Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer
Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer
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DOI：
10.1158/1078-0432.ccr-17-1941
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发表时间：
2017-12-15
影响因子：
11.5
通讯作者：
Jones, Steven J. M.
中科院分区：
文献类型：
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作者：
Zhao, Eric Y.;Shen, Yaoqing;Jones, Steven J. M.
目的：最近的研究已经在超过20%的乳腺癌以及胰腺癌、卵巢癌和胃癌中发现了同源重组缺陷(HRD)的突变特征。迫切需要了解HRD信号的临床意义。虽然BRCA1/2突变赋予了铂类化疗的敏感性，但尚不清楚突变特征是否可以独立预测铂类药物的疗效。实验设计：在这项观察性研究中，我们对93例晚期乳腺癌(33例铂类治疗)的肿瘤全基因组(100倍深度)和匹配的正常人(60倍)进行了测序。我们计算了一种名为HRDetect的已发表指标，该指标经过独立训练以预测BRCA1/2状态，并评估了其预测铂类化疗结果的能力。临床终点为总生存期(OS)、铂类药物治疗总持续时间(TDT)和临床改善的放射学证据(CI)。结果：HRDetect预测BRCA1/2状态的曲线下面积(AUC)为0.94，最佳阈值为0.7。即使在调整了BRCA1/2突变状态和治疗时机后，HRDetect升高也与以铂为基础的治疗的CI显著相关(AUC0.89；P=0.006)，具有相同的最佳阈值。HRDetect评分大于0.7时，TDT延长3个月(P=0.0003)，OS延长1.3年(P=0.04)。结论：我们的研究结果不仅独立地验证了HRDetect的有效性，而且首次为其与晚期乳腺癌铂类药物疗效的相关性提供了证据。我们证明，HRD突变特征可以提供独立于BRCA1/2突变状态的临床相关信息，并希望这项工作将指导临床试验的发展。(C)2017年AACR。
Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRDsignatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.Experimental Design: In this observational study, we sequenced tumor whole genomes (100 x depth) and matched normals (60 x) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. (C) 2017 AACR.