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. 2019 Jun 18;10(40):4018-4025.
doi: 10.18632/oncotarget.26998.

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma

Celina Ang  1 , Samuel J Klempner  2 , Siraj M Ali  3 , Russell Madison  3 , Jeffrey S Ross  3 , Eric A Severson  3 , David Fabrizio  3 , Aaron Goodman  4 , Razelle Kurzrock  4 , James Suh  3 , Sherri Z Millis  3
Affiliations

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma

Celina Ang et al. Oncotarget. .

Abstract

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC.

Keywords: biomarkers; hepatocellular carcinoma; immunotherapy; tumor mutation burden.

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Conflict of interest statement

CONFLICTS OF INTEREST SMA, JSR, EAS, DF, JS, RM and SZM are employees of Foundation Medicine.

Figures

Figure 1
Figure 1. Mutational landscape of HCC across study cohort and biomarker subgroups.
Figure 2
Figure 2. Differences in gene alteration frequencies by TMB level.
Figure 3
Figure 3. Differences in gene alteration frequencies using modified TMB cutoffs (all genes shown have statistically significant differences between 2 or 3 groups).
See this image and copyright information in PMC

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