Background: EarlyR is a prognostic signature computed from expression values of ESPL1, SPAG5, MKI67, PLK1 and PGR that stratifies ER+ breast cancer (BC) into EarlyR^Low, EarlyR^Int, and EarlyR^High risk strata. Here, we show that EarlyR is also predictive of pathological complete response (pCR) following neoadjuvant anthracycline-taxane (AT) based chemotherapy. Methods: The ability of EarlyR gene signature to predict pCR was assessed in Affymetrix microarrays datasets (GSE25065, GSE25066, GSE20194, GSE20271; n = 541, pCR = 42 (7.8%) collectively labeled as Cohort A) derived from patients with ER+ breast cancer treated with neoadjuvant TFAC or FEC. For 2 of these datasets (GSE25065, GSE25066 (n = 291)) distant metastasis-free survival (DMFS) results were also available. The DMFS data in cohort A were compared to that of BC patients not treated with chemotherapy (denoted Cohort B, n = 1269) derived from ER+ samples from 7 GEO datasets (GSE3494, GSE7390, GSE12093, GSE6532, GSE2034, GSE11121, GSE17705). Results: In cohort A, EarlyR is a significant predictor of pCR (p = 1.0 x 10^-6) (EarlyR^Low, n = 273, pCR = 5, 1.8%; EarlyR^Int, n = 11, pCR = 1, 9.1% and EarlyR^High, n = 256, pCR = 36, 14.1%). Notably, 86% of the 42 cases with pCR have EarlyR^High. Of the 291 patients with 8-year DMFS data from Cohort A, who had received chemotherapy, the survival of EarlyR^High [0.79 (95%CI 0.70-0.89)] was nearly the same as that of EarlyR^Low [0.82 (95%CI 0.74-0.90)]. In contrast, in cohort B, who were not treated with chemotherapy, 8-year DMFS is significantly (p = 5 x 10^-15) lower in EarlyR^High [0.57 (95%CI 0.51-0.64)] than in EarlyR^Low[0.81 (95%CI 0.78-0.84)]. Conclusions: EarlyR is a strong predictor of pathological complete response in patients treated with TFAC or FEC. In addition, EarlyR also predicts poor DMFS outcomes for patients in EarlyR^High not receiving chemotherapy. More importantly, neoadjuvant chemotherapy dramatically improved survival of patients in EarlyR^High. These results document that EarlyR identifies a set of patients, EarlyR^High, with a high risk of distant metastasis, who are also likely to respond favorably to chemotherapy.