NEW YORK – Patients of certain genetic ancestries are less likely to be eligible for precision oncology treatments, according to a new study. The findings highlight a disparity rooted in the lack of inclusion of patients from diverse backgrounds in genetic research and clinical trials.
The paper, published in JAMA Oncology on Thursday, included an analysis of more than 59,000 patients who underwent mutational profiling using the MSK-IMPACT assay between January 2014 and December 2022. The researchers used OncoKB, Memorial Sloan Kettering Cancer Center's precision oncology knowledge database, to identify biomarkers associated with drugs approved by the US Food and Drug Administration, called level 1 biomarkers. For each ancestry group, they determined the annual clinical actionability, calculated as the percentage of patients with at least one tumor-type specific level 1 biomarker based on drug approvals between 1998 and 2023.
Patient genetic ancestry was inferred by MSK-IMPACT test results using a method previously reported by MSK researchers that was found to have high concordance with self-reported race.
Kanika Arora, first author of the JAMA Oncology study and principal computational biologist in the Michael Berger Lab at MSK, said this study grew out of previous research showing the rapid increase of available precision oncology treatments in recent years.
"There was a big shift in the level 1 alterations in OncoKB, which are FDA-approved drugs for FDA recognized biomarkers, from 2017 to 2022," Arora said. "That led to us asking if that jump was consistent for all patients or did certain some patients benefit more than others?"
Across all tumor types, patients of African ancestry had significantly lower clinical actionability, beginning in 2019. For instance, between 2012 and 2023, the non-Ashkenazi Jewish European ancestry group saw a ninefold increase in clinical actionability as new precision oncology drugs were approved, compared to a sixfold increase in the African ancestry group.
"In the last decade, there was a surge in the number of precision oncology therapies that were FDA-approved that benefited all patients. However, the odds of receiving a precision oncology drug increased … only two-thirds as much for patients of African ancestry," said Debyani Chakravarty, senior author of the paper and lead scientist for OncoKB at the Kravis Center for Molecular Oncology at MSK. "This is due, in part, to drug development efforts based on biomarkers that were discovered in patient cohorts that were predominantly patients of European ancestry."
The researchers in particular focused their analysis on the three most prevalent tumors in the study cohort: non-small cell lung, breast, and colorectal cancers.
In NSCLC, one approval that shifted the eligibility for biomarker-targeted therapies was the 2013 approval of Genentech's Tarceva (erlotinib) as a first-line treatment of EGFR-mutant NSCLC. Following that approval, there was a higher proportion of clinical actionability in the East Asian ancestry, 50.1 percent, and South Asian ancestry, 44.9 percent, groups compared to the non-Ashkenazi Jewish European ancestry group, 15.9 percent.
However, by 2023, new approvals in NSCLC for high tumor mutational burden, KRAS-mutant, and MET-altered tumors, the difference in actionability narrowed between the East Asian and South Asian groups, with 81.1 percent and 76.6 percent eligible for precision treatments, respectively, compared to the European ancestry group, with 61.1 percent of patients eligible.
By contrast, in breast and colorectal cancer, the non-Ashkenazi Jewish European ancestry group saw greater benefit from new targeted therapy drug approvals.
African ancestry patients, meanwhile, saw the least benefit from new drug approvals in breast cancer. African ancestry patients had 8.9 percent to 14 percent lower actionability compared with patients of other ancestry groups after the 2019 approval of Novartis' Piqray (alpelisib) for PIK3CA-mutant breast cancer, due to a lower prevalence of PIK3CA mutations among those of African descent.
A similar gap arose with the 2023 approval of Menarini Group's Orserdu (elacestrant) in ESR1-mutant breast cancer. The proportion of breast cancer patients with clinically actionable mutations after that approval was 47.5 percent for African ancestry patients, compared to 58.5 percent to 60.4 percent in the other ancestry groups.
In colorectal cancer, East Asian and African ancestry groups had the lowest clinical actionability by the end of 2023, 17.7 percent and 18.7 percent, respectively. This was caused by fewer East Asian and African patients being eligible for new approvals such as Merck's Keytruda (pembrolizumab) for patients with microsatellite instability high and tumor mutational burden high solid tumors and Pfizer's Braftovi (encorafenib) for BRAF V600E-mutant colorectal cancer.
"African and East Asian ancestry patients have the lowest prevalence of these level 1 biomarkers … so they didn't benefit from drugs targeting [those biomarkers]," Arora said.
As new drugs are approved, eligibility will continue to shift. One area that Arora sees potential for change is in colorectal cancer and KRAS-targeted therapies. Patients of African ancestry have a higher prevalence of KRAS-driven colorectal cancer compared to other groups, so new approvals could help close the gap, she said.
While there already have been approvals for KRAS G12C-targeted drugs, African ancestry patients typically harbor mutations in other KRAS variants, she added.
"If there was a pan-KRAS drug approved that could target other KRAS G12 alterations, we could see this difference between patients of African ancestry and patients of European ancestry lessen because of increased actionability for African ancestry patients," Arora explained.
Arora and Chakravarty pointed to several ongoing efforts to increase representation of African, Asian, and other non-European ancestry groups in genetic and clinical research but highlighted the need for large databases of genetic information about these groups to identify ancestry-specific biomarkers.
Chakravarty noted that changing standards that highlight the inclusion and discussion of diverse patient populations in research as a shift in the right direction. She pointed to the American Society of Clinical Oncology (ASCO) requirement to include information about the patient population included in every manuscript and the National Cancer Institute's requirement to include patients from certain backgrounds in studies funded by its grants as first steps.
"There has been a shift where it's not only individual labs or patient advocacy groups that have been aware of and researching disparities over decades that have been ringing the bell of alarm, but institutionally, locally and globally, the focus has turned to addressing these disparities," Chakravarty said. "It's not a single factor; it's a multifactorial combination that's initiated a call to action that feels more urgent in recent years. Only through multipronged efforts involving academic center hospitals, safety net hospitals, industry partners, and the government can we really address [this issue] which has been a cumulative effect over decades."