Evaluating the Prognostic Performance of a Polygenic Risk Score for Breast Cancer Risk Stratification

Abstract Background: Polygenic risk scores (PRS) could potentially improve breast cancer screening recommendations. We analyzed how well a recently developed prevalence-based breast cancer PRS (Läll et al., 2009) performs in expressing women’s future risk of incident breast cancer. Objectives: To evaluate the prognostic performance of models using PRS and age as predictors, vs age alone, for breast cancer incidence in women from the Estonian biobank (EstBB) cohort. Methods: We analyzed data on 30,312 women from the EstBB cohort. They entered the cohort between 2002 and 2011, were between 20-89 years, without history of breast cancer, and with full 5-year follow-up by 2015. We examined PRS and other potential risk factors as possible predictors in Cox regression models for breast cancer incidence. With 10-fold cross validation we estimated 3- and 5-year breast cancer incidence from age alone and PRS plus age, fitting models on 90% of the data. Calibration, discrimination, and reclassification then expressed prognostic performance on the left-out folds. Results: A total of 101 (3.33‰) and 185 (6.1‰) incident breast cancers were observed within 3 and 5 years, respectively. For women in the current Estonian screening age (50-62 years), the ratio of observed vs PRS-age modelled 3-year incidence was 0.86 for women in the 75-85% PRS-group, 1.34 for the 85-95% PRS-group, and 1.41 for the top 5% PRS-group. For 5-year incidence, this was respectively 0.94, 1.15, and 1.08. Yet, the number of breast cancer events were relatively low in each PRS-subgroup. The model’s AUC was 0.720 (95% CI: 0.675-0.765) for 3-year and 0.704 (95% CI: 0.670-0.737) for 5-year, respectively, just 0.022 and 0.023 higher than for the model with age alone. Using a 1% risk prediction threshold, the 3-year NRI for the PRS-age model was 0.09 and 0.05 for 5 years.Conclusion: The model including PRS had modest incremental performance. This suggests that the potential benefit of adding PRS to age for guiding screening likely affects a relatively small proportion of women. A larger, independent study is needed to assess whether and how the PRS can meaningfully contribute to developing more efficient screening strategies.