In this retrospective study of primary tumors from patients with ER+ breast cancer, including a main study cohort of 684 patients and a validation cohort of 273 patients, we identified high cancer cell levels of PD-L2 protein as an independent predictor of early recurrence after multivariable adjustment for age, race, histological grade, tumor size, node status, and radiation, chemotherapy, and hormone therapy. This evidence concerns the gene ESR1 and neoplasm.