Abstract PO3-08-01: Decision curve analysis to compare breast cancer risk predictions for a polygenic integrated clinical risk model with those of a gold standard

Abstract Risk-based guidelines have been developed to provide advice on options that are available to women who are at increased risk of breast cancer. We and others are focused on improving risk prediction models for general population use. For breast cancer, polygenic risk has been identified as important for risk prediction, especially when combined with clinical risk factors such as family history, anthropometric measures, breast imaging measures, and hormonal and reproductive risk factors. When comparing the performance of risk prediction models, the AUC is most often used but it focuses on performance in terms of distinguishing between affected and unaffected individuals and does not take into account differences in the specificity (true negative rate) and sensitivity (true positive rate) of the models being compared. In contrast, decision curve analysis takes sensitivity and specificity into account and enables the comparison of the net benefit of risk prediction tools at the clinical risk thresholds that are used to guide clinical management decisions. Herein, we use decision curve analysis to compare breast cancer risk prediction guidelines for BRISK and the Breast Cancer Risk Assessment Tool (BCRAT) in the UK Biobank, and for BRISK and IBIS version 7 in the Nurses’ Health Study. We evaluated the net benefit at the 5-year risk thresholds (1.67% and 3%) that are used to guide clinical management decisions around risk-reducing medication and at the remaining lifetime risk of 20% that is used to guide supplemental MRI surveillance. In the UK Biobank, BRISK showed a net benefit over BCRAT at the 5-year risk thresholds of 1.67% and 3.0%. The AUCs were 0.649 (95% CI = 0.640, 0.695) for BRISK and 0.567 (95% CI = 0.556, 0.577) for BCRAT and showed that, overall, BRISK discriminated between affected and unaffected women better than BCRAT (P 0.001). In the Nurses’ Health Study, BRISK showed a net benefit over IBIS at the remaining lifetime risk threshold of 20%. The AUCs were 0.647; 95% CI = 0.627, 0.668 for BRISK and 0.571; 95% CI = 0.546, 0.595 for IBIS, a statistically significant improvement for BRISK over IBIS (P 0.0001). We also looked at sensitivity, specificity, positive predictive value and negative predictive value even though these risk models are one-step removed from breast cancer diagnosis by screening/risk-reduction options. The positive predictive values are higher for the BRISK (27.1%) model compared to BCRAT (5.5%) in the UK Biobank dataset and higher for BRISK (15.4%) compared to IBISv7 (14.0%) in the Nurses’ dataset. We have shown the application of a statistical tool that can be used to directly compare risk models at clinically relevant thresholds. We have shown that BRISK, which comprises polygenic risk and clinical risk factors, shows higher net benefit at both 1.67% and 3% thresholds compared to BCRAT and at 20% remaining lifetime risk for IBIS version 7. In breast cancer risk prediction, a tool with high specificity (and therefore a necessary trade-off for low sensitivity) is preferred because we do not want to incorrectly classify women as not being at high risk and deny them the opportunity for intervention in the form of more frequent screening, alternative modes of screening or risk-reducing medication. This improvement in general population risk stratification that BRISK can provide has the potential to have a clinically significant effect on women’s health. Citation Format: Erika Spaeth, Bernard A Rosner, Gill Dite. Decision curve analysis to compare breast cancer risk predictions for a polygenic integrated clinical risk model with those of a gold standard abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-01.