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

UBC Faculty Research and Publications

Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women Ho, Peh Joo; Loo, Christine Kim Yan; Lim, Ryan Jak Yang; Goh, Meng Huang; Abubakar, Mustapha; Ahearn, Thomas U.; Andrulis, Irene L.; Antonenkova, Natalia N.; Aronson, Kristan J.; Augustinsson, Annelie; Behrens, Sabine; Bodelon, Clara; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brantley, Kristen D.; Brenner, Hermann; Byers, Helen; Camp, Nicola J.; Castelao, Jose E.; Cessna, Melissa H.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Choi, Ji-Yeob; Colonna, Sarah V.; Czene, Kamila; Daly, Mary B.; Derouane, Francoise; Dörk, Thilo; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fletcher, Olivia; Fritschi, Lin; Gago-Dominguez, Manuela; Genkinger, Jeanine M.; Geurts-Giele, Willemina R. R.; Glendon, Gord; Hall, Per; Hamann, Ute; Ho, Cecilia Y. S.; Ho, Weang-Kee; Hooning, Maartje J.; Hoppe, Reiner; Howell, Anthony; Humphreys, Keith; Ito, Hidemi; Iwasaki, Motoki; Jakubowska, Anna; Jernström, Helena; John, Esther M.; Johnson, Nichola; Kang, Daehee; Kim, Sung-Won; Kitahara, Cari M.; Ko, Yon-Dschun; Kraft, Peter; Kwong, Ava; Lambrechts, Diether; Larsson, Susanna; Li, Shuai; Lindblom, Annika; Linet, Martha; Lissowska, Jolanta; Lophatananon, Artitaya; MacInnis, Robert J.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Michailidou, Kyriaki; Milne, Roger L.; Mohd Taib, Nur Aishah; Muir, Kenneth R.; Murphy, Rachel Anne; Newman, William G.; O'Brien, Katie M.; Obi, Nadia; Olopade, Olufunmilayo I.; Panayiotidis, Mihalis I.; Park, Sue K.; Park-Simon, Tjoung-Won; Patel, Alpa V.; Peterlongo, Paolo; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Rashid, Muhammad U.; Rennert, Gad; Rodriguez, Juan; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Scott, Christopher G.; Shahi, Shamim; Shu, Xiao-Ou; Shulman, Katerina; Simard, Jacques; Southey, Melissa C.; Stone, Jennifer; Taylor, Jack A.; Teo, Soo-Hwang; Teras, Lauren R.; Terry, Mary Beth; Torres, Diana; Vachon, Celine M.; Houdt, Maxime Van; Verhoeven, Jelle; Weinberg, Clarice R.; Wolk, Alicja; Yamaji, Taiki; Yip, Cheng Har; Zheng, Wei; Hartman, Mikael; Li, Jingmei; on behalf of the ABCTB Investigators; kConFab Investigators; MyBrCa Investigators; SGBCC Investigators

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.

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Title	Threshold-Based Overlap of Breast Cancer High-Risk Classification Using Family History, Polygenic Risk Scores, and Traditional Risk Models in 180,398 Women
Creator	Ho, Peh Joo; Loo, Christine Kim Yan; Lim, Ryan Jak Yang; Goh, Meng Huang; Abubakar, Mustapha; Ahearn, Thomas U.; Andrulis, Irene L.; Antonenkova, Natalia N.; Aronson, Kristan J.; Augustinsson, Annelie; Behrens, Sabine; Bodelon, Clara; Bogdanova, Natalia V.; Bolla, Manjeet K.; Brantley, Kristen D.; Brenner, Hermann; Byers, Helen; Camp, Nicola J.; Castelao, Jose E.; Cessna, Melissa H.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Choi, Ji-Yeob; Colonna, Sarah V.; Czene, Kamila; Daly, Mary B.; Derouane, Francoise; Dörk, Thilo; Eliassen, A. Heather; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Fletcher, Olivia; Fritschi, Lin; Gago-Dominguez, Manuela; Genkinger, Jeanine M.; Geurts-Giele, Willemina R. R.; Glendon, Gord; Hall, Per; Hamann, Ute; Ho, Cecilia Y. S.; Ho, Weang-Kee; Hooning, Maartje J.; Hoppe, Reiner; Howell, Anthony; Humphreys, Keith; Ito, Hidemi; Iwasaki, Motoki; Jakubowska, Anna; Jernström, Helena; John, Esther M.; Johnson, Nichola; Kang, Daehee; Kim, Sung-Won; Kitahara, Cari M.; Ko, Yon-Dschun; Kraft, Peter; Kwong, Ava; Lambrechts, Diether; Larsson, Susanna; Li, Shuai; Lindblom, Annika; Linet, Martha; Lissowska, Jolanta; Lophatananon, Artitaya; MacInnis, Robert J.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Matsuo, Keitaro; Michailidou, Kyriaki; Milne, Roger L.; Mohd Taib, Nur Aishah; Muir, Kenneth R.; Murphy, Rachel Anne; Newman, William G.; O'Brien, Katie M.; Obi, Nadia; Olopade, Olufunmilayo I.; Panayiotidis, Mihalis I.; Park, Sue K.; Park-Simon, Tjoung-Won; Patel, Alpa V.; Peterlongo, Paolo; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Rashid, Muhammad U.; Rennert, Gad; Rodriguez, Juan; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Scott, Christopher G.; Shahi, Shamim; Shu, Xiao-Ou; Shulman, Katerina; Simard, Jacques; Southey, Melissa C.; Stone, Jennifer; Taylor, Jack A.; Teo, Soo-Hwang; Teras, Lauren R.; Terry, Mary Beth; Torres, Diana; Vachon, Celine M.; Houdt, Maxime Van; Verhoeven, Jelle; Weinberg, Clarice R.; Wolk, Alicja; Yamaji, Taiki; Yip, Cheng Har; Zheng, Wei; Hartman, Mikael; Li, Jingmei; on behalf of the ABCTB Investigators; kConFab Investigators; MyBrCa Investigators; SGBCC Investigators
Contributor	BC Cancer Agency. Cancer Control Research Unit
Publisher	Multidisciplinary Digital Publishing Institute
Date Issued	2025-11-03
Description	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.
Subject	breast cancer; ductal carcinoma in situ (DCIS); polygenic risk score (PRS); Gail model; risk stratification; BRCA1; BRCA2; risk-based screening
Genre	Article
Type	Text
Language	eng
Date Available	2025-12-01
Provider	Vancouver : University of British Columbia Library
Rights	CC BY 4.0
DOI	10.14288/1.0450935
URI	http://hdl.handle.net/2429/93097
Affiliation	Medicine, Faculty of; Non UBC; Population and Public Health (SPPH), School of
Citation	Cancers 17 (21): 3561 (2025)
Publisher DOI	10.3390/cancers17213561
Peer Review Status	Reviewed
Scholarly Level	Faculty; Researcher; Other
Rights URI	https://creativecommons.org/licenses/by/4.0/
Aggregated Source Repository	DSpace

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