Polygenic and classical risk integration reshapes breast cancer screening recommendations in 9,761 Asian women
Abstract
Background Age-based mammography screening fails to account for individual breast cancer risk variation, particularly in Asian populations where prospective evidence is absent. Methods The BREAst Screening Tailored for HEr (BREATHE) study is a multicentre prospective cohort of 4,513 women aged 35–59 years recruited across six Singapore clinical sites (2021–2023). Risk-stratified screening recommendations were assigned using a five-year absolute risk threshold of 0.9% (equivalent to the population-average risk of an average 50-year-old Singaporean woman) to initiate screening based on polygenic risk score (PRS) and Gail model, as well as mammographic density, family history, abnormal prior screening. Two independent breast cancer case cohorts provided comparative analyses: Singapore Breast Cancer Cohort (SGBCC, n = 2,782) and Malaysian Breast Cancer Genetic Study (MyBrCa, n = 2,466); combined n = 9,761. Results Among 2,003 healthy women aged 40–49 years currently recommended annual mammography, risk stratification downgraded 776 (38.7%) to no screening and 960 (47.9%) to biennial as they were not in the top 2.5th percentile of PRS and Gail risk and did not have any additional risk indicators. Of 41 breast cancers diagnosed after BREATHE enrolment, 35 (85.4%) occurred in women assigned to screening-eligible categories at baseline. Risk stratification combining PRS and Gail model captured 68–69% of cases aged 40–49 in SGBCC (n = 1,184) and MyBrCa (n = 1,122), versus ~ 54% by PRS alone. Relative to cases meeting screening criteria for both PRS and Gail model, PRS-missed cases were enriched for progesterone receptor negativity (OR 1.24; 95% CI 1.01–1.52), tumour size ≥ 50 mm (OR 1.43; 95% CI 1.02–2.00), and germline protein-truncating variants (PTVs) in breast cancer predisposition genes (OR 1.53; 95% CI 1.03–2.29). Conclusions Risk stratification combining PRS with classical risk factors reshapes mammography recommendations in Asian women. However, due to the limited number of events in BREATHE, this finding requires evaluation in larger prospective studies. PRS-missed cancers exhibit a biologically aggressive profile, defining the current limits of common-variant prediction and identifying the biology that future precision screening tools must address.
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BibTeX
@article{li2026polygenic,
title = {{Polygenic and classical risk integration reshapes breast cancer screening recommendations in 9,761 Asian women}},
author = {Jingmei Li and Nicole Sze Ting Lim and Chi Hui Chin and Philip Tsau Choong Iau and Sing Cheer Kwek and Geok Hoon Lim and Peh Joo Ho and Han Boon Oh and Desmond Luan Seng Ong and Judith Ong and Swee Tian Quek and Benita Kiat-Tee Tan and Ern Yu Tan and Veronique Kiak Mien Tan and Sujith Wijerathne and Zhi Zhang Peng and Jon Emery and Mei-Chee Tai and Weang-Kee Ho and Soo-Hwang Teo and MyBrCa Investigators and Mikael Hartman},
journal = {BMC Medicine},
year = {2026},
month = oct,
doi = {10.1186/s12916-026-05334-5},
url = {https://link.springer.com/article/10.1186/s12916-026-05334-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Polygenic and classical risk integration reshapes breast cancer screening recommendations in 9,761 Asian women
AU - Jingmei Li
AU - Nicole Sze Ting Lim
AU - Chi Hui Chin
AU - Philip Tsau Choong Iau
AU - Sing Cheer Kwek
AU - Geok Hoon Lim
AU - Peh Joo Ho
AU - Han Boon Oh
AU - Desmond Luan Seng Ong
AU - Judith Ong
AU - Swee Tian Quek
AU - Benita Kiat-Tee Tan
AU - Ern Yu Tan
AU - Veronique Kiak Mien Tan
AU - Sujith Wijerathne
AU - Zhi Zhang Peng
AU - Jon Emery
AU - Mei-Chee Tai
AU - Weang-Kee Ho
AU - Soo-Hwang Teo
AU - MyBrCa Investigators
AU - Mikael Hartman
PY - 2026
DA - 2026/10/01
JO - BMC Medicine
DO - 10.1186/s12916-026-05334-5
UR - https://link.springer.com/article/10.1186/s12916-026-05334-5
AB - Background Age-based mammography screening fails to account for individual breast cancer risk variation, particularly in Asian populations where prospective evidence is absent. Methods The BREAst Screening Tailored for HEr (BREATHE) study is a multicentre prospective cohort of 4,513 women aged 35–59 years recruited across six Singapore clinical sites (2021–2023). Risk-stratified screening recommendations were assigned using a five-year absolute risk threshold of 0.9% (equivalent to the population-average risk of an average 50-year-old Singaporean woman) to initiate screening based on polygenic risk score (PRS) and Gail model, as well as mammographic density, family history, abnormal prior screening. Two independent breast cancer case cohorts provided comparative analyses: Singapore Breast Cancer Cohort (SGBCC, n = 2,782) and Malaysian Breast Cancer Genetic Study (MyBrCa, n = 2,466); combined n = 9,761. Results Among 2,003 healthy women aged 40–49 years currently recommended annual mammography, risk stratification downgraded 776 (38.7%) to no screening and 960 (47.9%) to biennial as they were not in the top 2.5th percentile of PRS and Gail risk and did not have any additional risk indicators. Of 41 breast cancers diagnosed after BREATHE enrolment, 35 (85.4%) occurred in women assigned to screening-eligible categories at baseline. Risk stratification combining PRS and Gail model captured 68–69% of cases aged 40–49 in SGBCC (n = 1,184) and MyBrCa (n = 1,122), versus ~ 54% by PRS alone. Relative to cases meeting screening criteria for both PRS and Gail model, PRS-missed cases were enriched for progesterone receptor negativity (OR 1.24; 95% CI 1.01–1.52), tumour size ≥ 50 mm (OR 1.43; 95% CI 1.02–2.00), and germline protein-truncating variants (PTVs) in breast cancer predisposition genes (OR 1.53; 95% CI 1.03–2.29). Conclusions Risk stratification combining PRS with classical risk factors reshapes mammography recommendations in Asian women. However, due to the limited number of events in BREATHE, this finding requires evaluation in larger prospective studies. PRS-missed cancers exhibit a biologically aggressive profile, defining the current limits of common-variant prediction and identifying the biology that future precision screening tools must address.
SN - 1741-7015
ER -