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Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer.
Annals of Oncology ( IF 56.7 ) Pub Date : 2018-01-01 , DOI: 10.1093/annonc/mdx483
C Fribbens 1, 2 , I Garcia Murillas 1 , M Beaney 1 , S Hrebien 1 , B O'Leary 1 , L Kilburn 3 , K Howarth 4 , M Epstein 4 , E Green 4 , N Rosenfeld 4, 5, 6 , A Ring 2 , S Johnston 2 , N Turner 1, 2
Affiliation  

Background Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Patients and methods Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI. Results Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival. Conclusions Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

中文翻译:


通过转移性乳腺癌循环肿瘤 DNA 分析追踪芳香酶抑制剂耐药性的演变。



背景 抗性突变的选择可能在内分泌抗性的发展中发挥重要作用。 ESR1 突变在原发性乳腺癌中很少见,但在接受芳香酶抑制剂 (AI) 治疗的晚期乳腺癌患者中发生率很高。我们使用晚期乳腺癌患者的连续 ctDNA 采样研究了一线 AI 疗法的遗传耐药性的演变。患者和方法 83 名接受一线 AI 治疗转移性乳腺癌的患者被纳入一项前瞻性研究。每 3 个月收集一次血浆样本,观察疾病进展情况,并通过数字微滴 PCR 和增强型标记扩增子测序 (eTAm-Seq) 进行 ctDNA 分析。通过测序在进展样本中识别出的突变在进展前通过样本进行追踪,以研究治疗中突变的演变。在 Faslodex 与依西美坦加或不加瑞宁得的研究 (SoFEA) 试验中,新突变的频率在可用基线血浆样本的独立队列中得到验证,该试验纳入了既往对 AI 敏感的患者。结果 在接受一线 AI 治疗后出现进展的 39 名患者中,56.4% (22/39) 的患者在进展时可检测到 ESR1 突变,其中 40.9% (9/22) 的患者为多克隆突变。在连续追踪中,在临床进展前中位 6.7 个月(95% 置信区间 3.7-NA)可检测到 ESR1 突变。利用进展血浆的 eTAm-Seq ctDNA 测序,证明 72.2% (13/18) 的患者中 ESR1 突变为亚克隆。在 15.4% (6/39) 的进展患者中发现 RAS 基因突变(4 名 KRAS、1 名 HRAS、1 名 NRAS)。在 SoFEA 中,21 例中检测到 KRAS 突变。2% (24/113) 的患者,尽管没有证据表明 KRAS 突变状态可预测无进展生存或总生存。结论 一线 AI 进展的癌症表现出高水平的遗传异质性,并伴有频繁的亚克隆突变。亚克隆 KRAS 突变的发现频率很高。 AI 耐药癌症的遗传多样性可能会限制后续的靶向治疗方法。
更新日期:2018-01-26
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