Breast cancer pathology and stage are better predicted by risk stratification models that include mammographic density and common genetic variants

Breast Cancer Res Treat. 2019 Jul;176(1):141-148. doi: 10.1007/s10549-019-05210-2. Epub 2019 Apr 2.


Purpose: To improve breast cancer risk stratification to enable more targeted early detection/prevention strategies that will better balance risks and benefits of population screening programmes.

Methods: 9362 of 57,902 women in the Predicting-Risk-Of-Cancer-At-Screening (PROCAS) study who were unaffected by breast cancer at study entry and provided DNA for a polygenic risk score (PRS). The PRS was analysed alongside mammographic density (density-residual-DR) and standard risk factors (Tyrer-Cuzick-model) to assess future risk of breast cancer based on tumour stage receptor expression and pathology.

Results: 195 prospective incident breast cancers had a prediction based on TC/DR/PRS which was informative for subsequent breast cancer overall [IQ-OR 2.25 (95% CI 1.89-2.68)] with excellent calibration-(0.99). The model performed particularly well in predicting higher stage stage 2+ IQ-OR 2.69 (95% CI 2.02-3.60) and ER + BCs (IQ-OR 2.36 (95% CI 1.93-2.89)). DR was most predictive for HER2+ and stage 2+ cancers but did not discriminate as well between poor and extremely good prognosis BC as either Tyrer-Cuzick or PRS. In contrast, PRS gave the highest OR for incident stage 2+ cancers, [IQR-OR 1.79 (95% CI 1.30-2.46)].

Conclusions: A combined approach using Tyrer-Cuzick/DR/PRS provides accurate risk stratification, particularly for poor prognosis cancers. This provides support for reducing the screening interval in high-risk women and increasing the screening interval in low-risk women defined by this model.

Keywords: Breast cancer; Early detection; Mammographic density; Pathology; Polygenic risk score; SNPs.

MeSH terms

  • Aged
  • Biomarkers, Tumor*
  • Breast Density*
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Early Detection of Cancer
  • Female
  • Genetic Variation*
  • Humans
  • Incidence
  • Mammography*
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Risk Assessment
  • Risk Factors


  • Biomarkers, Tumor