Black individuals have a higher incidence of colorectal cancer than White individuals, and their outcomes are worse. Undoubtedly, reasons for this are multifaceted, but the disparity in outcomes may be partly explained by genomic differences, documented in a large retrospective study presented at the 2023 American Association for Cancer Research (AACR) Annual Meeting.1 The main findings of the study were that Black patients with colorectal cancer had fewer clinically actionable genetic mutations that are targetable with available drugs and that they were less likely to qualify for immunotherapy based on their genomic profile than their White counterparts.
Henry Walch, MS
Francisco Sanchez-Vega, PhD
“African Americans are known to have worse clinical outcomes from colorectal cancer than patients from other racial backgrounds. This is a complex problem involving many unseen factors, and the genomic landscape is a piece of the larger puzzle,” said initial author Henry Walch, MS, a computational biologist at Memorial Sloan Kettering Cancer Center (MSK), New York. “The extent to which differences in germline or somatic genomic alterations influence outcomes remains unknown.” The senior author of the study is Francisco Sanchez-Vega, PhD, assistant attending computational oncologist in the Colorectal Cancer Service, Department of Surgery, MSK.
“Our findings provide novel insights into the genomic basis of racial disparities in colorectal cancer and highlight the need for ancestry stratification in the analysis of associations between molecular profiles and clinical outcomes. This study is part of a larger effort, where we aim to understand the reasons for poor outcomes in African Americans with colorectal cancer. Our goal is to identify opportunities to intervene and improve outcomes for this underserved health population,” Mr. Walch continued.
The median overall survival of patients with African ancestry was almost 2 years less than that of patients with European ancestry. Based on genomic profiling, 13.5% of patients with African ancestry vs 20.4% of those with European ancestry met U.S. Food and Drug Administration criteria for immunotherapy (ie, microsatellite instability [MSI] or high tumor mutational burden [TMB]). Among patients with microsatellite-stable or low-TMB tumors, twice as many with European ancestry had targetable mutations as those with African ancestry.
Unlike the group with European ancestry, the group with African ancestry also had worse survival regardless of the alteration status (mutated or wild-type) of the tumor suppressor gene APC (adenomatous polyposis coli), often called the “first hit” in the development of colon cancer. Having fewer actionable mutations suggests that patients with African ancestry have fewer treatment options and that they may not be responsive to the types of drugs that have improved outcomes in colon cancer.
“I think [the study] highlights the need to find alternative treatment strategies and the need to find new targets for these patients, because they don’t have the molecular profiles that would qualify them for more powerful treatments that they might receive otherwise,” Mr. Walch continued. Other cancer types may have differences in genomic patterns based on race, but Mr. Walch noted that this research is focused solely on colorectal cancer.
The study was based on next-generation sequencing of tumor samples from 4,441 patients with colorectal cancer treated at MSK between 2014 and 2022. The study population included 3,265 patients of European ancestry, 245 of African ancestry, 263 of East Asian ancestry, 89 of South Asian origin, 15 North American natives, and 564 with mixed ancestry. Samples were analyzed using MSK-IMPACT, a gene-sequencing panel that looks for mutations in up to 505 genes.
Patients of African ancestry with colorectal cancer had a median overall survival of 45.7 months vs 67.1 months for the European ancestry subgroup (P < .0001). Genomic analysis showed that significantly fewer patients of African ancestry met criteria (eg, MSI or high TMB) for treatment with targeted therapies or immunotherapy (P = .008).
Among patients with microsatellite-stable and low-TMB tumors, 5.6% of patients of African ancestry vs 11.2% of patients of European ancestry had clinically actionable genetic alterations (P = .01). Most of the difference was driven by a lack of BRAF mutations in patients of African ancestry (1.8% vs 5.0%, P = .04). APC alterations (vs wild-type) were associated with significantly better overall survival among the Europeans (64.6 months vs 45.6 months, P < .0001), East Asians (63.1 months vs 35 months, P = .0015), and South Asians (not reached vs 39.4 months, P < .001). By contrast, the presence or absence of APC alterations did not have prognostic value among patients of African ancestry (45.0 months vs 45.9 months, respectively, P = .91).
The study did not provide information on environmental exposures, lifestyle, and socioeconomic factors, which play a role in colorectal cancer incidence and outcomes. Mr. Walch and his coauthors hope to incorporate these factors into future models.
DISCLOSURE: Mr. Walch reported no conflicts of interest.
1. Walch H, Luthra A, Arora KS, et al: Clinical genomic profiling identifies lower frequency of therapeutically actionable alterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry. 2023 AACR Annual Meeting. Abstract 1908/14. Presented April 17, 2023.
Lisa Newman, MD, MPH, FACS, FASCO
Commenting on this study on clinical genomic profiling for colorectal cancer, Lisa Newman, MD, MPH, FACS, FASCO, Chief of the Section of Breast Surgery and leader of the Multidisciplinary Breast Oncology Programs at Weill Cornell Medicine and...