Carneiro B A, Collier K A, Nagy R J, Pamarthy S, Sagar V, Fairclough S, Odegaard J, Lanman R B, Costa R, Taxter T, Kuzel T M, Fan A, Chae Y K, Cristofanilli M, Hussain M H, Abdulkadir S A, Giles F J
Developmental Therapeutics Program, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
JCO Precis Oncol. 2018;2. doi: 10.1200/PO.17.00176. Epub 2018 Feb 14.
PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in or genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline mutation with acquired resistance to olaparib related to biallelic reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline mutations. Within the germline -positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.
PARP1/2抑制剂对BRCA2缺陷型肿瘤有效。PARP抑制剂（PARPi）奥拉帕利获得了美国食品药品监督管理局（FDA）的突破性认定，用于治疗携带 或 基因 突变的转移性去势抵抗性前列腺癌（CRPC）。对PARPi的获得性耐药与肿瘤特异性BRCA2突变有关，这些突变恢复了正常开放阅读框，挽救了同源重组。我们描述了一例患有胚系 突变的转移性CRPC病例，该病例对奥拉帕利产生了获得性耐药，这与通过循环肿瘤DNA检测发现的胚系和体细胞功能丧失等位基因的双等位基因 回复突变有关。我们还总结了一项对1534例前列腺癌病例进行的回顾性分析，ctDNA分析显示胚系 突变的发生率为1.6%。在接受铂类化疗或PARP抑制的胚系 阳性病例中，回复突变的发生率为40%。本报告记录了携带BRCA突变的大量前列腺癌患者中回复突变的频率。它还显示了ctDNA分析在早期检测驱动肿瘤耐药的回复突变方面的潜在效用。
