3期双盲临床试验（BOLERO-2）24个国家189个中心724例转移性乳腺癌女性血液标本分离出来的细胞游离DNA（cfDNA）采用液滴数字聚合酶链反应（ddPCR）二次分析两种最常见的ESR1突变（Y537S和D538G）。所有女性都随机接受芳香化酶抑制剂依西美坦＋安慰剂或依西美坦＋mTORC1抑制剂依维莫司治疗。
结果，在541例可评估患者（74.7%）血浆标本cfDNA中，发现D538G突变114例（21.1%）、Y537S突变72例（13.3%）、D538G突变和Y537S突变30例（5.5%）。
其中，无突变、D538G突变、Y537S突变、同时突变患者的总生存分别为32.1、25.99、19.98、15.15个月。依西美坦＋安慰剂、依西美坦＋依维莫司的患者无进展生存分别为3.2、7.8个月，依西美坦＋依维莫司的D538G突变与无突变患者无进展生存相似。依西美坦＋依维莫司病例数量有限，Y537S突变与无进展生存未见显著相关性，有迹象表明该突变可能干扰mTOR抑制剂效果，但是尚未发现等位基因与mTOR通路变化有相关性。
因此，两种ESR1突变（D538G和Y537S）在雌激素受体阳性转移性乳腺癌患者中非常普遍，并且与治疗效果较差有相关性。依西美坦＋依维莫司可增加无进展生存。由于缺乏足够的Y537S变异病例数，无法确定依维莫司的益处。初步数据表明，无论Y537S单独突变或Y537S和D538G共同突变，均与疾病生物学侵袭性较高有相关性。
对此，德克萨斯医学中心贝勒医学院的乳腺肿瘤内科分子细胞生物学家发表同期述评，认为ESR1突变在乳腺癌细胞游离DNA中或为预测疗效的“冰山一角”。
JAMA Oncol. 2016 Aug 11. [Epub ahead of print]
Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial.
Sarat Chandarlapaty; David Chen; Wei He; Patricia Sung; Aliaksandra Samoila; Daoqi You; Trusha Bhatt; Parul Patel; Maurizio Voi; Michael Gnant; Gabriel Hortobagyi; José Baselga; Mary Ellen Moynahan.
Memorial Sloan Kettering Cancer Center, New York, New York; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; University of Texas MD Anderson Cancer Center, Houston.
Importance: Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established.
Objective: To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes.
Design, Setting, and Participants: From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm.
Interventions: Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo.
Main Outcomes and Measures: The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival.
Results: Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane.
Conclusions and Relevance: ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology.
Trial Registration: clinicaltrials.gov Identifier: NCT00863655
DOI: 10.1001/jamaoncol.2016.1279
JAMA Oncol. 2016 Aug 11. [Epub ahead of print]
ESR1 Mutations in Cell-Free DNA of Breast Cancer: Predictive "Tip of the Iceberg"
Suzanne A. W. Fuqua; Yassine Rechoum; Guowei Gu.
Lester and Sue Smith Breast Center, Dan L. Duncan Cancer Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
DOI: 10.1001/jamaoncol.2016.1268
联系客服
