Genetic Clues to Early-Onset TNBC in Black Women

Microscopic image of breast cancer cells - Generated with Google Gemini AI

A study evaluated a multiple-ancestry polygenic risk score (MA-PRS) in a large cohort of Black women, seeking to analyze clinical and genetic data to assess the association between MA-PRS and triple-negative breast cancer (TNBC).

Black women in the US often develop aggressive breast cancer, particularly TNBC, at a younger age than White women, and accurate risk prediction tools are needed for early detection and intervention. PRS can improve risk assessment, but most PRS perform poorly in non-European populations.

The MA-PRS significantly improved TNBC risk prediction compared with clinical factors in both the full cohort and the younger subgroup. Women in the top 5% of the MA-PRS distribution had a roughly 2-fold increased risk of TNBC. MA-PRS into risk assessment can help identify women at high risk and improve their outcomes.

In an interview with Targeted Oncology^TM, Holly Pederson, MD, director of medical breast services at Cleveland Clinic and professor of medicine at Cleveland Clinic Lerner College of Medicine, and Elisha Hughes, PhD, director of research biostatistics at Myriad Genetics, discussed the study and its findings.

Targeted Oncology: What are the unmet needs in the patient population of this study?

Pederson: The unmet needs in the Black population, when it comes to breast cancer, start at the beginning and go all the way through the spectrum. Even when you look at risk factors and risk management, it is different even before the age at which a woman might get breast cancer. Then you have suboptimal screening and long delays in diagnosis. There are so many unmet needs.

One of the unmet needs that we chose to focus on is why young Black women get breast cancer earlier. Why do they get triple-negative breast cancer? We have not been able to answer that question with the genetic panel testing that we currently have available. What we did was use a polygenic risk score. You have your big genes, your moderate genes, and then the single nucleotide polymorphisms, which are common genetic variants that individually confer small levels of risk. But when you put them together in aggregate, they can significantly affect risk. We wondered if we looked at a large cohort of Black women who had presented for genetic testing, was there a difference in their polygenic load? Could we potentially identify young Black women before they get breast cancer?

What were you evaluating in this study? What was your methodology?

Hughes: In this study, we were evaluating a polygenic score that we have previously established as an important risk factor for overall breast cancer. Here, as Holly said, we specifically looked at how it affects risk of triple-negative disease in Black women and how it affects early onset triple-negative disease in Black women.

We were able to work with this study cohort of over 17,000 self-reported Black women and test how this polygenic score predicts triple-negative breast cancer risk and early onset triple-negative breast cancer risk, and importantly, what it adds above and beyond traditional risk factors that are already being used. Over half and up to 60% of women who develop breast cancer under 40 have no family history of breast or ovarian cancer in first- or second-degree relatives, so it’s a real problem. We need more tools like this.

Can you summarize your findings?

Hughes: The polygenic score was a powerful risk stratifier. It explains a lot of the genetic susceptibility that many women have for overall breast cancer and specifically triple-negative disease. [It was] about as powerful as everything else, except for maybe mammographic density. The polygenic score and mammographic density are both, I would say, equally powerful risk stratifiers.

Could you explain the implications of these findings for clinicians?

Pederson: This may help to change screening recommendations even, because [guidelines] should not just be based on age, but also on ancestry and genetics.

The other main implication is that we are looking at is to evaluate young women and identify those families that seem as if they may have a heritable disorder to prevent future cancers. But we would also love to identify the woman who might be at risk. It is about 6% of women who fall into that high-risk category. But that is an important 6%. We would like to make a difference there.

What are the implications of these findings for patients?

Pederson: All women should be aware of factors that go into breast health in terms of modifiable things. The 2 main things that can reduce the risk of triple-negative breast cancer specifically are breastfeeding and achieving and maintaining your ideal body weight. No specific diet is recommended. But weight control and breastfeeding are the 2 in terms of preventing breast cancer overall. Reducing alcohol consumption is also important, and regular exercise has been shown to be important, too.

What do you see as the next steps from this research?

Hughes: On the scientific development side, there is more we can do. Historically, there has been a lack of data in polygenic research for diverse ancestries. Another thing that we are working on is considering how we can improve triple-negative breast cancer risk prediction. This score that we evaluated was just designed to predict overall breast cancer. And it turns out, it works. It is also an important factor to consider in terms of triple-negative risk, but it is possible we could continue to make improvements there.

Pederson: We are hoping to get this technology into the clinical setting. It has been validated back to 2015. There are many studies in many parts of the world that have evaluated and validated this approach.

REFERENCE:

Pederson H, Hu E, Kucera M, et al. Evaluation of a polygenic risk score as a predictor of early onset triple-negative breast cancer in Black women. J Clin Oncol. 42, 2024 (suppl 16; abstr 10501). doi:10.1200/JCO