Purpose: Residual risk of relapse remains a substantial concern for patients with hormone receptor– positive breast cancer, with approximately half of all disease recurrences occurring after five years of adjuvant antiestrogen therapy. Experimental Design: The objective of this study was to examine the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression–based signature, for prediction of early (0–5 years) and late (>5 years) risk of distant recurrence in patients with estrogen receptor–positive (ERþ), lymph node–negative (LN ) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n 1⁄4 317) and a multi-institutional cohort (n 1⁄4 358). Results:Within the Stockholm TAM cohort, BCI risk groups stratified themajority ( 65%) of patients as low risk with less than 3%distant recurrence rate for 0 to 5 years and 5 to 10 years. In themulti-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. Conclusions: The prognostic sustainability of BCI to assess earlyand late-distant recurrence risk at diagnosis has clinical use for decisions of chemotherapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five years. Clin Cancer Res; 19(15); 4196–205. 2013 AACR.