Hidden Risks

Damaris Olagundoye, MD, grew up knowing that her maternal grandmother was a breast cancer survivor. She would listen as her mother talked with cousins who had also been diagnosed with the disease, but her family didn’t learn until decades later that they carried a mutation in the BRCA2 gene.

Her mother’s heritage was Afro Panamanian, and her father immigrated from Nigeria. When the BRCA2 gene was linked to breast cancer in 1995, it was identified mainly based on data from white women and recognized to be more common in those of Ashkenazi Jewish ancestry. The awareness and importance of this gene across all populations, including those of African ancestry, was not recognized until many years later. 

Researchers at Vanderbilt-Ingram Cancer Center, where Olagundoye is a patient, are putting Black women front and center as they investigate why breast cancer is deadlier in women of African ancestry than other racial groups. They have led the largest-ever study of breast cancer genetics in Black women and have identified many new risk factors. Their work continues as they further delve into the clinical and genetic reasons for racial disparities in breast cancer recurrence and survival.

“My mother, Eneida, did her due diligence; she did her darndest,” Olagundoye said. “My grandmother, who was named Agnes, was our family’s cancer triumph story. She lived for 25 years after her diagnosis, but my cousin, Ana, died of breast cancer soon after having a baby. Because of this family history of breast cancer, my mother got her mammograms religiously. Unfortunately, my mom was diagnosed with ovarian cancer.”

It was only then that genetic testing was offered to her mother and revealed that she carried a BRCA2 mutation, which also puts women at greater risk for ovarian cancer. Olagundoye underwent testing and learned that she too had inherited the mutation.

“That was around 2020 in the midst of the pandemic, so I get a mammogram, and everything is normal,” she said. “Then on July 5, 2021, I felt a lump. Then I get another mammogram, and I have breast cancer.”

Olagundoye was diagnosed at age 42, much younger than the median age for breast cancer of 62. Black women are more likely to be diagnosed at younger ages and at more advanced stages of the disease. They are also more likely to have more aggressive subtypes.

Olagundoye, who is an obstetrician/gynecologist in Nashville, experienced shock, depression and self-doubt. She worried she had neglected her own health while being in the business of caring for others.

“Life comes at you fast, there’s no break and there’s no reprieve,” she said. “I had just lost my 45-year-old cousin, Perla, to breast cancer in 2018, then my mom in 2019. COVID was here, and then I had breast cancer. Yeah, even though I am a doctor and an OB-GYN, I felt hurt. I felt angry. I thought ‘How did this happen in such a quick span of time?’ You look up, and now you have cancer. I didn’t even have time to grieve. It was like ‘Girl, you got to save yourself. That ship has sailed.’ It was a lot. It was super painful. It was just hard.”

GENOMIC RESEARCH

Olagundoye went for treatment at the Vanderbilt Breast Center, where her medical oncologist was Sonya Reid, MD, MPH, assistant professor of Medicine, who joined Vanderbilt University Medical Center in 2020 because she wanted to be part of a research program where she could delve into outcome disparities. Black women are 42% more likely to die from breast cancer compared to white women, Reid noted.

“The factors that contribute to disparities among racial groups are complex and likely have to do with a variety of circumstances, including tumor biology, genetics, access to health care and other social determinants of health,” Reid said.

The genetics piece of the puzzle is especially complex. However, a research team led by Wei Zheng, MD, PhD, MPH, the Anne Potter Wilson Professor of Medicine, has made great progress in this realm with the Breast Cancer Genetic Study in African-Ancestry Populations, which began in 2016. With $12 million in funding from the National Cancer Institute, it is the largest-ever study of breast cancer genetics in Black women.

“This is actually three or four times bigger than any study before on this topic,” said Zheng.

A study published by his research team in July 2022 in the journal Genetics in Medicine revealed that 1 in 24 women of African ancestry with breast cancer have a pathogenic variant in a breast cancer susceptibility gene. They discovered 11 novel pathogenic variants in breast cancer predisposition genes and confirmed previous findings for BRCA1, BRCA2, PALB2, ATM, TP53, NF1 and CHEK2 with breast cancer risk. They also found new evidence to extend the associations of breast cancer risk for Black women with RAD51C and RAD51D that had previously been identified for white women.

“We did this analysis with our own data and also data from previous studies, so we increased the sample size and made this the most powerful study ever conducted to date on this topic,” Zheng said.

The data were drawn from the Southern Community Cohort Study, the Nashville Breast Health Study, the Southern Tri-State Breast Health Study – which Vanderbilt researchers collected working with partner investigators – and the Multiethnic Cohort Study, which was conducted in Los Angeles and Hawaii. 

The team has also studied data sets collected in Africa. They investigated structural variants in breast cancer risk genes with data from the Ghana Breast Health Study as well as the African American Breast Cancer Genetic Consortium. They identified 25 large deletions in breast cancer predisposition genes, including eight deletions that are predicted to disrupt protein function. They also detected 56 deletions in suspected breast cancer predisposition genes.

AGGRESSIVE SUBTYPE 

A primary focus of the research is triple-negative breast cancer, an aggressive subtype that occurs at double the rate in women of African ancestry than in white women. The team is conducting research to identify if genetic factors may explain some of the high risk of triple-negative breast cancer in African ancestry women.

Triple-negative breast cancer gets its name because it does not have any of the three receptors – estrogen, progesterone and HER2 – for which there are drugs that can destroy the cancer cells. 

“I don’t have triple-negative breast cancer,” Olagundoye said. “I have hormone receptor-positive breast cancer. I feel like I am lucky and dodged that bullet. There are hormone blockers I can take that are beneficial for my disease.”

Vanderbilt researchers are currently investigating the combination of standard chemotherapies with the immunotherapy atezolizumab as part of an effort to maximize drug potency for triple-negative breast cancer. They are also working to identify biomarkers of response for this subtype.

 In 2021, Justin Balko, PharmD, PhD, associate professor of Medicine and Pathology, Microbiology and Immunology, and colleagues reported that a proven biomarker for response to immunotherapies in melanoma patients also has clinical relevance for breast cancer patients. Also in 2021, Brian Lehmann, PhD, research associate professor of Medicine, and colleagues identified a subtype of triple-negative breast cancer that appears to be able to escape detection by the immune system and evade immunotherapy. Using mouse models, they found that drugs called epigenetic inhibitors enhanced the efficacy of chemotherapy with this subtype.

 In 2020, Jennifer Pietenpol, PhD, holder of the Brock Family Directorship in Career Development and Executive Vice President for Research at Vanderbilt University Medical Center, and colleagues made another discovery that may lead to more effective treatments for this aggressive breast cancer. They determined that experimental drugs called BET inhibitors are effective against triple-negative breast cancers in model systems that overexpress MYCN, a well-known oncogene.

TESTING DISPARITIES

It’s crucial that more Black women participate in clinical trials for emerging breast cancer treatments, Reid said. Although Black patients accounted for 12% of breast cancer cases in the United States, they accounted for only 3% of participants in clinical trials that led to new drug approvals from 2008-2018. This means that drugs are approved based on data primarily from white women. Yet, studies have shown that when asked, Black patients are just as willing to participate in clinical trials as white patients.

“In the era of precision oncology, eligibility for specific drugs may be guided by results from germline and somatic testing,” Reid said. “As more targeted approaches to improve cancer outcomes emerge, there is an urgent need to ensure that patients across diverse racial/ethnic populations are identified and offered genomic testing and enrollment in clinical trials when eligible.” 

Tuya Pal, MD, Ingram Professor of Cancer Research, professor of Medicine and associate director for Cancer Health Disparities at Vanderbilt-Ingram Cancer Center, authored a study in 2017 that found young Black women with breast cancer were less likely to receive genetic testing compared to white women. The study showed that health care providers were less likely to refer Black women for genetic testing compared to white women.

“Genetic risk factors have great potential to identify those at higher risk for breast cancer and also to guide personalized treatments,” Pal said. “The rates of genetic testing are lower in Black women compared to white women, not because Black women aren’t interested in testing, but rather because they are not aware of it or were not offered it. As genetic testing becomes increasingly important in guiding medical care, we must address this disparity such that women with breast cancer across all populations may benefit from these tremendous advances.”

Together with Reid, Pal published a study in June 2020 to report that only about 1 in 5 young women with breast cancer, including Black, white, and Hispanic women, sees a genetics expert for care as suggested by many clinical practice guidelines. They also showed that not seeing a genetics expert for care is associated with getting less information about key items that should be discussed before someone is tested. But sometimes it can be hard to get an appointment with a genetics expert, often with long wait times to get into clinics. To combat this problem, the team is now studying strategies to provide genetic education through a web-based tool, so that more people have access to this information. Funded in part through the Susan G. Komen Foundation, they have recently tested the tool in young Black women with breast cancer, and it was well received and useful in providing these women with information about inherited cancer risks.

Reid received funding in 2021 from the Breast Cancer Research Foundation for an initiative to assess connections between genes, clinical and pathological features, such as age at diagnosis, tumor subtype and stage at diagnosis across a diverse population. Together with funding secured through the Susan G. Komen Foundation by Pal, they are studying the genomics of breast cancers in diverse women with inherited mutations in predisposition genes, such as BRCA1, BRCA2 and PALB2. Breast tumors in these women are being evaluated through tumor genomic studies, to identify patterns of changes that may eventually be used to guide treatments or help identify possible treatment targets.

Precision oncology advances also include using many parts of the genomic information to predict diseases such as cancer. Predictions are based on existing genomic data. Because 80% of all genomics research has been done among individuals of European descent, even though they only represent about 16% of the world’s population, the ability to predict cancer is much better among individuals of European descent.

“This is a problem because research has shown that our ability to use genomic information from white patients to predict cancer risks in Black patients does not work very well,” Pal said. “This is also another important reason to include all populations in genomics research, so that all populations can equally benefit, and we don’t widen existing health disparities. Making genomics research available and accessible to populations of African ancestry also has the advantage of leading to more scientific discoveries for everyone. This is because humans originated from Africa, and individuals of African ancestry have the most genomic diversity.” 

Ultimately, inclusion in genomics research is a matter of health equity.

SOCIOECONOMIC FACTORS 

Access to care is a primary factor for why Black and Latina women are diagnosed with breast cancer at more advanced stages. The uninsured rate in 2019 for Black women was 14.2% and 25.7% for Latina women, according to a report by The Commonwealth Fund, compared to 9% for white women. The disparities were more glaring in states, such as Tennessee, that have not expanded their Medicaid programs. In those states, 18.9% of Black women, 35.2% of Latina women and 13% of white women were uninsured.

“While genomics is important, equally or even more important is to consider, incorporate and address how social determinants of health — including access to care — may be contributing to more deadly disease,” Pal said. 

Socioeconomic and lifestyle factors for survival disparities also merit more attention, said Zheng, who has primarily been focused on closing the gap on genomic knowledge.

“This kind of work is important,” Zheng said. “We can identify what other determinants cause these racial disparities, then we can do calls for action and improve care.”

Olagundoye said she considers herself fortunate. She underwent chemotherapy then had a bilateral mastectomy in February 2022, followed by 30 radiation sessions. She also had surgery to remove her ovaries and fallopian tubes as a preventive measure against ovarian cancer. She continues to take hormone blockers as a treatment to avoid breast cancer recurrence. She is also receiving olaparib (a PARP inhibitor), which received FDA approval in March 2022 to reduce the risk of recurrence among germline BRCA mutation carriers with high-risk, localized HER2-negative breast cancer. 

During the process, she decided to take time to pursue her passions, to write opinion pieces for The 

Tennessean, complete a public health master’s degree, run a half-marathon and be a mother to her two sons — and even form a family jazz trio with saxophone, piano and drums. Olagundoye, like many women, is used to juggling multiple duties. She realizes she’s fortunate to be highly educated and have a good job with good benefits.

“Often times, Black women have a superhero complex,” she said. “They are dealing with 20 different things, like keeping their family together, keeping meals on the table and things like that. They really don’t worry about themselves. Between going to work and having the luxury to get a day off and be able to go get a mammogram, they don’t take good care of themselves. Many don’t have insurance or are underinsured. Then there are the copays. Just getting in to see a doctor is more difficult.”

She stressed the need for more women of diverse groups to participate in research initiatives and clinical trials.

“Because of the historical context — things like the Tuskegee Study — there is definitely trepidation in the Black community about research, but I do think that by word of mouth, by hearing it from people in our community like Dr. Reid, who is of African descent, it lends credibility and validity to these types of projects. It’s so important for brown and Black women, who have the worst outcomes because of late detection and more aggressive types of breast cancer, to take part.”