Prospective evaluation of a breast-cancer risk model integrating classical risk factors and polygenic risk in 15 cohorts from six countries

Int J Epidemiol. 2022 Jan 6;50(6):1897-1911. doi: 10.1093/ije/dyab036. Epub 2021 Mar 23.


Background: Rigorous evaluation of the calibration and discrimination of breast-cancer risk-prediction models in prospective cohorts is critical for applications under clinical guidelines. We comprehensively evaluated an integrated model incorporating classical risk factors and a 313-variant polygenic risk score (PRS) to predict breast-cancer risk.

Methods: Fifteen prospective cohorts from six countries with 239 340 women (7646 incident breast-cancer cases) of European ancestry aged 19-75 years were included. Calibration of 5-year risk was assessed by comparing expected and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future cases crossing clinically relevant risk thresholds.

Results: Among women <50 years old, the median (range) expected-to-observed ratio for the integrated model across 15 cohorts was 0.9 (0.7-1.0) overall and 0.9 (0.7-1.4) at the highest-risk decile; among women ≥50 years old, these were 1.0 (0.7-1.3) and 1.2 (0.7-1.6), respectively. The proportion of women identified above a 3% 5-year risk threshold (used for recommending risk-reducing medications in the USA) ranged from 7.0% in Germany (∼841 000 of 12 million) to 17.7% in the USA (∼5.3 of 30 million). At this threshold, 14.7% of US women were reclassified by adding the PRS to classical risk factors, with identification of 12.2% of additional future cases.

Conclusion: Integrating a 313-variant PRS with classical risk factors can improve the identification of European-ancestry women at elevated risk who could benefit from targeted risk-reducing strategies under current clinical guidelines.

Keywords: Breast cancer; iCARE; model validation; polygenic risk score; risk prediction; risk stratification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / genetics
  • Female
  • Genetic Predisposition to Disease
  • Germany
  • Humans
  • Middle Aged
  • Multifactorial Inheritance*
  • Risk Assessment
  • Risk Factors
  • Young Adult