Researchers identified fewer actionable mutations among colorectal cancer patients with African ancestry compared with those of European descent. These findings, which were presented during the AACR Annual Meeting 2023, also revealed that these patients were less likely to qualify for treatment with immunotherapy (Abstract 1908).
"Black patients with colorectal cancer have higher incidence [and] mortality, and lower rates of survival compared to other populations," noted first study author Henry Walch, MS, a computational biologist at the Marie-Josee and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center, during a press conference. "The reasons for this are complex and largely reflect differences in socioeconomic inequalities, risk factors, and access to care. However, the extent to which germline and somatic genomic alterations influence these differences in outcomes remains unknown."
Results & Methods
The study authors analyzed targeted DNA sequencing data from 4,441 colorectal cancer patients who were treated at Memorial Sloan Kettering between 2014 and 2022. They used MSK-IMPACT-a next-generation gene sequencing panel that looks for mutations in up to 505 genes-to sequence tumors.
Reference populations from the 1000 Genomes Project were used to estimate genetic ancestry. Study participants were labeled European, African, East Asian, South Asian, or Native American when the predominant ancestry fraction was greater than 80 percent. Individuals with less than 80 percent of any one ancestry were considered admixed.
This study included 3,265 patients of European ancestry, 263 East Asian, 245 African, and 89 South Asian. Fifteen Native American and 564 admixed patients were excluded due to a small sample size and heterogeneity of the respective cohorts, according to Walch.
"In our cohort at Memorial Sloan Kettering, African ancestry patients had worse outcomes compared to all other ancestry groups," Walch and colleagues reported. Data showed that the African ancestry group had a median overall survival of 45.7 months from the time of diagnosis compared with 67.1 months for the European ancestry group.
"We found that African and East Asian ancestry patients had fewer microsatellite unstable and TMB-high tumors compared to European ancestry patients," Walch noted. "Based on their molecular profiles, fewer of these patients would qualify for immunotherapy."
Walch and colleagues observed that 13.5 percent of patients of African ancestry qualified for immunotherapy based on FDA guidelines for certain biomarkers-including microsatellite instability and tumor mutational burden-versus 20.4 percent of European ancestry patients. Among microsatellite stable patients and those with a low tumor mutational burden, African ancestry patients had fewer actionable alterations compared with European ancestry patients (5.6% vs. 11.2%), according to Walch, who noted that "this difference was driven largely by a depletion of actionable BRAF mutations in the African ancestry patients (1.8% vs. 5.0%)."
He explained that adenomatous polyposis coli (APC) is the most frequently altered gene in colorectal cancer, while also noting that, in the Memorial Sloan Kettering colorectal cancer cohort, they typically see an association between APC alteration status and patient outcomes. The presence of APC alterations is associated with worse patient outcomes versus wild-type APC.
"When we stratified the cohort by genetic ancestry and APC status, we still saw that trend in the European, East Asian, and South Asian ancestry patients," Walch reported. However, Walch and colleagues observed no differences in outcomes after APC stratification among African ancestry patients.
The study authors also performed multivariate outcomes incorporating known colorectal cancer driver genes, primary tumor location, stage at diagnosis, sex, and age. A significant association between APC status and outcomes was seen among European ancestry patients, but not African ancestry patients, according to Walch.
"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," Walch and colleagues stated in their abstract.
Next Steps
While discussing study limitations and next steps, Walch acknowledged that this is a "complex problem with many unseen factors, and the genomic landscape is a small piece of a much larger puzzle."
The investigators noted that one limitation of this study is the absence of comprehensive treatment information, as well as lifestyle factors, environmental exposures, and socioeconomic factors-all of which play a role in colorectal cancer incidence and outcomes. They are currently working to incorporate this information into future models.
"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," Walch concluded. "Our ultimate goal is to identify opportunities to intervene and improve outcomes in this underserved population."
Catlin Nalley is a contributing writer.