Alterations in DNA Damage Repair Genes in Primary Liver Cancer.

PURPOSE: Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC). EXPERIMENTAL
DESIGN: Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board.
RESULTS: A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response.
CONCLUSIONS: The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment. ©2019 American Association for Cancer Research.