Breast cancer risk prediction model for racially diverse women with benign breast disease

Purpose: Existing breast cancer risk prediction models are ineffective for women with benign breast disease (BBD) and do not stratify risk by key histologic subtypes, especially in racially and ethnically diverse populations. Although BBD and breast cancer share several risk factors, women with BBD have a higher underlying risk due to accumulated changes in benign breast tissue compared to the general population. The magnitude of risk varies by morphologic subtype-modestly increased for proliferative disease without atypia (PDWA), and highest for atypical hyperplasia (AH). We aimed to refine a prediction model for breast cancer through risk stratification by PDWA and AH subtypes, using data from a contemporary and racially diverse cohort of women. Methods: 8,870 women diagnosed with histologically confirmed benign lesions were identified at the Siteman Cancer Center in St. Louis from 2010-2023 (followed until June 10, 2025). Risk modeling was performed with Cox regression and internally validated through a bootstrap resampling method (i.e., corrected for overfitting). Model discrimination was estimated with Harrell's C-index. Model calibration was assessed by the 5-year observed-to-expected (O/E) ratio. Positive and negative predictive values (PPV/NPV) were estimated for a 3% 5-year risk threshold per national guidelines to define increased risk. Results: Among the 8,870 women with BBD, there were 362 subsequent breast cancers at least 6 months following a benign biopsy. 11.2% were triple negative tumors (ER-PR-HER2-); 73.8% were invasive breast cancers. The cohort is 64.3% White, 32.5% Black, and 3.2% Asian. On average, women were 50 (SD=13) years of age at biopsy. Average age at menarche was 13 (SD=1.8) and average BMI 29.6 kg/m2 (SD=7.7). Harrell's C-index was 0.68 (95% CI: 0.65-0.71) in the original sample and 0.67 (95% CI: 0.65-0.70) in the bootstrap sample. At 5 years, the overall model calibration was 0.99 (95% CI: 0.86-1.13). Women predicted to be in the high-risk group (≥3%, 5y) included those with atypia and half of those with proliferative disease without atypia. Of these women, 7.0% developed breast cancer, and in the average-risk group, 97.5% did not in the 5 years following a benign biopsy. Conclusion: Our model demonstrates sound discriminatory ability in the internal validation within a racially diverse cohort of women followed after benign biopsy. With a 5-year PPV of 7%, the model effectively flags women at high-risk (≥3%, 5y), providing a meaningful basis for intensified surveillance or preventive measures for early detection after benign biopsy showing proliferative disease with or without atypia.