Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition.
Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition.
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DOI：
10.1158/2159-8290.cd-17-0261
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发表时间：
2017-09
期刊：
影响因子：
28.2
通讯作者：
TOPARP-A investigators
中科院分区：
文献类型：
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作者：
Goodall J;Mateo J;Yuan W;Mossop H;Porta N;Miranda S;Perez-Lopez R;Dolling D;Robinson DR;Sandhu S;Fowler G;Ebbs B;Flohr P;Seed G;Rodrigues DN;Boysen G;Bertan C;Atkin M;Clarke M;Crespo M;Figueiredo I;Riisnaes R;Sumanasuriya S;Rescigno P;Zafeiriou Z;Sharp A;Tunariu N;Bianchini D;Gillman A;Lord CJ;Hall E;Chinnaiyan AM;Carreira S;de Bono JS;TOPARP-A investigators
在转移性前列腺癌（mPC）中需要用于更精确的患者护理的生物标志物。我们报告了一项在mPC中进行的聚（ADP）-核糖聚合酶（PARP）抑制剂olaparib的II期试验（TOPARP-A），证明了与同源重组DNA修复缺陷相关的抗肿瘤活性。我们现在报告在本试验期间收集的系列循环游离DNA（cfDNA）样品的靶向和全外显子组测序。cfDNA浓度的降低与多变量分析中的结果独立相关（第8周时总生存期的HR：0.19; 95%CI 0.06-0.56 p=0.003）。在cfDNA中可检测到所有肿瘤组织体细胞DNA修复突变;体细胞突变的等位基因频率在响应患者中选择性降低（卡方p<0.001）。在疾病进展时，在奥拉帕尼应答后，多个亚克隆畸变将种系和体细胞DNA修复突变（BRCA 2、PALB 2）恢复到正常范围内，成为耐药机制。这些数据支持液体活检作为mPC的预测、预后、反应和耐药性生物标志物的作用。
Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95%CI 0.06-0.56 p=0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (Chi-squared p<0.001). At disease progression, following response to olaparib, multiple sub-clonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as predictive, prognostic, response and resistance biomarker in mPC.