Molecular profile of hepatocellular carcinoma (HCC) in older versus younger adults: Does age matter?
Authors: Arora Sukeshi Patel , Gandhi Nishant , Walker Phillip , Shields Anthony Frank , Seeber Andreas , Lopes Gilberto , Yee Nelson , He Aiwu Ruth , Saeed Anwaar , Shroff Rachna T. , El-Deiry Wafik S. , Hsieh David , Philip Philip A. , Sohal Davendra P. S. , El-Khoueiry Anthony B. , Lou Emil , Spetzler David , Marshall John , Korn W. Michael , Kapoor Vidit 
Published: January 2022

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Background: HCC is increasingly prevalent in older adults with rising incidence and an aging population worldwide. Retrospective studies show older patients with HCC may have an increased survival compared to younger patients. However, data is lacking regarding the genomic and biologic differences, that if identified, would potentially change how we treat this disease in younger vs. older patients. Hence, there is a need to better characterize the molecular landscape of the disease in an age-specific manner. We analyzed the association of age with genomic alterations and therapeutic response to sorafenib in a cohort of advanced HCC that had undergone comprehensive molecular profiling. Methods: 487 HCC samples (excluding variants) were analyzed using Next Generation Sequencing (592 gene panel, NextSeq), Whole Exome and Whole Transcriptome Sequencing (NovaSeq), and IHC at Caris Life Sciences (Phoenix, AZ). PD-L1 positivity was determined by IHC (SP-142 clone, cutoff ≥1, 1%). Tumor mutational burden (TMB) was a measure of total somatic mutations per Mb. Immune cell populations were determined by Microenvironment Cell Population (MCP) counter analysis of RNA expression data. Overall survival (OS) calculated from tissue collection to last contact and time on treatment (TOT) with sorafenib were extracted from insurance claims and calculated using Kaplan-Meier curves. Statistical analysis was done using Chi-square, Fisher Exact and Wilcoxon rank sum tests, with p values adjusted for multiple comparisons and q<0.05. Results: Differences in the molecular landscape of HCC stratified by patient age were assayed using a ternary classification based on 1 standard deviation from the mean age (mean age=65; <53: A1 (n=51), 53-77: A2 (n=361), >77: A3 (n=75)). With age, mutational frequencies in CTNNB1 (A1=13.04%, A2=33.43%, A3=38.24%) and TERT (A1=25%, A2=68.84%, A3=76.92%) increased, while ATM (A1=6.52%, A2=0.93%, A3=1.49%) decreased (p<0.05, q>0.05). There were fold increases in median TMB (A2/A1=1.33, A3/A1=1.33, p<0.01), LAG3 (A2/A1=1.75, A3/A1=1.93 p<0.01), CTLA4 (A2/A1=2.05, A3/A1=2.15, p<0.05) expression; median cell fractions of CD8+ T cells (A2/A1=1.37, A3/A1=1.50, p<0.05) & B cells (A3/A1=3.01 p<0.05) increased while cancer associated fibroblasts (A1/A2=0.62, A1/A3=0.69, p<0.01) decreased with age. PD-L1 was not statistically significant. While there was no change in OS, reduced TOT with sorafenib was observed in patients aged>65 (p=0.013). Conclusions: Increased alterations in oncogenic drivers and estimates of CD8+ T cells and B cells were observed in the elderly population with HCC. The enhanced presence of co-inhibitory molecules suggests potential immune evasion. While we observed reduced TOT with sorafenib, additional studies are needed to elucidate the impact of molecular alterations on outcomes with sorafenib and newer therapies (i.e. immunotherapy) in older adults.