Polygenic and classical risk integration reshapes breast cancer screening recommendations in 9,761 Asian women
Year: 2026
Type: article
Study design: Observational Study
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.
Source: BMC Medicine
Authors: Jingmei Li, Nicole Sze Ting Lim, Chi Hui Chin, Philip Tsau Choong Iau, Sing Cheer Kwek, Geok Hoon Lim, Peh Joo Ho, Han Boon Oh, Desmond Luan Seng Ong, Judith Ong, Swee Tian Quek, Benita Kiat-Tee Tan, Ern Yu Tan, Veronique Kiak Mien Tan, Sujith Wijerathne, Zhi Zhang Peng, Jon Emery, Mei-Chee Tai, Weang-Kee Ho, Soo-Hwang Teo, MyBrCa Investigators, Mikael Hartman
Institutions: Agency for Science, Technology and Research, SingHealth, National University of Singapore, National Cancer Centre Singapore, National University Health System, Genome Institute of Singapore, National University Polyclinics, Ng Teng Fong General Hospital, National University Hospital, KK Women's and Children's Hospital, Singapore General Hospital, Sengkang General Hospital, Nanyang Technological University, Tan Tock Seng Hospital, Institute of Molecular and Cell Biology, Alexandra Hospital, The University of Melbourne, Cancer Research Malaysia, Sunway University, University of Malaya, Subang Jaya Medical Centre
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,190
Awards: G1852416255, G1983372883, G6754860478
OpenAlex ID: W7224944781