Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.
Publication Title
Genetics in medicine : official journal of the American College of Medical Genetics
Document Type
Article
Publication Date
7-1-2024
Keywords
california; los angeles
Abstract
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.
Clinical Institute
Cancer
Clinical Institute
Women & Children
Specialty
Oncology
DOI
10.1016/j.gim.2024.101128
Recommended Citation
Mabey, Brent; Hughes, Elisha; Kucera, Matthew; Simmons, Timothy; Hullinger, Brooke; Pederson, Holly J; Yehia, Lamis; Eng, Charis; Garber, Judy; Gary, Monique; Gordon, Ora; Klemp, Jennifer R; Mukherjee, Semanti; Vijai, Joseph; Offit, Kenneth; Olopade, Olufunmilayo I; Pruthi, Sandhya; Kurian, Allison; Robson, Mark E; Whitworth, Pat W; Pal, Tuya; Ratzel, Sarah; Wagner, Susanne; Lanchbury, Jerry S; Taber, Katherine Johansen; Slavin, Thomas P; and Gutin, Alexander, "Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors." (2024). Articles, Abstracts, and Reports. 8978.
https://digitalcommons.providence.org/publications/8978
10.1016/j.gim.2024.101128