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

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10549-019-05210-2) contains supplementary material, which is available to authorized users.