Journal Article

DKFZ-2025-02431

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women.

Ho, P. J. ; Loo, C. K. Y. ; Lim, R. J. Y. ; Goh, M. H. ; Abubakar, M. ; Ahearn, T. U. ; Andrulis, I. L. ; Antonenkova, N. N. ; Aronson, K. J. ; Augustinsson, A. ; Behrens, S.DKFZ* ; Bodelon, C. ; Bogdanova, N. V. ; Bolla, M. K. ; Brantley, K. D. ; Brenner, H.DKFZ* ; Byers, H. ; Camp, N. J. ; Castelao, J. E. ; Cessna, M. H. ; Chang-Claude, J.DKFZ* ; Chanock, S. J. ; Chenevix-Trench, G. ; Choi, J.-Y. ; Colonna, S. V. ; Czene, K. ; Daly, M. B. ; Derouane, F. ; Dörk, T. ; Eliassen, A. H. ; Engel, C. ; Eriksson, M. ; Evans, D. G. ; Fletcher, O. ; Fritschi, L. ; Gago-Dominguez, M. ; Genkinger, J. M. ; Geurts-Giele, W. R. R. ; Glendon, G. ; Hall, P. ; Hamann, U.DKFZ* ; Ho, C. Y. S. ; Ho, W.-K. ; Hooning, M. J. ; Hoppe, R. ; Howell, A. ; Humphreys, K. ; Ito, H. ; Iwasaki, M. ; Jakubowska, A. ; Jernström, H. ; John, E. M. ; Johnson, N. ; Kang, D. ; Kim, S.-W. ; Kitahara, C. M. ; Ko, Y.-D. ; Kraft, P. ; Kwong, A. ; Lambrechts, D. ; Larsson, S. ; Li, S. ; Lindblom, A. ; Linet, M. ; Lissowska, J. ; Lophatananon, A. ; MacInnis, R. J. ; Mannermaa, A. ; Manoukian, S. ; Margolin, S. ; Matsuo, K. ; Michailidou, K. ; Milne, R. L. ; Mohd Taib, N. A. ; Muir, K. R. ; Murphy, R. A. ; Newman, W. G. ; O'Brien, K. M. ; Obi, N. ; Olopade, O. I. ; Panayiotidis, M. I. ; Park, S. K. ; Park-Simon, T.-W. ; Patel, A. V. ; Peterlongo, P. ; Plaseska-Karanfilska, D. ; Pylkäs, K. ; Rashid, M. U. ; Rennert, G. ; Rodriguez, J. ; Saloustros, E. ; Sandler, D. P. ; Sawyer, E. J. ; Scott, C. G. ; Shahi, S. ; Shu, X.-O. ; Shulman, K. ; Simard, J. ; Southey, M. C. ; Stone, J. ; Taylor, J. A. ; Teo, S.-H. ; Teras, L. R. ; Terry, M. B. ; Torres, D. ; Vachon, C. M. ; Houdt, M. V. ; Verhoeven, J. ; Weinberg, C. R. ; Wolk, A. ; Yamaji, T. ; Yip, C. H. ; Zheng, W. ; Hartman, M. ; Li, J. ; On Behalf Of The Abctb Investigators ; kConFab Investigators ; MyBrCa Investigators ; Sgbcc Investigators

2025
MDPI Basel

Abstract: Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case-control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62-1.64, AUC = 0.551-0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94-0.99, AUC = 0.523-0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Keyword(s): BRCA1 ; BRCA2 ; Gail model ; breast cancer ; ductal carcinoma in situ (DCIS) ; polygenic risk score (PRS) ; risk stratification ; risk-based screening

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Contributing Institute(s):

1. Epidemiologie von Krebs (C020)
2. C070 Klinische Epidemiologie der Krebsfrüherkennung (C070)
3. DKTK HD zentral (HD01)
4. Molekulargenetik des Mammakarzinoms (B072)

Research Program(s):

1. 319H - Addenda (POF4-319H) (POF4-319H)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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