Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and shows minimal response to existing chemotherapies. Tumor mutational burden (TMB) and microsatellite instability (MSI) are predictive biomarkers of response to immune checkpoint inhibitors. Comprehensive genomic profiling (CGP) is a hybrid capture-based next-generation sequencing (NGS) test that may help optimize therapy regimens for advanced stage HCC patients.
CGP of up to 315 cancer-related genes was performed on 614 consecutive cases of hepatocellular carcinoma (2012-16) using a hybrid-capture, adaptor ligation based NGS assay and genomic alterations (GA: point mutations, small indels, copy number changes and rearrangements) were recorded. TMB was calculated from up to 1.1 megabase (Mb) of cancer genome as the number of somatic, coding point mutations and indels per Mb (low: <6; intermediate: 6-19; high: ≥20 mutations/Mb).
In 614 HCC, the median age was 61 years and 70% were male. HBV/HCV infection status was not available. The most frequent GA occurred in TERT (51%), TP53 (34%), CTNNB1 (32%), MALT1 (14%), PASK (14%), CD36 (14%), MYC (13%), ARID1A (12%), CDKN2A (8.5%) and RB1 (7.6%). Potentially targetable GA involved CCND1 (5.5%), FGF19 (5.1%), FGF3/4 (4.2%), MET (2.0%), ERBB2 (1.1%), EGFR (0.7%), BRAF (0.5%) and ALK (0.4%). TMB was low in 394 (64%), intermediate in 214 (35%) and high in 6 (1.0%) patients. Of 378 patients with available MSI status, 1 HCC was MSI-H; GA involving MLH1 (0.4%), MSH2 (0.4%), MSH6 (1.1%) and POLE (0.2%) were also detected. Clinical examples of responders to everolimus and nivolumab will be presented.
CGP of HCC reveals rarer GA and small subsets of patients with high TMB and MSI that may open new avenues of medical treatment for select advanced HCC as well as understudied, recurrently altered genes such as PASK and MALT1, suggesting a role in the management of advanced-stage HCC.
Foundation Medicine, Inc.
None
J. Suh, E. Severson, G. Frampton, D. Fabrizio, J. Sun, S. Ali, V. Miller, P. Stephens, J. Ross: Foundation Medicine (employment, equity). All other authors have declared no conflicts of interest.