Genomic Data May Provide Therapeutic Options in Advanced HCC

Comprehensive genomic profiling detects genetic alterations occurring in hepatocellular carcinoma

The tumours of patients with hepatocellular carcinoma (HCC) harbour genomic alterations that may be targetable with already approved drugs, investigators reported at the ESMO Asia 2017 in Singapore, an Annual Congress organised by the European Society for Medical Oncology.

James Suh of the Pathology Department, Foundation Medicine in Morrisville, USA and colleagues used comprehensive genomic profiling (CGP), a hybrid capture-based next-generation sequencing (NGS) technique, to determine the tumour mutational burden (TMB) and microsatellite instability (MSI) in samples from patients with HCC. Both TMB and MSI serve as biomarkers for response to immune checkpoint inhibitors and may offer information allowing the determination of optimal therapy in patients with advanced stage HCC.

The investigators performed CGP of up to 315 cancer-related genes from 614 consecutive patients with HCC from 2012 to 2016 using a hybrid-capture, adaptor ligation based NGS assay to detect genomic alterations, including point mutations, small indels, copy number changes and rearrangements. TMB was calculated from up to 1.1 megabase (Mb) of the cancer genome and was defined as the number of somatic, coding point mutations and indels per Mb. The cut-off for low TMB was <6, intermediate was from 6 to 19, and high TMB was defined as ≥20 mutations/Mb.

Of the 614 patients providing samples, 70% were male and their median age was 61 years, which was similar to the population of the CheckMate 040 trial. No information on the HBV/HCV infection status was available.

Potentially targetable genomic alterations identified

TMB was low in 394 (64%) tumour samples, intermediate in 214 (35%), and high in 6 (1.0%) patients’ tumours. The median TMB was 3.6 mutations/Mb.

The MSI status was determined in 378 patients; one HCC sample was MSI-High.

Genomic alterations were most often observed in the TERT, TP53 and CTNNB1 genes; genomic alterations were detected in 51% of TERT, 34% of TP53, and 32% of CTNNB1 genes. Genomic alterations occurred less frequently in 14% of MALT1, PASK, and CD36 genes, followed by 13% of MYC, 12% of ARID1A 8.5% of CDKN2A, and 7.6% of RB1 genes. Genomic alterations were also detected in 0.4% of MLH1, and MSH2 genes, 1.1% of MSH6, and 0.2 % of POLE genes.

Genomic alterations that were potentially targetable with approved agents 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%) genes.

Clinical example of responder with intermediate TMB to nivolumab

An 82 year old Asian-American male with untreated hepatitis C presented with HCC in 2013.  Following TACE, sorafenib and tivantinib, CGP of 2015 liver biopsy detected TMB of 15 mutations/Mb. Nivolumab was started in mid-2016 with rapid symptomatic improvement and concurrent decline in serum AFP, now 15 months on therapy with only mild pruritis.

Conclusions

Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide but limited response to existing chemotherapies has been reported, creating a high unmet need for new therapies.

TMB (36% intermediate or high) and MSI assessed by CGP rather than PD-L1 IHC status may predict benefit from nivolumab, which showed ~20% response rate in the overall population of CheckMate 040.

CGP of HCC also reveals rarer genomic alterations involving understudied, recurrently altered genes such as PASK and MALT1 that may open new avenues of medical treatment, suggesting a role in the management of advanced-stage HCC.

Disclosure

This study was sponsored by Foundation Medicine, Inc.

Reference

194O – Suh J, et al. Hybrid-Capture Based Comprehensive Genomic Profiling of Hepatocellular Carcinoma Identifies Patients Who May Benefit from Targeted Therapies and Immune Checkpoint Blockade.