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Purpose: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort., Methods: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs., Results: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC., Conclusion: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention., Competing Interests: Conflict of Interest Brent Mabey, Elisha Hughes, Matthew Kucera, Timothy Simmons, Brooke Hullinger, Sarah Ratzel, Susanne Wagner, Jerry S. Lanchbury, Katherine Johansen Taber, Thomas P. Slavin, and Alexander Gutin were employed by Myriad Genetics, Inc. at the time of the study and received salaries and stocks as compensation. Holly J. Pederson and Monique Gary have received consulting fees from Myriad Genetics, Inc. Charis Eng has ownership interests in MyLegacy/MyFHH/Family Care Path. Judy Garber has received research funding from Ambry Genetics and Invitae and has other relationships, or an immediate family member with relationships, with AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrianne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered, Novartis, GTx, Aleta BioTherapeutics, H3 Biomedicine, and Kronos Bio. Ora Gordon has had a consulting or advisory role with GRAIL and Genetic Technologies, has received travel or accommodation expenses from GRAIL, and has received research funding from GRAIL. Jennifer R. Klemp has received consulting fees and speakers’ bureaus fees from AstraZeneca, has ownership interests in Cancer Survivorship Training, is employed by Caris Life Sciences, Inc, and has received a salary as compensation and consulting fees. Olufunmilayo I. Olopade has an ownership interest in 54Gene and Tempus, has an ownership interest and has received a salary from CancerIQ, and has other interests in Color Genomics, Healthy Life for All Foundation, and Roche/Genetech. Mark E. Robson has provided clinical trial services to AstraZeneca and Merck and has received consulting fees from and/or been on advisory boards for Change Healthcare, Intellisphere, MyMedEd, Physician’s Education Resources, and Research to Practice. Pat W. Whitworth has received consulting fees from or had contracted research with Agendia, Biotheranostics, Genomic Health, Impedimed, Myriad Genetics, Inc, Prelude, and Veracyte, and has an ownership interest in Medneon. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Polygenic risk scores (PRSs) for breast cancer (BC) risk stratification have been developed primarily in women of European ancestry. Their application to women of non-European ancestry has lagged because of the lack of a formal approach to incorporate genetic ancestry and ancestry-dependent variant frequencies and effect sizes. Here, we propose a multiple-ancestry PRS (MA-PRS) that addresses these issues and may be useful in the development of equitable PRSs across other cancers and common diseases., Materials and Methods: Women referred for hereditary cancer testing were divided into consecutive cohorts for development (n = 189,230) and for independent validation (n = 89,126). Individual genetic composition as fractions of three reference ancestries (African, East Asian, and European) was determined from ancestry-informative single-nucleotide polymorphisms. The MA-PRS is a combination of three ancestry-specific PRSs on the basis of genetic ancestral composition. Stratification of risk was evaluated by multivariable logistic regression models controlling for family cancer history. Goodness-of-fit analysis compared expected with observed relative risks by quantiles of the MA-PRS distribution., Results: In independent validation, the MA-PRS was significantly associated with BC risk in the full cohort (odds ratio, 1.43; 95% CI, 1.40 to 1.46; P = 8.6 × 10 -308 ) and within each major ancestry. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women., Conclusion: The MA-PRS uses genetic ancestral composition to expand the utility of polygenic risk prediction to non-European women. Inclusion of genetic ancestry in polygenic risk prediction presents an opportunity for more personalized treatment decisions for women of varying and mixed ancestries.