Identifying Patients With Low Relapse Rate Despite High-Risk Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer: Development and Validation of a Clinicopathologic Assay

PURPOSE Escalation of adjuvant systemic therapies (eg, with cyclin-dependent kinase 4 and 6 inhibitors) is now indicated for patients with clinically defined high-risk estrogen receptor–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2–) early breast cancer, although it is unclear which will benefit from additional therapies. We developed and validated a prognostic clinicopathologic assay identifying a subpopulation of high-risk patients with good prognosis after standard adjuvant therapies, who may safely forgo treatment escalation. METHODS We trained a Cox proportional-hazards model that integrates clinicopathologic variables with features derived from digitized hematoxylin-and-eosin–stained resection slides from a retrospective data set. The model assigns each patient to a low-risk or not low-risk group, reflecting their predicted risk of recurrence. Blind validation was successively performed on high-risk patients from the prospective trials CANTO (ClinicalTrials.gov identifier: NCT01993498 ) and UNIRAD (ClinicalTrials.gov identifier: NCT01805271 ). RESULTS Built on data from 6,164 patients with ER+/HER2– early-stage breast cancer, this assay integrates four clinicopathologic variables, and 10 slide-derived features capturing tumor architecture, microenvironment, and proliferation. In the combined CANTO and UNIRAD trials (n = 633), 95.4% of the low-risk patients remained free of distant recurrence and death from breast cancer at 9 years, compared with 76.8% for the not low-risk group. Distant recurrence-free interval (subdistribution hazard ratio HR, 0.21 95% CI, 0.09 to 0.52; P < .001), invasive disease-free survival (HR, 0.31 95% CI, 0.16 to 0.60; P < .001), and overall survival (HR, 0.35 95% CI, 0.13 to 0.97; P = .044) were all statistically significant. Multivariate analyses showed that the assay provided predictive information beyond clinicopathologic variables. Analytical validation showed robustness to data variability. CONCLUSION The assay demonstrated robust performance in identifying a core group of patients with high-risk ER+/HER2– breast cancer for whom additional adjuvant treatment may be futile.