Schiavon Gaia, Hrebien Sarah, Garcia-Murillas Isaac, Cutts Rosalind J, Pearson Alex, Tarazona Noelia, Fenwick Kerry, Kozarewa Iwanka, Lopez-Knowles Elena, Ribas Ricardo, Nerurkar Ashutosh, Osin Peter, Chandarlapaty Sarat, Martin Lesley-Ann, Dowsett Mitch, Smith Ian E, Turner Nicholas C
The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
Sci Transl Med. 2015 Nov 11;7(313):313ra182. doi: 10.1126/scitranslmed.aac7551.
Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with advanced breast cancer. ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies and was accurately assessed in samples shipped at room temperature in preservative tubes. ESR1 mutations were found exclusively in estrogen receptor-positive breast cancer patients previously exposed to AI. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy [hazard ratio, 3.1; 95% confidence interval (CI), 1.9 to 23.1; P = 0.0041]. ESR1 mutation prevalence differed markedly between patients who were first exposed to AI during the adjuvant and metastatic settings [5.8% (3 of 52) versus 36.4% (16 of 44), respectively; P = 0.0002]. In an independent cohort, ESR1 mutations were identified in 0% (0 of 32; 95% CI, 0 to 10.9) tumor biopsies taken after progression on adjuvant AI. In a patient with serial sampling, ESR1 mutation was selected during metastatic AI therapy to become the dominant clone in the cancer. ESR1 mutations can be robustly identified with ctDNA analysis and predict for resistance to subsequent AI therapy. ESR1 mutations are rarely acquired during adjuvant AI but are commonly selected by therapy for metastatic disease, providing evidence that mechanisms of resistance to targeted therapy may be substantially different between the treatment of micrometastatic and overt metastatic cancer.
获得性ESR1突变是对芳香化酶抑制剂（AI）耐药的主要机制。我们开发了用于检测循环肿瘤DNA（ctDNA）中ESR1突变的超高灵敏度多重数字聚合酶链反应检测方法，并研究了171例晚期乳腺癌女性患者中ESR1突变的临床相关性及来源。ctDNA中的ESR1突变状态与同期肿瘤活检结果高度一致，并且在室温下保存在保存管中的样本中也能准确评估。ESR1突变仅在先前接受过AI治疗的雌激素受体阳性乳腺癌患者中发现。ESR1突变患者在后续基于AI的治疗中无进展生存期显著缩短[风险比，3.1；95%置信区间（CI），1.9至23.1；P = 0.0041]。首次在辅助治疗和转移阶段接触AI的患者中，ESR1突变发生率显著不同[分别为5.8%（52例中的3例）和36.4%（44例中的16例）；P = 0.0002]。在一个独立队列中，辅助AI治疗进展后采集的肿瘤活检样本中未发现ESR1突变（32例中的0例；95% CI，0至10.9）。在一名进行连续采样的患者中，ESR1突变在转移性AI治疗期间被选择成为癌症中的优势克隆。通过ctDNA分析可以可靠地鉴定ESR1突变，并预测对后续AI治疗的耐药性。ESR1突变在辅助AI治疗期间很少获得，但在转移性疾病治疗中通常会被治疗选择，这表明微转移癌和明显转移癌的靶向治疗耐药机制可能存在很大差异。
