Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors Journal Article
| Authors: | Mabey, B.; Hughes, E.; Kucera, M.; Simmons, T.; Hullinger, B.; Pederson, H. J.; Yehia, L.; Eng, C.; Garber, J.; Gary, M.; Gordon, O.; Klemp, J. R.; Mukherjee, S.; Vijai, J.; Offit, K.; Olopade, O. I.; Pruthi, S.; Kurian, A.; Robson, M. E.; Whitworth, P. W.; Pal, T.; Ratzel, S.; Wagner, S.; Lanchbury, J. S.; Taber, K. J.; Slavin, T. P.; Gutin, A. |
| Article Title: | Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors |
| 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. © 2024 The Authors |
| Keywords: | adult; controlled study; aged; middle aged; major clinical study; genetics; clinical feature; cancer risk; comparative study; follow up; genetic predisposition to disease; breast cancer; incidence; cohort analysis; genetic association; genetic variability; risk factors; cancer screening; validation study; breast neoplasms; prediction; risk factor; risk assessment; breast tumor; diagnosis; clinical evaluation; patient coding; high risk population; pathogenicity; cancer control; genetic predisposition; genetic screening; validation; health care planning; patient referral; genetic testing; longitudinal study; sample size; germline mutation; procedures; ancestry group; longitudinal; multifactorial inheritance; low risk population; very elderly; humans; human; female; article; polygenic risk score; disease assessment; administrative claims (health care); genetic risk score; breast prediction |
| Journal Title: | Genetics in Medicine |
| Volume: | 26 |
| Issue: | 7 |
| ISSN: | 1098-3600 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-07-01 |
| Start Page: | 101128 |
| Language: | English |
| DOI: | 10.1016/j.gim.2024.101128 |
| PUBMED: | 38829299 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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