Why Is Colorectal Cancer in African Americans Hard To Treat? One Reason Is Genetics

The disparities are disturbing: Black men and women are more likely to get colorectal cancer than any other racial group in the United States. They also are 40% more likely to die from it than other racial groups.

There are many possible explanations, including differences in risk factors, access to healthcare, and other social and economic variables. But new research suggests there could be another reason: genetic factors in the tumors of Black patients. Studies have shown that even among patients with colorectal cancer treated at the same institution, people with African ancestry don’t live as long after diagnosis as those of European or East or South Asian ancestry.

New Research Finds Patients of African Ancestry May Be Less Likely To Have Targetable Cancer Mutations 

Now a Memorial Sloan Kettering Cancer Center (MSK) research team led by computational biologist Henry Walch, MS, has found that colorectal cancer patients of African ancestry are less likely to have tumors that respond well to two important classes of newer treatments: immunotherapy and targeted therapy. These treatments work better against tumors that have certain genetic mutations — or have a larger number of mutations overall. The research found that a smaller fraction of the Black patients whose tumors were sequenced at MSK had molecular profiles that could be targeted by these therapies.

The new study comparing outcomes among people of different ancestries found: 

• People of African ancestry had a significantly shorter median survival time after diagnosis — about two-thirds as long — than patients of all other ancestry groups. 
• The presence of some genetic mutations that can typically be used to group patients into predicted outcomes was not helpful in predicting outcomes in patients of African ancestry.
• Patients of African ancestry whose tumors were sequenced at MSK were about 30% less likely to have the mutations that would make them good candidates for immunotherapy.

“Our findings suggest that the type of molecular profiles observed in the tumors of patients with African ancestry could reduce the number of options that these patients have for treatment,” says Walch, who presented the findings April 17 at the American Association for Cancer Research (AACR) annual meeting in Orlando, Florida. “They also underscore the urgent need to include racially diverse populations in cancer research and drug development studies.”

APC Gene Mutations Don’t Predict Outcomes in Patients of African Ancestry 

The research team discovered an important difference in the relationship between tumor mutations and outcomes in patients of African ancestry. In people of other ancestries, those whose tumors have a mutation in a gene called APC tend to have better outcomes. The gene, which normally suppresses cancer from starting, is mutated in about 80% of colorectal tumors. Among the Black patients analyzed in this study, however, having an APC mutation in the tumor seemed to make no difference in outcome.

“This finding surprised us. For patients of other ancestries, we observed a very significant difference in overall survival based on the presence of APC mutations, which allows us to classify the prognosis of patients,” Walch says. “However, in patients of African ancestry, APC status was not associated with any differences in overall survival at all.”

Comparing Colorectal Cancer Survival by Ancestry Using MSK-IMPACT® Genetic Data

Walch and colleagues analyzed genetic data from 4,441 people treated for colorectal cancer at MSK. The tumors had been analyzed using MSK-IMPACT®, a tumor-sequencing test that looks for mutations in more than 500 genes. The researchers were able to determine genetic ancestry by using reference information from the 1000 Genomes Project, a collaboration among research groups around the world to create a complete and detailed catalog of human genetic variations that may be related to cancer.

Patients were labeled as having European, African, East Asian, South Asian, or Native American ancestry when one of these estimated ancestries was predominant. Most patients were of European ancestry, and the most striking differences in outcomes and genetics were observed between this group and patients with colorectal cancer of African ancestry.

For example, 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.

Fewer Patients With Colorectal Cancer of African Ancestry Qualify for Immunotherapy and Targeted Therapy Based on Their Genomic Profile

Compared with other groups, a significantly smaller fraction of patients within the African ancestry group had genetic markers indicating that immunotherapy will be effective against colorectal cancer. The U.S. Food and Drug Administration has guidelines for giving immunotherapy based on genetic markers, including a tumor subtype called microsatellite instability (MSI). Another criteria relies on a tumor having a high number of mutations overall, known as tumor mutational burden (TMB).

While 20.4% of patients of European ancestry qualified for immunotherapy under these guidelines, only 13.5% of patients of African ancestry were eligible.;

Moreover, within the subset of non-MSI patients with low TMB, people of African ancestry were less likely than patients of European ancestry to have other therapeutically actionable alterations — 5.6% versus 11.2%. This was mainly because patients of African ancestry were less likely than people of European ancestry to have the BRAF ^V600E mutation, which responds well to certain targeted cancer drugs (1.8% versus 5.0%).

Patients of African ancestry also had a higher frequency of alterations in a gene called KRAS, which is associated with aggressive tumors and poor survival.

Walch said the findings are “pieces of a much larger puzzle” and highlight the importance of including genetic ancestry when analyzing the genetic factors involved in cancer development. He credits MSK’s extensive genomic and clinical data repositories, made possible by MSK-IMPACT and clinical collaborators, which allow access to highly detailed genetic and clinical information on patients.

MSK’s Effort To Understand Colorectal Cancer in African Americans

“This study is part of a much larger effort where we are trying to tease out the multiple reasons behind poor outcomes in African American patients with colorectal cancer,” he says. “Our ultimate goal is to identify opportunities to intervene and improve outcomes in this underserved community of patients.”

To that end, MSK does outreach to underserved communities to highlight the importance of colorectal screening and health through patient information sessions, health fairs, and other health equity efforts. Since 2003, physicians at MSK have been involved in an initiative in New York City called C5 — Citywide Colorectal Cancer Control Coalition. The group has been part of the NYC Department of Health and Mental Hygiene outreach efforts to increase colorectal screening. Over the past two decades, C5 has helped increase colorectal screening rates by 64% in New York City — and the rates of screening among Black adults are among the highest of any group in the city.

In addition, Francisco Sanchez-Vega, PhD, the senior author of the study presented at AACR, was recently awarded the Corning-MSK Health Equity Research Fellowship, which funds research into the broad disparities in cancer outcomes for patients in historically underserved communities. The fellowship will allow Dr. Sanchez-Vega, an Assistant Attending computational oncologist in MSK’s Colorectal Service in the Department of Surgery, to research the genomic, clinical, and socioeconomic causes behind the disproportionately negative outcomes of colorectal cancer in Black communities.