Patients of African ancestry less likely to qualify for colorectal cancer immunotherapy
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Key findings:
- A significantly smaller proportion of patients of African vs. European ancestry had clinically actionable alterations.
- Somatic genetic alterations may contribute to disparities in colorectal cancer outcomes.
Individuals of African ancestry treated for colorectal cancer had fewer actionable genetic alterations than those of European ancestry, making them less likely to be eligible for immunotherapy, study results showed.
The findings, presented at American Association for Cancer Research Annual Meeting, revealed that patients of European ancestry who had microsatellite-stable disease and low tumor mutational burden had double the rate of clinically actionable alterations compared with those of African ancestry. In addition, researchers reported markedly shorter median OS among individuals of African ancestry.
The results suggest somatic alterations may be a significant contributor to disparities in colorectal cancer outcomes, researchers noted.
“Patients with colorectal cancer of African ancestry have molecular profiles that less often qualify them for immunotherapy per FDA guidelines,” Henry S. Walch, MS, a computational biologist at the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center, told Healio. “Lack of a mutation to target limits what a doctor has available in their toolbelt when it comes to potential treatments.”
Background
Poorer outcomes among African Americans with colorectal cancer when compared with other races and ethnicities is an established trend, according to Walch.
Members of his research team conducted a previous study on individuals with young-onset colorectal cancer that showed “striking differences” in patient outcomes based on race, he said. The researchers had access to next-generation DNA sequencing data of patient tumors, he added.
“No one had done an analysis delving into the full cohort to look at racial disparities,” Walch said. “We were interested in seeing what level of involvement genomics may have with these differences in outcomes.”
The presence of an actionable genomic alteration is an important criterion for eligibility to receive immunotherapies that target colorectal cancer, Walch noted.
“Patients who have an actionable mutation in their tumor can receive a targeted therapy that is precisely matched to that actionable change in their tumor,” he said. “This can help to improve survival, particularly in microsatellite-stable patients who are resistant to first-line therapies.”
Methodology
Walch and colleagues evaluated genetic alterations based on ancestry by analyzing targeted DNA sequencing data of 4,441 patients with colorectal cancer treated at Memorial Sloan Kettering Cancer Center between 2014 and 2022.
Investigators examined tumor tissue using MSK-IMPACT, a next-generation sequencing assay that evaluates for up to 505 different gene mutations.
The study cohort included patients of European (n = 3,265), East Asian (n = 263), African (n = 245), South Asian (n = 89) and Native American (n = 15) ancestry. Researchers excluded patients of mixed ancestry, defined as those without a predominate ancestry fraction greater than 80%.
Investigators used Memorial Sloan Kettering’s OncoKB database to determine the clinical actionability of specific genomic alternations.
Key findings
Patients of African ancestry had significantly shorter median OS from time of diagnosis than those of European ancestry (45.7 months vs. 67.1 months; P < .0001).
Significantly fewer patients of African ancestry qualified for immunotherapy compared with those of European ancestry based on FDA guidelines (13.5% vs. 20.4%; P = .008). Patients of African vs. European ancestry also had significantly lower rates of actionable genetic alterations (5.6% vs. 11.2%, P = .01), driven largely by a difference in actionable BRAF mutations (1.8% vs. 5%; P = .04).
Researchers observed an association between somatic APC alterations and significantly longer OS among patients with microsatellite-stable disease of European (median, 64.6 months in APC-altered vs. 45.6 months in APC wild-type; P < .0001), East Asian (median, 63.1 months vs. 35 months, P = .0015) and South Asian (median, not reached vs. 39.4 months; P = .012) ancestry. However, APC alterations lacked prognostic value among those of African ancestry (median OS, 45 months vs. 45.9 months).
A multivariate analysis adjusting for sex, age, primary tumor location and tumor stage at diagnosis demonstrated a significant association between APC mutational status and OS among those of European ancestry (HR = 0.64; 95% CI, 0.52-0.79) but not among those of African ancestry (HR = 0.74; 95% CI, 0.31-1.7).
Clinical implications
Fewer actionable alterations means patients of African Ancestry had fewer targeted therapeutic options for treatment of their colorectal cancer once the disease progressed following first-line therapy, Walch noted.
“These differences in molecular profiles have had clinical ramifications,” he told Healio.
His group will continue to examine additional reasons for racial disparities in colorectal cancer outcomes, including treatment choices and socioeconomic impacts.
Meanwhile, Walch said the results should remind clinicians treating patients with colorectal cancer of African ancestry that they must have an alternative treatment strategy ready following genomic analysis.
“We need to sequence a more diverse [group of] patients so that we can provide the best care for those in underserved communities,” he said. “By reaching out to these communities and sequencing more patients, we hope to identify new targets.”
Perspective
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Stephanie Greco, MD, FACS
The findings from Walch and colleagues are very important for several reasons.
Colorectal cancer disproportionally affects African Americans, who have a 20% higher rate of the disease and are significantly more likely to die of it than other ethnic groups in the United States.
The study highlights the importance of ensuring that patients of minority ethnicities complete molecular profiling and are well represented in biobanks that store tissue used for translational research. Additionally, it well known that minority patients are often poorly represented in large clinical trials for which standard-of-care therapies are developed and recommended.
The association of APC mutations with longer OS among patients of European ancestry but not among those of African American ancestry, despite controlling for important clinical and demographic factors, suggests that even patients with the same mutations may not respond the same way to targeted therapies based on their genetic ancestry and overall mutational profile. Thus, is it critically important that patients of unrepresented genetic ancestries be included in clinical trials in order to guide use of therapies specific to these patient populations. Further, research should investigate the reasons behind the above findings, which are likely multifactorial, and how the genetic differences may be linked to various environmental and demographic factors.
Future studies should also aim to develop new prognostic models to predict response to therapy based upon the differences in the molecular profile, not just solitary mutations. Lastly, the study provides novel insights and implications for similar work to be completed across cancer types.
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Walch HS, et al. Abstract 1908. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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