Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Guardant Health, Redwood City, California.
Clin Cancer Res. 2020 Jun 1;26(11):2546-2555. doi: 10.1158/1078-0432.CCR-19-2933. Epub 2020 Feb 7.
PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of mutations.
Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in , and distinguishes somatic/reversion from germline mutations with high accuracy.
Among 828 patients, one or more deleterious mutations were detected in 60 (7.2%) patients, including germline ( = 42) and somatic ( = 18) mutations. Common coexisting mutations included (61.6%), (30%), (26.6%), (15%), and (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.
cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂（PARPi）在多种携带有胚系（和可能的体细胞）突变的癌症中有效。获得的回复突变可以恢复功能，导致对 PARPi 和/或铂类化疗的耐药性。尚未确定鉴定 中胚系、体细胞和/或回复突变患者的最佳方法。循环游离 DNA（cfDNA）的下一代测序（NGS）提供了一种识别这三种类型 突变的平台。
使用经过临床验证的 73 基因 cfDNA 检测方法对晚期乳腺癌、卵巢癌、前列腺癌或胰腺癌患者进行检测，该方法评估 中的单核苷酸变异和插入缺失突变（indels），并以高精度区分体细胞/回复突变与胚系突变。
在 828 名患者中，60 名（7.2%）患者检测到一个或多个有害 突变，包括胚系（=42）和体细胞（=18）突变。常见共存突变包括 （61.6%）、 （30%）、 （26.6%）、 （15%）和 （11.5%）。在 42 名胚系突变患者中有 9 名（21.4%）检测到多克隆回复突变（中位数，5），其中大多数（77.7%）患者曾接受过 PARPi 治疗（中位时间，10 个月）。在初始 PARPi 暴露的治疗压力下，cfDNA 显示出回复 突变的出现，这导致了对 PARPi 和铂类治疗的后续耐药性。
cfDNA NGS 在没有预先了解胚系或组织检测结果的情况下，鉴定出了高比例的治疗相关突变，包括胚系检测错过的有害体细胞 突变和具有重要治疗意义的回复突变。需要进一步的研究来证实这些发现的临床实用性，以指导晚期恶性肿瘤患者的精准医学方法。
