The association between different molecular alterations in retinoblastoma (RB) signaling pathway and response to treatment with immune checkpoint inhibitors

The association between different molecular alterations in retinoblastoma (RB) signaling pathway and response to treatment with immune checkpoint inhibitors. Background: The Retinoblastoma (RB) pathway is a network of genes and proteins that regulates cell cycle progression and cell death. Genes involved in the RB pathway include CDKN2A, CDKN2B, CDKN2C, CDK4, CDK6, CCND2, and RB1. Mutations in the RB pathway can lead to resistance to immune checkpoint inhibitors (ICPIs) ultimately hindering the effectiveness of immunotherapy drugs. We aim to explore the association between different molecular alterations in RB signaling and the response to treatment with ICPIs in solid tumors. Methods: We used the cBioPortal for Cancer Genomics server to gather genomic data. The Tumor Mutational Burden (TMB) and Immunotherapy study from 2019 was used to collect data, and it consisted of 1661 patients who had received at least one dose of ICPIs. This cohort included patients with cancers of the colon, gastroesophageal, lung, skin, kidney, breast, head and neck, bladder, brain and cancers of unknown primary. Kaplan-Meier survival curves were generated for median overall survival (mOS) analysis and compared by using log-rank test. A Cox proportional hazards model was used to calculate hazard ratios (HR) and 95CI), with a significance level set at p lt; 0.05. Results: In our cohort, the prevalence of CDKN2A, CDKN2B, CDKN2C, CDK4, CDK6, CCND2 and RB1 was 9.1 0.4 0.7 0.8 0.6 0.7.8 respectively. CDKN2B, CDKN2C, CDK4, CDK6, CCND2 and RB1 mutations were associated with a mOS that was not statistically significant. The non-altered RB pathway group yielded a mOS of 17 months (95 15.00-20.00) compared to the group with genetic alterations in CDKN2A gene which had a mOS of 27 months (95 16.00-NA). This difference was statistically significant (p = 0.043) with a HR of 0.758 (95 0.607-0.972). Conclusion: Our study suggests that mutations in CDKN2A among patients treated with ICPIs were associated with improved mOS compared to patients without genetic alterations in the RB signaling pathway. Additionally, while mutations in CDKN2B, CDKN2C, CDK4, CDK6, CCND2, and RB1 demonstrated a trend toward better mOS, these findings did not reach statistical significance. If these results are validated in larger datasets, distinguishing between various molecular alterations within the RB signaling pathway could enhance patient selection for combination therapy involving ICPIs and targeted interventions against the RB pathway.Citation Format: Raed Zaidan, Bayan Khasawneh, Ebtesam Al-Najjar, Abdullah Esmail, Maen Abdelrahim. The association between different molecular alterations in retinoblastoma (RB) signaling pathway and response to treatment with immune checkpoint inhibitors [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 A045.