Abstract 1908: Clinical genomic profiling identifies lower frequency of therapeutically actionable alterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry

Abstract Intro. We compared molecular profiles and clinical outcomes in a large cohort of colorectal cancer (CRC) patients treated at a single tertiary center to investigate differences in the frequency of therapeutically targetable alterations and the prognostic value of somatic driver alterations across ancestry groups. Methods. We analyzed targeted DNA sequencing data from 4,441 CRC patients treated at Memorial Sloan Kettering between 2014 and 2022. Tumors were sequenced using MSK-IMPACT, a next-generation tumor-normal sequencing assay containing up to 505 genes. Genetic ancestry was estimated using reference populations from the 1000 Genomes Project, including European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and Native American (NAM). Patients were assigned specific ancestry labels when the predominant ancestry fraction was >80% and considered to have admixed ancestry (ADM) otherwise. Clinical actionability of individual genomic features was determined using the OncoKB knowledgebase. Results. Our cohort included 3,265 EUR, 263 EAS, 245 AFR, 89 SAS, and 15 NAM patients; 564 ADM patients were excluded from subsequent analyses. The AFR group had shorter overall survival (OS) from time of diagnosis (median 45.7 months vs. 67.1 months, p<0.0001). The fraction of patients who qualify for immunotherapy based on FDA guidelines, including microsatellite unstable (MSI) or highly mutated (TMB>10 mut/Mb), was lower in AFR vs. EUR (13.5% vs. 20.4%, p=0.008) patients. Among microsatellite stable (MSS) and not highly mutated (TMB<10 mut/Mb) patients, AFR patients had lower rates of clinically actionable alterations than EUR patients (5.6% vs 11.2%, p=0.01). This difference was driven by a depletion of actionable BRAF mutations in the AFR group (1.8% vs. 5.0%, p=0.04). Somatic APC alterations were associated with longer OS in MSS EUR patients (median 64.6 months in APC altered vs. 45.6 months in APC wildtype, p<0.0001), EAS patients (median 63.1 vs. 35.0 months, p=0.0015), and SAS patients (median not reached vs. 39.4 months, p=0.012). However, APC alterations exhibited no prognostic value for the AFR patients (median OS 45.0 vs. 45.9 months, p=0.91). Multivariate analyses accounting for sex, age, primary tumor location, and stage at diagnosis showed an association between APC status and OS in EUR patients (HR 0.64, CI 0.52-0.79, p<0.001), but not in AFR patients (HR 0.74, CI 0.31-1.7, p=0.492). Conclusions. AFR patients had fewer clinically actionable alterations than patients from other ancestries. The prognostic value of somatic APC alterations was also lower in AFR patients. Our findings provide novel insights into the genomic basis of racial disparities in CRC and highlight the need of ancestry stratification for the analysis of associations between molecular profiles and clinical outcomes. Citation Format: Henry Walch, Anisha Luthra, Kanika S. Arora, Michele Waters, Samantha Chin, Christopher J. Fong, Doori Rose, Hannah Williams, Jeese J. Smith, Nikolaus Schultz, Michael F. Berger, Karuna Ganesh, Julio Garcia-Aguilar, Rona Yaeger, Walid K. Chatila, Francisco Sanchez-Vega. Clinical genomic profiling identifies lower frequency of therapeutically actionable alterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1908.