Patients of African heritage have fewer actionable mutations

Genetics

Genomic profiling of patients who were treated for colorectal cancer showed that patients with African ancestry had fewer actionable mutations than patients with European ancestry.

These patients were also less likely to qualify for treatment with immunotherapy, according to data presented at the AACR Annual Meeting 2023.

“African American patients are known to have worse clinical outcomes from colorectal cancer than patients from other racial backgrounds. The reasons for this are complex and likely reflect differences in risk factors, access to health care, and other socioeconomic variables,” explained the study’s first author, Henry Walch, a computational biologist at the Marie-Josée and Henry R Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center (MSK).

“However, the extent to which differences in germline or somatic genomic alterations influence outcomes remains unknown.”

Genetic sequencing

To assess these alterations in groups of different ancestries, Walch and colleagues analysed targeted DNA sequencing data from 4,441 patients treated for colorectal cancer at MSK between 2014 and 2022.

Tumours were sequenced using MSK-IMPACT, a gene sequencing panel that looks for mutations in up to 505 genes. Genetic ancestry was estimated using reference populations from the 1000 Genomes Project.

The study population comprised 3,265 patients of European ancestry, 263 East Asian, 245 African, 89 South Asian, and 15 Native American patients.

The African ancestry group had a median overall survival of 45.7 months from time of diagnosis compared with 67.1 months for the European ancestry group.

The study also showed that 13.5% of patients of African ancestry qualified for immunotherapy based on US Food and Drug Administration guidelines for certain biomarkers, including microsatellite instability and tumour mutational burden. This compared with 20.4% of patients of European ancestry.

Among microsatellite stable patients and those with a low tumour mutational burden, patients of African ancestry had lower rates of clinically actionable alterations than patients of European ancestry – 5.6% compared with 11.2%.

Reduced access to targeted therapies

The reduced rate of actionable mutations in patients of African ancestry may mean that these patients have fewer options of targeted therapies and immunotherapies that yield improved outcomes for many colorectal cancer patients.

“Patients who have an actionable mutation in their tumour can receive a targeted therapy that is precisely matched to that actionable change in their tumour. This can help to improve survival, particularly in microsatellite-stable patients who are resistant to first-line therapies,” Walch explained.

“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 added. “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.”

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