Abstract 3634: Integrative analysis of the contribution of genomic and clinical factors to worse clinical outcomes in non-Hispanic Black patients with colorectal cancer

Abstract

Abstract Non-Hispanic Black (NHB) patients have higher incidence and higher mortality from colorectal cancer (CRC) than non-Hispanic white (NHW) patients. The extent to which this aggressive behavior in NHB patients is driven by differences in cancer genomics is presently unknown. We analyzed clinical and genomic data from 3,963 CRC patients treated at Memorial Sloan Kettering, including 336 (8%) NHB and 3,627 (92%) NHW patients. Tumors were sequenced using the clinical MSK-IMPACT test, a targeted next-generation DNA sequencing assay that identifies mutations, copy number changes and structural rearrangements in 341-505 genes using solid tissue and matched blood. No significant differences by race were observed for stage at diagnosis or sex. While the difference in median age at diagnosis was small (53.4 for NHB vs. 55 years for NHW patients, p=0.012), significantly fewer NHB patients were diagnosed after 65 years of age (17% vs. 27%, p=0.001). Right-sided colon tumors were more common among NHB patients (37% vs. 25%, p=0.02); the proportion of rectal tumors was similar in both racial groups (31% in NHB vs. 34% in NHW patients, n.s.). Hypermutated tumors, including tumors with microsatellite instability (MSI) and POLE hypermutants, were more frequent among NHW patients (12% vs. 8%, p=0.02). Right-sided tumors were more frequently MSI/hypermutated in the NHW patients (27% vs. 13%, p=0.008), whereas no differences by race were observed for left-sided colon (5% vs. 1%, n.s.) or rectal primaries (4% vs. 5%, n.s.). Genomic analysis of the non-hypermutated tumors revealed no significant differences in tumor mutational burden or fraction of genome altered between racial groups. Tumors in NHB patients were enriched in KRAS mutations (60% vs. 45%, p<0.001), but G12C mutations accounted only for 3% of all driver KRAS mutations in NHB patients vs. 8% of all driver mutations in NHW patients (p=0.01). BRAF mutations were more frequent in non-hypermutated NHW patients (7% vs. 3%, p=0.006), but the overall frequency of RTK/RAS pathway alterations was higher in the NHB group (74% vs. 66%, p=0.004). Even though all patients were treated at the same single institution during the study, NHB patients had shorter overall survival (OS) from the time of sequencing (median 28 months [95% CI 25-38] vs. 50 months [95% CI 47-53], p<0.001). NHB patients also had worse OS [HR 1.64, CI 1.3 - 2.1, p<0.001] in a multivariate analysis using Cox Proportional-Hazards and accounting for age at diagnosis, stage at diagnosis, body mass index, primary tumor location, MSI status and oncogenic alterations in APC, TP53, KRAS, SMAD4, and BRAF. Our data confirms that NHB patients with CRC have worse clinical outcomes than NHW patients. Clinically relevant differences in the frequency of alterations in cancer driver genes are observed based on racial origin, but they do not fully explain the difference in survival. Citation Format: Henry Walch, Anisha Luthra, Walid K. Chatila, Fan Wu, Debyani Chakravarty, Chin-Tung Chen, Rupa Sood, Dana M. Omer, Jesse J. Smith, Nikolaus Schultz, Karuna Ganesh, Julio Garcia-Aguilar, Rona Yaeger, Francisco Sanchez-Vega. Integrative analysis of the contribution of genomic and clinical factors to worse clinical outcomes in non-Hispanic Black patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3634.