Background: Despite high endocrine therapy (ET) efficacy in HR+ EBC, there is an unmet need to improve outcomes across risk statuses. We describe HR+ EBC demographic and tumor characteristics, treatment, and outcomes by risk status, to inform trial design, outcomes, and care. Methods: Pts from the de-identified, nationwide US, Flatiron Health electronic health record-derived database had HR+ EBC diagnosed from January 1, 2011 to November 30, 2020. We grouped pts into EBC with clinically relevant, high risk (stage T4 or ≥N2; or N1 with ≥1 of ≥T3, grade 3, Ki67 ≥20%, Oncotype DX ≥26), medium risk (N1, not high risk; or N0 with ≥1 of grade 3, Ki67 ≥20%, Oncotype DX ≥26), or low risk (N0, not medium risk) of recurrence. Chi-square and Kruskal–Wallis tests compared characteristics and treatments; Kaplan–Meier methods estimated event-free/overall survival (EFS/OS). Results: Of 7924 pts, 3908 (49.3%), 2477 (31.3%), and 1213 (15.3%) were classified as low-, medium-, and high-risk EBC, respectively (326 missing). Pts with medium-/high-risk EBC vs low-risk were less likely to be non-Hispanic white (p < 0.001), more likely to receive BRCA, MammaPrint, or next-generation sequencing testing (p < 0.001), be slightly younger (p < 0.001), pre-menopausal at diagnosis (p < 0.001), diagnosed in earlier calendar years (p = 0.01), and have invasive lobular carcinoma (p < 0.001). Pts with high-risk EBC were more likely to receive neoadjuvant chemotherapy (NACT) ± ACT vs lower risk. High-risk EBC had significantly lower 3-year EFS/OS vs medium-/low-risk (EFS 0.85 [95% CI = 0.82, 0.87] vs 0.95 [0.94, 0.96]/0.98 [0.98, 0.99], p < 0.0001; OS 0.9 [0.88, 0.92] vs 0.97 [0.96, 0.97]/0.97 [0.96, 0.97], p < 0.0001). Conclusions: Real-world differences in US characteristics, treatments, and outcomes by risk status exist in HR+ EBC. As expected, pts with higher risk EBC were more likely to receive NACT ± ACT. Despite missing risk factors and limited follow-up, and potential misclassification of risk status/treatment and overestimation of time-to-events, US treatment patterns are guideline-aligned. Inferior outcomes in high-risk HR+ EBC show a continued need for improved treatments.

Data: n (%) unless specified. ¹Other/missing: 826 (21.1), 400 (16.1), 228 (18.6); predominantly pts with evidence of surgery only (i.e. no systemic therapy) – many were likely lost to follow-up prior to systemic therapy and/or received therapy outside of Flatiron Health.