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.

Abstract

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. 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 <i>low-risk</i> or <i>not low-risk</i> 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). 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 <i>low-risk</i> patients remained free of distant recurrence and death from breast cancer at 9 years, compared with 76.8% for the <i>not low-risk</i> group. Distant recurrence-free interval (subdistribution hazard ratio [HR], 0.21 [95% CI, 0.09 to 0.52]; <i>P</i> < .001), invasive disease-free survival (HR, 0.31 [95% CI, 0.16 to 0.60]; <i>P</i> < .001), and overall survival (HR, 0.35 [95% CI, 0.13 to 0.97]; <i>P</i> = .044) were all statistically significant. Multivariate analyses showed that the assay provided predictive information beyond clinicopathologic variables. Analytical validation showed robustness to data variability. 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.