Genetic differences in breast tumors may contribute to racial disparities

Clinicians know the odds tend to be stacked against Black breast cancer patients. They have more dangerous and aggressive subtypes of breast cancer more frequently than white patients. Within breast cancer subtypes, Black patients tend to have worse outcomes compared to white patients, too. But what biological factors contribute to these disparities — and how much — is an open question.

Now, there’s evidence that ancestry correlates with key mutations that can shape the biology of certain tumors and how those tumors respond to treatments. Research published on Thursday in the JAMA Network Open found that Black patients tended to have worse responses to pre-surgical chemotherapy in nearly every subtype of breast cancer, but the disparity was most dramatic in HR-negative and HER2-positive tumors. When they looked deeper, the researchers found Black patients were more likely to have tumors with mutations that are associated with treatment resistance.

That suggests biological differences may be contributing to health disparities alongside other, social reasons, said Dezheng Huo, a cancer epidemiologist at the University of Chicago and one of the authors on the study. “Many think about access to care and how that causes disparity,” he said. “But most studies have not looked deeper at breast cancer subtypes and how different biology determines treatment response.”

To do the study, researchers followed 690 patients with breast cancer at the University of Chicago who underwent neoadjuvant chemotherapy — chemotherapy before surgery. In general, that means their cancers tended to be a little more advanced. “If the tumor is small, we do surgery first. If the tumor is big, we give chemotherapy first to make the tumor smaller, then surgery,” Huo said.

Then, the researchers collected data on how many patients had no invasive cancer cells by the time they had surgery — considered a complete pathologic response to the neoadjuvant chemotherapy. They also conducted testing on the patients’ tumors to determine what subtype of breast cancer they had and what mutations were present in the cancers’ genomes, and they measured other, clinical factors like how long it took for patients to go from diagnosis to chemotherapy. “We really tried to collect as much data as we could,” Huo said.

When the team analyzed the data, they found a greater proportion of white patients had a complete response to the neoadjuvant chemotherapy compared to Black patients across nearly all subtypes of breast cancer. Overall, 36.6% of white patients had a complete response to the chemo, compared to 28.6% of Black patients. While that was also true for triple-negative breast cancer, Huo said that the difference didn’t reach statistical significance “due to the small sample size,” he said. “National data clearly shows that African Americans have a lower response rate in triple negative breast cancer, though.”

The biggest racial disparity was among cancers that were hormone receptor negative but HER2 positive. “That was really striking to us,” Huo said. “In this subtype, treatment should be very successful, so this result is quite alarming. It tells you that when two groups of people with different ancestry get the same treatment for the same subtype of cancer, they have a different response.”

When the investigators looked at the genetic data, they found that some key mutations showed up more frequently in Black patients. For example, 30% of Black patients with HR-negative HER2-positive cancers had mutations in genes related to a key protein system called the MAPK pathway, compared to 4.6% of white patients that had similar mutations. Mutations in this pathway are linked to resistance to certain therapies for HER2-positive cancers, said Mariana Chavez Mac Gregor, a breast cancer researcher and oncologist at MD Anderson Cancer Center who was not involved with the work.

“There’s a clear disparity crisis in breast cancer with marginalized groups tending to have worse outcomes. We often think that has to do with access to care and other social determinants to care, but there might be something else,” Chavez Mac Gregor said. “There could be biological differences as well. This study suggests the tumors could be different.”

The work also underlines how important biomarker testing is in cancer therapy and how that might help reduce disparities, Chavez Mac Gregor said. “Better understanding the biology is going to help us see how therapies should be tailored differently for patients,” she said. “At the population level, things like helping access, navigation programs, getting patients to the right treatment in a timely manner will be key.”

Huo and the team at the University of Chicago are planning future studies to further investigate the MAPK pathway and how it affects resistance to chemotherapy. “Maybe future clinical trials can look for better combination treatments targeting HER2+ patients,” he said.

And future research on this might help improve cancer therapy for patients from more privileged backgrounds, too, Huo said. “Even white patients might have resistance due to alterations in the MAPK pathway,” he said.