A genetic signature widely used to guide cancer treatments may not work for patients with African and Asian ancestries, according to a new study. The finding could mean people with these backgrounds are receiving an expensive therapy that won’t help them and could even worsen their prognosis, scientists say.
“It’s really important that this has been demonstrated,” says Aedín Culhane, a cancer computational biologist at the University of Limerick who studies cancer therapies but was not involved with the work.
Sequencing tumor DNA is now a part of routine cancer care. Identifying specific mutations can help physicians narrow down the best treatment. Clinical trials have shown tumors with many mutations—what’s known as a high tumor mutational burden (TMB)—respond well to drugs known as immune checkpoint inhibitors, which release a brake on immune cells and enable them to attack tumors.
A study from 2021 found a high TMB could predict whether patients would respond well to a type of immune checkpoint inhibitor known as pembrolizumab. A few months later, the U.S. Food and Drug Administration (FDA) approved the drug for the treatment of tumors with high TMB, which are found in some lung cancers, melanoma, and cervical cancer.
“It’s essentially one of the few FDA-approved pancancer biomarkers,” says Alexander Gusev, a statistical geneticist at the Dana-Farber Cancer Institute who led the new study.
But what determines whether a patient truly has a high TMB? Doctors typically compare a tumor’s genetic material against reference genomes found in huge databases that compile DNA from thousands of people. But these databases are not diverse, Gusev says. For instance, gnomAD is made up of 56,885 European sequences, but only 8128 African ones.
To find out whether this disparity matters, Gusev and his colleagues compared the tumor sequences from more than 3600 cancer samples with sequences from a reference panel, and with the patient’s own DNA taken from healthy cells. When compared with a reference panel, the tumors of people with European ancestry showed a 50% higher TMB than they actually had, the researchers found. For patients who didn’t have European ancestry, their estimated TMB was more than twice as large as their actual TMB, the team reported last week in Cancer Cell.
The disparity was largest in patients with African and Asian ancestry. If the results hold up in the clinic, it could mean doctors are prescribing these patients an expensive drug—each dose of pembrolizumab costs more than $10,000—that may not help them, the authors say.
A common algorithm used to compare disease and reference genomes also led to more false positives among people of non-European descent. Only 21% of patients of European ancestry had false high-TMB misclassifications, compared with 37% and 44% of patients of Asian or African descent, respectively, the team found.
To see the real-world consequences of the TMB inflation, the researchers applied a corrected algorithm to a smaller group of patients with non–small-cell lung cancer who had received immunotherapy. Only the patients with European ancestry and a true high TMB survived for longer. The immunotherapy did not improve the survival of the patients with African or Asian ancestry and a true high TMB. In some type of cancers, patients with Asian ancestry given immune check inhibitor therapy were less likely to get better or survive.
“They’re not just saying that certain ethnicities will do poorly with checkpoint immunotherapy,” says Vamsidhar Velcheti, an oncologist at New York University’s Grossman School of Medicine who was not involved with the study. “They’re actually telling you exactly the mechanisms of why that may be the case.”
The ideal TMB test in these patients, Gusev says, should be done by comparing the patient’s tumor DNA with their own normal DNA, not with a reference panel.
Both doctors and patients need to be aware of these issues, Gusev says. “Non-European individuals are already typically getting substandard care,” he says. “This is just exacerbating those problems.”
Research has shown, for instance, that systemic racism and discrimination mean Black people have the highest cancer mortality rate, and that cancer screening is lower among nonwhite patients.
Less than 4% of patients enrolled in such immune checkpoint inhibitors trials are Black, according to a 2019 review. If the study population of immunotherapy clinical trials was more diverse, Velcheti argues, the issue with the biomarker in non-European patients may have been caught sooner.
The same is true for the human reference genomes that are routinely used for cancer care and other genetic diseases. “All of those are continuing to underrepresent non-European ancestry,” Gusev says. “I think people don’t appreciate how these biases can actually cascade into other biomarkers that you wouldn’t have even thought to be relevant.”
Source: Science Mag