Landscape of DNA-damage-repair/homologous recombination deficiency (DDR/HRD) in hepatopancreaticobiliary (HPB) cancers.

Abstract

4620 Background: Biallelic HR-gene mutations (HRm) confer HRD and sensitivity to DDR-targeted therapies including platinum and PARPi in pancreatic cancer (PDAC). The landscape of DDR/HRD phenotypes in HPB cancers and their clinical implication is yet to be evaluated, the subject of this effort. Methods: Hybrid capture-based comprehensive genomic profiling was performed in a CLIA-certified, CAP-accredited lab (Foundation Medicine, Inc.) on up to 395 genes, including the HR-genes ( BRCA1/2, PALB2, RAD50/51B/C/D, MRE11, ATRX, ATR, ATM, BAP1, BRIP1, CHEK2, NBN, and FANCA). Putative DDR/HRD phenotype was assessed using percent genome under LOH (gLOH) (PMID: 28916367). Variant zygosity was assessed as previously described (PMID: 29415044). From an independent PDAC subgroup among HPB cancers, we evaluated their outcomes on first-line platinum. Results: From a total of 11,174 tumors, pathogenic DDR/HRm were identified in 18% (1980/11174) of HPB cancers, 15% (863/5941) of PDAC, 25% (744/2998) of cholangiocarcinoma, 15% (141/958) of hepatocellular carcinoma, and 17% (152/873) of gallbladder carcinoma. We observed a majority (63%) of DDR/HRm with LOH. Rigorous filtering for tumor purity and copy number quality metrics yielded 34% (4051/11774) cases evaluable. The median gLOH of any biallelic DDR/HRm was 12.9% compared to 8.8% in no DDR/HRm (p=5.7E-33). Strength of the association varied by gene, with the strongest association in BRCA1 (22.3, p=1.5E-10), BRCA2 (20.1, p=1.7E-35), RAD51C (16.7, p=7.8E-4), PALB2 (16.4, p=1.4E-5), BRIP1 (14.3, p=0.02), RAD51B (13.7, p=0.02), and ATM (13.6, p=7.7E-12) (Table). Most other DDR/HR-genes and monoallelic DDR/HRm had weak gLOH. PDAC accounted for 60% of this HPB dataset. In an independent dataset of PDAC at MSK (n=262), biallelic DDR/HRm patients (n=29, 11%) had mostly germline mutations and had significantly improved median PFS on first-line platinum vs. non-platinum (13.3 [95%CI: 9.57-NR] vs 3.8 [95%CI: 2.79-NR] months, p<0.0001). Conclusions: Biallelic DDR/HRm is a distinct population of HPB cancers beyond PDAC and may confer better phenotype in DDR-targeted treatment. Further independent validation is underway. [Table: see text]