Background: Mutations in TP53 and CTNNB1 are common in resected early stage HCC tumors. The frequency and prognostic impact of these and other mutations in advanced HCC is not known. We conducted this retrospective analysis using NGS to explore for association between tumor genetics, clinicopathologic features, and prognosis in an advanced HCC cohort. Methods: Archival samples were obtained from patients with unresectable HCC or mixed HCC-cholangiocarcinoma (CCA) enrolled on NCT01008917 or NCT01687673 clinical trials of sorafenib plus temsirolimus. Tumor and germline (blood) DNA pairs were sequenced using a capture-based 500+-gene NGS panel (UCSF500). Analysis was based on human reference sequence UCSC build hg19. Variants were called using GATK Unified Genotyper. Somatic, non-synonymous, exonic calls were curated using COSMIC, cBioPortal, and Pubmed. Overall survival (OS) was calculated from start of sorafenib. Results: Cohort (N = 26): HCC (n = 24), mixed HCC-CCA (n = 2); BCLC stage: B 11%, C 88%; male: 85%; race: Asian 35%, white 54%; etiology: HBV 31%, HCV 38%; source: liver 85%, metastasis 15%. NGS identified cardinal HCC mutations, some at higher frequency than reported in early stage cohorts (Table). There was no significant relationship between mutation and etiology, stage, or other clinical covariates. Median OS was 324 (95% CI: 203, 815) days, with no significant difference by mutation though CTNNB1 mutants had trend towards longer OS (452 vs. 203 days, p = 0.08). Conclusions: NGS in this advanced HCC cohort identified higher frequencies of TP53 and CDKN2Amutations than have been reported in early stage HCC resection cohorts, suggesting difference in biology between early and advanced stages. Tumor genetic biomarkers warrant further study in larger advanced HCC populations to determine if associated with prognosis or treatment response.

¹TCGA cBioPortal: http://bit.ly/1MeZzuF; *Data for 2 additional cases pending.