Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma
Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma
复制标题
DOI：
10.1038/s41388-020-01519-1
复制
发表时间：
2020-10-23
期刊：
影响因子：
8
通讯作者：
Villanueva, Augusto
中科院分区：
文献类型：
--
作者：
von Felden, Johann;Craig, Amanda J.;Villanueva, Augusto
关于晚期肝细胞癌（HCC）的突变景观知之甚少，缺乏对系统治疗反应的预测性生物标志物。我们的目的是描述晚期HCC的突变情况，并使用循环肿瘤DNA（ctDNA）确定对系统治疗的原发性耐药的预测因子。我们在2015年10月至2019年1月期间前瞻性入组了121例患者。我们对25个基因进行了靶向超深度测序，并对TERT启动子进行了Digital Droplet PCR，包括整个治疗过程中的连续样本。主要终点是按ctDNA突变谱分层的无进展生存期（PFS）。次要终点为总生存期和客观缓解率。晚期HCC中最常见的ctDNA突变是TERT启动子（51%）、TP 53（32%）、CTNNB 1（17%）、PTEN（8%）、AXIN 1、ARID 2、KMT 2D和TSC 2（各6%）。TP 53和CTNNB 1突变是相互排斥的。在酪氨酸激酶抑制剂治疗后，PI 3 K/MTOR通路突变患者的PFS显著短于无突变患者（2.1 vs 3.7个月，p < 0.001），但在免疫检查点抑制（CPI）治疗后则不然。WNT通路突变与CPI后的PFS、总生存期或客观缓解无关。与治疗反应相关的子集中ctDNA的系列分析。晚期HCC中ctDNA的突变谱显示，与早期阶段相比，已知HCC驱动因素的突变频率相似，并确定了对全身治疗反应的预测性生物标志物。
Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.