Abstract A010: Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors
Authors: Ashour Ahmed M. , Al-Omari Amro M. , Amer Mohammad S. Bani , Kamal Zaid R. 
Published: January 2024

Title: Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors Background: Fanconi anemia repair (FAR) genes have crucial involvement in determining immunogenicity of solid tumors due to their substantial involvement in DNA damage repair (DDR). Previous work has alluded to the significance of DDR pathways such as mismatch repair and homologous recombination genes in treatment guidance. Herein, we study the potential impact of FAR genes mutations on immunotherapy parameters in solid tumors. Methods: We used the MSK immunotherapy and Tumor Mutational Burden (TMB) dataset was used in our analysis, which includes mutational and clinical data for 1661 patients on immune checkpoint inhibitors (anti-PD-1/L1, anti-CTLA-4, or combinational therapy) from ten cancer types (bladder, breast, colorectal, esophagogastric, glioma, head and neck, melanoma, non- small cell lung, renal cell, and unknown primary cancer). All clinical ang genomic data was retrieved through the cBioPortal database. Patients were categorized into the FAR mutated group if they harbored a mutation in at least one of the FAR genes (FANCA, FANCC, BRCA2, BRIP1, PALB2, RAD51C, SLX4) included in the MSK-IMPACT targeted next-generation sequencing panel. The log rank test and the Wilcoxon test, Chi-squared test were used to compare overall survival (OS), continuous and categorical data between FAR mutated and wildtype groups. Results: The MSK TMB cohort included 220 (13%) patients with FAR mutations, of which melanoma comprised the highest percentage (26.4%) followed by non-small cell lung cancer (NSCLC; 19.6%). The most common altered FAR gene was BRCA2 (6%), followed by SLX4 (5%), while the least altered gene was RAD51C (0.7%). FAR mutated patients had significantly higher OS compared to the wildtype group (median OS (mOS): 29 vs 17 months, log rank p &lt; 0.001). Among melanoma patients (n = 320), there was no significant difference in OS between the mutated and FAR groups, whereas the NSCLC (n = 350) and colorectal cancer (CRC, n = 110) subgroups had significantly higher OS in the FAR mutated groups (NSCLC - mOS: 19 vs 10 months, p = 0.0256, CRC – mOS: not reached vs 13 months, p &l; 0.001). TMB was significantly higher in the FAR mutated group (median TMB: 22.3 vs 5.2, p &lt; 0.001). Notably, the most frequent co-mutations in the FAR mutated group included CTLA4, STK19, E2F3, CD276, MYCL. Conclusion: Our analysis highlights the potential role of FAR genes mutations in predisposing solid tumor patients to ICI benefit, specifically in NSCLC and CRC patients. Insights into the potential interactions between FAR genes and other DDR pathways as well as their impact on tumor immune microenvironment parameters are needed in future research to understand the drivers of ICI benefit in this subset of patients.

Citation Format: Ahmed M. Ashour, Amro M. Al-Omari, Mohammad S. Bani Amer, Zaid R. Kamal. Insights into the Impact of Fanconi Anemia Repair Genes on Immunotherapy Response in Solid Tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A010.