Black individuals are disproportionately affected by colorectal cancer. They have the highest rates of the disease of any racial or ethnic group in the United States, and are about 20% more likely to develop colorectal cancer and about 40% more likely to die of the disease than most other groups.
A study by Walch et al presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 1908/14) investigating whether germline or somatic genomic alterations influence outcomes in Black patients with colorectal cancer has found that patients of African ancestry had lower rates of clinically actionable alterations than patients of European ancestry—5.6% vs 11.2%, respectively. In addition, patients with African ancestry had a median overall survival of 45.7 months from the time of diagnosis vs 67.1 months for patients with European ancestry. The findings provide novel insights into the genomic basis of racial disparities in colorectal cancer and highlight the role of ancestry stratification for the analysis of associations between molecular profiles and clinical outcomes.
Study Methodology
The researchers analyzed targeted DNA sequencing data from 4,441 patients with colorectal cancer treated at Memorial Sloan Kettering Cancer Center in New York City 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, African, East Asian, South Asian, and Native American. The cohort included 3,265 European, 263 East Asian, 245 African, 89 South Asian, and 15 Native American patients; 564 patients considered to have admixed ancestry otherwise were excluded from subsequent analyses.
Patients were assigned specific ancestry labels when the predominant ancestry fractions were > 80%. Clinical actionability of individual genomic features was determined using the OncoKB knowledgebase.
Results
The researchers found the African patient group had shorter overall survival from time of diagnosis (median = 45.7 months vs 67.1 months, P < .0001). The fraction of patients who would be eligible for treatment with immunotherapy based on biomarkers highlighted in U.S. Food and Drug Administration guidelines, including microsatellite-unstable disease (MSI) or high tumor mutational burden (TMB >10 mut/Mb), was lower in African vs European patients (13.5% vs 20.4%, P = .008).
Among patients with microsatellite-stable disease (MSS) and those with a lower tumor mutational burden (TMB < 10 mut/Mb), African patients had lower rates of clinically actionable alterations than European patients (5.6% vs 11.2%, P = .01). This difference was driven by a depletion of actionable BRAF mutations in the African group (1.8% vs 5.0%, P = .04). Somatic APC alterations were associated with longer overall survival in MSS European patients (median = 64.6 months in APC-altered vs 45.6 months in APC wild-type, P < .0001), East Asian patients (median = 63.1 vs 35.0 months, P = .0015), and South Asian patients (median = not reached vs 39.4 months, P = .012).
However, APC alterations exhibited no prognostic value for the African patients (median overall survival = 45.0 vs 45.9 months, P = .91). Multivariate analyses accounting for sex, age, primary tumor location, and stage at diagnosis showed an association between APC status and overall survival in European patients (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.52–0.79, P < .001), but not in African patients (HR = 0.74, 95% CI = 0.31–1.7, P = .492).
“[African] patients had fewer clinically actionable alterations than patients from other ancestries. The prognostic value of somatic APC alterations was also lower in [African] patients. Our findings provide novel insights into the genomic basis of racial disparities in colorectal cancer and highlight the need of ancestry stratification for the analysis of associations between molecular profiles and clinical outcomes,” concluded the study authors.
Clinical Significance
“Even in a cohort where all patients were treated at the same institution, patients of African ancestry had shorter overall survival from time of diagnosis than patients of other ancestries,” said lead author of the study Henry Walch, MS, a computational biologist at the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center. “Our findings provide novel insights into the genomic basis of racial disparities in colorectal cancer and highlight the need of ancestry stratification for 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 behind poor outcomes in African American patients with colorectal cancer. Our ultimate goal is to identify opportunities to intervene and improve outcomes in this underserved population.”
Disclosure: Funding for this study was provided by the Colorectal Cancer Alliance and an AACR-Minority and Minority-serving Institution Faculty Scholar in Cancer Research Award. For full disclosures of the study authors, visit abstractsonline.com.
