A new study reported in Cancer Cell shows that immune checkpoint inhibitors may not work as well as previously thought in patients of African and Asian descent due to DNA reference databases containing an overabundance of European DNA sequences.
Tumor DNS sequencing is routinely used in cancer care to identify mutations in patients and determine the best course of treatment. High mutational tumor burdens (TMBs) have been found to respond well to immune checkpoint inhibitors (ICIs), with a 2021 study reporting that a high TMB can predict how well patients may respond to the ICI pembrolizumab. Several months later, the FDA approved pembrolizumab for the treatment of tumors with high TMB, commonly found in melanoma, cervical cancers, and lung cancer. To determine if a patient has high TMB, their tumor’s genetic material is compared against a reference database called The Genome Aggregation Database (gnomAD) that contains DNA sequences from thousands of people.
Issues in DNA Databases
However, gnomAD’s database has been found to not be diverse enough; for example, the database is comprised of 56,885 European sequences, but only 8,128 African ones. The disparity in non-European DNA sequences means that patients of non-European descent may not be receiving correct TMB information due to insufficient DNA data from their own race or ethnicity.
Alexander Gusev, a statistical geneticist from the Dana-Farber Cancer Institute who led the new study, compared tumor sequences from over 3,600 cancer samples with sequences from a reference panel. The tumors of those with European ancestry showed a 50% higher TMB than they actually had, and for patients with no European ancestry, their TMB estimate was over twice as large as their actual TMB. The disparity was more common in patients with African and Asian ancestry.
The researchers applied a corrected algorithm to a smaller group of patients with non-small-cell lung cancer who had undergone immunotherapy to see the real-world consequences of the TMB inflation. Only patients with European ancestry and a high TMB had a longer survival, while the immunotherapy did not improve survival in patients with African or Asian ancestry who had high TMB. Some patients with Asian ancestry who were given ICI therapy were less likely to get better or survive.
Fixing Disparities in Testing
Gusev notes that TMB testing for these patients should be done by comparing the patient’s tumor DNA with their own normal DNS and not that of a reference panel. “Non-European individuals are already typically getting substandard care,” he says. “This is just exacerbating those problems.”
To fix this issue, ICI trials need to enroll more diverse groups of patients to lessen the disparity in non-European patients. For example, according to a 2019 review, less than 4% of patients in ICI trials are Black. If immunotherapy clinical trial study populations were more diverse, these biomarker issues in non-European patients may have been found sooner. Gusev added that the human reference genomes that are used for cancer care and other diseases are “continuing to underrepresent non-European ancestry…people don’t appreciate how these biases can actually cascade into other biomarkers that you wouldn’t have even thought to be relevant.”
Cancer Treatment Predictor May Not Work in Patients With African and Asian Ancestries