Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women

<b>Background</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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 (<i>p</i> < 0.001) and Gail (<i>p</i> < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: <i>p</i> < 0.001; DCIS: <i>p</i> = 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 (<i>p</i> < 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. <b>Conclusions</b>: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.