Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes

Background: Genomic profiling has revolutionized therapeutic approaches and clinical management for liver cancer. However, the pathogenetic mechanisms, molecular drivers of recurrence, and predictive biomarkers remain only partially understood. An analysis of the United States Hepatocellular Carcinoma (HCC) cohort from The Cancer Genome Atlas showed that common mutations are mainly located in the TERT promoter region, TP53, and CTNNB1 genes. Recent studies on smaller Chinese have also identified TP53, TERT, and CTNNB1 as the most frequently mutated genes among Chinese HCC patients. Our study further explores the correlation between specific genomic mutations (TERT, TP53), and immunotherapy response in HCC cases. Methods: The cBioPorta was used for genomic profiling in multiple cohort studies of hepatobiliary cancer cases. Only HCC cases with TERT and TP53 mutation, and patients who had received immunotherapy, were included. Cases involving cholangiocarcinoma (CCA), HCC with CCA, other genetic mutations, or patients treated with chemotherapy were excluded from this study. Kaplan-Meier survival curves were created to assess the median overall survival (OS) based on immunotherapy response, and we calculated pooled 95CIs) to determine the reliability and precision of our result. The log-rank P-value was used to assess differences in OS between mutated genes. Results: The total cases were 1915 of hepatobiliary cancer after excluding 873 cases remaining with HCC among them, 400 patients (45.8 had mutations in TERT, and 403 patients (46.2 had mutations in TP53. The finalized number was 65 (64.4 with TERT and 43 (42.4 with TP53 who received immunotherapy. The median OS differed substantially across mutation types: 42 months for TERT mutations, 37 months for TP53 mutations, and 58 months for cases with both mutations (p=0.5). Conclusion: Our study observed improved OS in patients with both TERT and TP53 mutations. Although patients with only TERT mutations had better OS compared to those with TP53 mutations alone. Further research is required to clarify the specific associations between TERT mutations and treatment outcomes.Citation Format: Ebtesam Al-Najjar, Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ala Abudayyeh. Immunotherapy responses in liver cancer: How TERT and TP53 mutations affect outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A002.