New Data Further Support Breast Cancer Polygenic Risk Score

Use of multiple-ancestry polygenic risk scores (MA-PRS) substantially add to clinical factors alone for the prediction of overall breast cancer, triple-negative breast cancer and young-onset disease in women of Hispanic ancestry, new data suggest.

The findings, from a large cohort, were presented at the 2024 San Antonio Breast Cancer Symposium by Cleveland Clinic’s Holly Pederson, MD, Director of Medical Breast Services. In June 2024, she presented similar findings from a large cohort of Black women at the annual American Association of Clinical Oncology meeting.

Taken together, the results suggest that “incorporation of MA-PRS into breast cancer risk assessment has the potential to improve breast cancer survival through more accurate identification of women at high risk,” Dr. Pederson says.

Although Hispanic women have a lower overall incidence of breast cancer compared with non-Hispanic white women, those who do develop breast cancer tend to be younger, have more advanced disease at the time of diagnosis and increased breast cancer mortality. Some evidence suggests that these differences may be due to a higher prevalence of aggressive subtypes, such as triple-negative breast cancer, in Hispanic women.

Similarly, Black women in the U.S. often develop early, biologically aggressive disease. Triple-negative breast cancer is more common in Black than in white women, and it often develops prior to age 40, when screening is first recommended.

Data from a previous study suggest that breast cancer is diagnosed at age younger than 40 years in about 7% of Black women and 8% of Hispanic women, versus just 4% of white women. Prior to age 50, those proportions are 23% and 29%, respectively, versus just 16% in white women.

“Although the majority of breast cancer diagnoses occur after age 40, there are a number that occur earlier than that. It's been very difficult to sub-stratify those early-onset patients, because at least half don't have any family history of either breast or ovarian cancer. Thus, more accurate risk prediction methods are urgently needed to identify young Hispanic and Black women with elevated risk for more aggressive breast cancers,” Dr. Pederson explains.

“If those high-risk women were identified early, they could be offered additional screening, such as with magnetic resonance imaging, and potentially risk-reducing medication,” she notes.

In the study of self-reported Hispanic women, the MA-PRS significantly improved upon clinical factors in predicting overall breast cancer by 63%, early-onset (<50 years) breast cancer by 62%, triple-negative breast cancer by 42% and early-onset triple negative by 48%. This effect on risk stratification represented a significant improvement over mammographic density, a risk factor with a similar effect.

Similarly, among the self-reported Black women, the MA-PRS improved overall breast cancer prediction by 33% and among those younger than 50 years by 43%. Those in the top 5% of the MA-PRS distribution were at a roughly two-fold increased risk of triple-negative breast cancer.

These new data build on previous work from Dr. Pederson’s group and others in collaboration with a genetics testing firm. Based on 56 ancestry-informative and 329 breast cancer-associated single nucleotide polymorphisms (SNPs), the test predicts overall breast cancer risk for diverse populations by characterizing genetic ancestry at each breast cancer SNP and applying ancestry-specific SNP risks and frequencies. All together, these SNPs contribute about 18-20% of the heritability of breast cancer.

On December 20, 2024, a study validating the MA-PRS, of which Dr. Pederson was an author, was named in the American Journal of Human Genetics as one of its top 10 significant advances in genomic medicine as selected by the Genomic Medicine Working Group of the National Human Genome Research Institute.

Despite all the impressive data, the MA-PRS is not yet recommended for clinical use by groups such as the National Comprehensive Cancer Network, pending further validation in diverse populations and greater education of the clinical community.

“We are still very early, both in our research and our educational efforts. There will need to be guidelines created around this for the primary care and even the medical oncology community,” Dr. Pederson says.

Ultimately, she believes all women should be screened with the MA-PRS in their 20s. “It's such a horror when we diagnose someone in their 30s, in the prime of their lives. If we could avoid that and identify high-risk patients earlier, that would really be the dream of this kind of technology.”