Purpose: Residual risk of relapse remains a substantial concern for patients with hormone receptorpositive 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 (ER þ ), lymph node-negative (LN À ) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n ¼ 317) and a multi-institutional cohort (n ¼ 358).Results: Within the Stockholm TAM cohort, BCI risk groups stratified the majority ($65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-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 early-and 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. Ó2013 AACR.

Background:A dichotomous index combining two gene expression assays, HOXB13 : IL17BR (H : I) and molecular grade index (MGI), was developed to assess risk of recurrence in breast cancer patients. The study objective was to demonstrate the prognostic utility of the combined index in early-stage breast cancer.Methods:In a blinded retrospective analysis of 588 ER-positive tamoxifen-treated and untreated breast cancer patients from the randomised prospective Stockholm trial, H : I and MGI were measured using real-time RT–PCR. Association with patient outcome was evaluated by Kaplan–Meier analysis and Cox proportional hazard regression. A continuous risk index was developed using Cox modelling.Results:The dichotomous H : I+MGI was significantly associated with distant recurrence and breast cancer death. The >50% of tamoxifen-treated patients categorised as low-risk had <3% 10-year distant recurrence risk. A continuous risk model (Breast Cancer Index (BCI)) was developed with the tamoxifen-treated group and the prognostic performance tested in the untreated group was 53% of patients categorised as low risk with an 8.3% 10-year distant recurrence risk.Conclusion:Retrospective analysis of this randomised, prospective trial cohort validated the prognostic utility of H : I+MGI and was used to develop and test a continuous risk model that enables prediction of distant recurrence risk at the patient level.