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

Ho, PJ; Loo, CKY; Lim, RJY; Goh, MH; Abubakar, M; Ahearn, TU; Andrulis, IL; Antonenkova, NN; Aronson, KJ; Augustinsson, A; Behrens, S; Bodelon, C; Bogdanova, NV; Bolla, MK; Brantley, KD; Brenner, H; Byers, H; Camp, NJ; Castelao, JE; Cessna, MH; Chang-Claude, J; Chanock, SJ; Chenevix-Trench, G; Choi, JY; Colonna, SV; Czene, K; Daly, MB; Derouane, F; D&#246;rk, T; Eliassen, AH; Engel, C; Eriksson, M; Evans, DG; Fletcher, O; Fritschi, L; Gago-Dominguez, M; Genkinger, JM; Geurts-Giele, WRR; Glendon, G; Hall, P; Hamann, U; Ho, CYS; Ho, WK; Hooning, MJ; Hoppe, R; Howell, A; Humphreys, K; Ito, H; Iwasaki, M; Jakubowska, A; Jernstr&#246;m, H; John, EM; Johnson, N; Kang, D; Kim, SW; Kitahara, CM; Ko, YD; Kraft, P; Kwong, A; Lambrechts, D; Larsson, S; Li, S; Lindblom, A; Linet, M; Lissowska, J; Lophatananon, A; MacInnis, RJ; Mannermaa, A; Manoukian, S; Margolin, S; Matsuo, K; Michailidou, K; Milne, RL; Mohd Taib, NA; Muir, KR; Murphy, RA; Newman, WG; O&#39;Brien, KM; Obi, N; Olopade, OI; Panayiotidis, MI; Park, SK; Park-Simon, TW; Patel, AV; Peterlongo, P; Plaseska-Karanfilska, D; Pylk&#228;s, K; Rashid, MU; Rennert, G; Rodriguez, J; Saloustros, E; Sandler, DP; Sawyer, EJ; Scott, CG; Shahi, S; Shu, XO; Shulman, K; Simard, J; Southey, MC; Stone, J; Taylor, JA; Teo, SH; Teras, LR; Terry, MB; Torres, D; Vachon, CM; Houdt, MV; Verhoeven, J; Weinberg, CR; Wolk, A; Yamaji, T; Yip, CH; Zheng, W; Hartman, M; Li, J; ABCTB Investigators; kConFab Investigators; MyBrCa Investigators; SGBCC Investigators

Author(s): Ho, PJ; Loo, CKY; Lim, RJY; Goh, MH; Abubakar, M; Ahearn, TU; Andrulis, IL; Antonenkova, NN; Aronson, KJ; Augustinsson, A; Behrens, S; Bodelon, C; Bogdanova, NV; Bolla, MK; Brantley, KD; Brenner, H; Byers, H; Camp, NJ; Castelao, JE; Cessna, MH; Chang-Claude, J; Chanock, SJ; Chenevix-Trench, G; Choi, JY; Colonna, SV; Czene, K; Daly, MB; Derouane, F; Dörk, T; Eliassen, AH; Engel, C; Eriksson, M; Evans, DG; Fletcher, O; Fritschi, L; Gago-Dominguez, M; Genkinger, JM; Geurts-Giele, WRR; Glendon, G; Hall, P; Hamann, U; Ho, CYS; Ho, WK; Hooning, MJ; Hoppe, R; Howell, A; Humphreys, K; Ito, H; Iwasaki, M; Jakubowska, A; Jernström, H; John, EM; Johnson, N; Kang, D; Kim, SW; Kitahara, CM; Ko, YD; Kraft, P; Kwong, A; Lambrechts, D; Larsson, S; Li, S; Lindblom, A; Linet, M; Lissowska, J; Lophatananon, A; MacInnis, RJ; Mannermaa, A; Manoukian, S; Margolin, S; Matsuo, K; Michailidou, K; Milne, RL; Mohd Taib, NA; Muir, KR; Murphy, RA; Newman, WG; O'Brien, KM; Obi, N; Olopade, OI; Panayiotidis, MI; Park, SK; Park-Simon, TW; Patel, AV; Peterlongo, P; Plaseska-Karanfilska, D; Pylkäs, K; Rashid, MU; Rennert, G; Rodriguez, J; Saloustros, E; Sandler, DP; Sawyer, EJ; Scott, CG; Shahi, S; Shu, XO; Shulman, K; Simard, J; Southey, MC; Stone, J; Taylor, JA; Teo, SH; Teras, LR; Terry, MB; Torres, D; Vachon, CM; Houdt, MV; Verhoeven, J; Weinberg, CR; Wolk, A; Yamaji, T; Yip, CH; Zheng, W; Hartman, M; Li, J; ABCTB Investigators; kConFab Investigators; MyBrCa Investigators; SGBCC Investigators;
Details: Publication Year 2025-11-03,Volume 17,Issue #21,Page 3561
Journal Title: Cancers
Publication Type: Research article
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.
Publisher: MDPI
Keywords: Brca1; Brca2; Gail model; breast cancer; ductal carcinoma in situ (DCIS); polygenic risk score (PRS); risk stratification; risk-based screening
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.3390/cancers17213561
Open Access at Publisher's Site: https://doi.org/10.3390/cancers17213561
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-08 02:25:11

Last Modified: 2026-01-08 02:25:33