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UPenn Study Finds Similar Rates of Risk Mutations Among Black, White Breast Cancer Patients


NEW YORK – In the US the prevalence of inherited breast cancer risk mutations is roughly the same among Black and non-Hispanic white women diagnosed with breast cancer, according to a recent JAMA study out of the University of Pennsylvania.

The study, which took a population-based approach and considered all patients regardless of age or breast cancer subtype, detailed the prevalence of pathogenic variants in 12 established breast cancer predisposition genes including ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53.

The UPenn researchers, led by Susan Domchek, considered patients who had been included in one of seven prospective cohort studies involved in the Cancer Risk Estimates Related to Susceptibility consortium. To avoid biasing the results, they excluded those studies in the consortium that had been specific to patients with early-onset breast cancers or with known family histories of cancer.

"Several prior studies were done that did suggest that there were higher rates [of breast cancer risk variants] among Black women," Domchek said. "But several of them were done by commercial testing laboratories, and that just suggests that it takes more for Black women to get tested. You need to be younger or have triple-negative cancer or have a very sure family history to get tested if you're Black compared to if you're white."

In their study, Domchek and colleagues wanted to avoid this referral bias wherein Black patients who were already at high risk of breast cancer based on clinical and family history would be offered genetic testing. So, they analyzed women of all ages, regardless of family histories or breast cancer subtypes.

In contrast to some of the earlier, commercial lab-initiated analyses that Domchek worried had been complicated by referral bias, the JAMA study highlighted no difference in risk variant prevalence according to race. Specifically, among nearly 4,000 Black patients and around 25,300 non-Hispanic white patients — all of whom had self-reported their race — 5.65 percent and 5.06 percent of patients respectively had a pathogenic variant in one of the 12 genes.

"This unselected, population-based work really gives you a sense that if you take women in general, the rates [of pathogenic variants] are about the same," Domchek said. "We need to make sure that those types of referral biases, and lower uptake of genetic testing in underrepresented minority communities doesn't continue."

Domchek and colleagues did break down their analysis by specific genes. In doing so, they found that non-Hispanic white women were more likely to have variants in CHEK2 and that Black patients were more likely to have variants in BRCA2 and PALB2, whereas the rates for the remaining genes were similar.

Researchers also stratified patients by estrogen receptor status and found similar findings among Black and white patients with hormone receptor-positive breast cancer. Black women, for example, were more likely than white women to have risk variants in BRCA2, but less likely to have variants in CHEK2.

In hormone receptor-negative breast cancer patients, the only significant difference researchers observed among Black and white patients was for PALB2, in which Black patients had higher rates of risk variants. In both hormone receptor groups, however, the overall prevalence of risk variants was not different between the race-stratified patient populations.

When they adjusted for patients' age at diagnosis, the researchers again found that variants in PALB2 were more prevalent among Black women than non-Hispanic white women, but that there was no longer a difference in the prevalence of BRCA2 variants. ATM, BRCA1, and TP53 were all more prevalent in the white population when adjusted for age.

Implications for risk stratification, test access

Based on the fact that the overall prevalence of pathogenic variants was similar in Black and white women, and that the differences were modest for specific genes between groups, Domchek and colleagues concluded that genetic testing guidelines should not be tailored to patients' race.

Currently, the NCCN recommends germline testing for patients with a personal history of breast cancer who have, among other factors, blood relatives with known pathogenic variants in cancer susceptibility genes; a diagnosis under age 45; a diagnosis of triple-negative breast cancer under age 60; and Ashkenazi Jewish ancestry. These recommendations should be consistent across race and ethnicity, according to Domchek and coauthors.

"This study is really showing us that you shouldn't really look at race [for risk stratification]," she said. "You should ask, is there a family history? What age is the patient? Do they have triple-negative breast cancer?"

While some in the field have argued in recent years that all breast cancer patients regardless of age or risk factors should undergo genetic testing, Domchek believes there is an important role for risk stratification, especially since the field has a long way to go when it comes to successfully testing all patients who are most likely have these variants in the first place.

"My point has always been that right now, we don't test people who clearly should be tested," she said, citing data indicating that only 30 percent of patients with ovarian cancer undergo genetic testing to assess their future cancer risk, even though such testing is universally recommended in guidelines. "My worry is that [universal germline testing in breast cancer] is going to worsen racial disparities because white patients or wealthier patients will see doctors who potentially have the capacity to take that on."

In other words, Domchek would want to see disparities in access to genetic testing addressed using current guidelines before expanding the pool of who is eligible to receive testing.

To this end, the Basser Center for BRCA at UPenn, which Domchek spearheads, is actively working to reduce these gaps. Just last year, the center launched its Black & BRCA initiative, through which the institution partners with community groups and local healthcare providers to disseminate tailored educational materials about breast cancer risk mutations and the importance of genetic testing for high-risk populations.

"Penn as a whole has been very committed to narrowing these gaps," Domchek said. "But it doesn't just happen. You have to work at it. ... It's a complex issue."

One of the initiative's overarching goals is to improve awareness of the fact that anyone, regardless of race, can have a breast cancer risk mutation. "If you don't see stories of people who look like you, it doesn't resonate," she said. "Most of the stories about BRCA1 and BRCA2 in the lay media mostly feature white women ... but you don't hear enough that every race and every ethnicity has BRCA1 and BRCA2 mutations."

Black & BRCA combines tailored education materials and patient stories with community outreach. Though the program is still in its very early stages, Domchek said that keeping track of metrics — particularly the percentage of patients for whom germline testing is recommended who actually end up getting it — will be a priority for the Basser Center going forward.

"You can't monitor what you can't measure," she said, explaining how Penn has put a tremendous amount of work into their electronic medical records in recent years to make it easier to access and analyze genetic testing percentages and reports. "In the past, it was very hard to keep track of genetic testing metrics in the medical records. ... Now, everything that we've done is transferrable to others that use Epic electronic medical records, which is 50 percent of the country."

Future work for researchers

In addition to improving access to genetic testing among Black patients with breast cancer, Domchek admitted that the field has much work ahead to better characterize breast cancer risk in this patient population.

For instance, the fact that Black women have higher risks of triple-negative breast cancer and early-onset breast cancers than their white counterparts, but not higher rates of inherited risk mutations — which are more likely to occur in TNBC and early-age diagnoses — underscores the need to account for what, if not for known pathogenic variants, is causing these disparities.

For instance, Black patients may have higher rates of risk variants not yet characterized — in part because genetics research has been performed in largely homogenous patient populations. Or, they may have certain mutations in BRCA1 or BRCA2 that are more difficult to detect via current sequencing methods.

"We're at that stage where we are asking, are these individually rare variants? Are these polygenic risk scores? Are these gene-by-environment interactions? All these things still need to be sorted out," Domchek said. "We do have ongoing work trying to find that missing heritability."