Background: SPAG5 is an ultimate proliferation marker and important driver that is commonly amplified in “luminal B” BC. Methods: SPAG5 copy number aberrations (CNAs), mRNA and protein expression and their association with BC specific survival (BCSS) were determined in 4998 cases of ER+ BC. The association between the pathological complete response (pCR) to neoadjuvant anthracycline based CT (NACT) and SPAG5 expression was evaluated in 1073 (mRNA) and 332 (protein) patients with ER+ BC . The association between the dynamic response to the neoadjuvant ET (NAET) and SPAG5 mRNA expression was evaluated in 101 cases of ER+ BC. The association between distant relapse risk (DRR) and SPAG5 expression were tested in ER+/HER2- patients who received (if eligible) NACT or adjuvant CT in addition to 5-year tamoxifen (mRNA: n = 2819; protein: n = 2501). Results: SPAG5 amplification (CNA) and overexpression (SPAG5+, mRNA, protein) were all associated with shorter BCSS (HR: 1.55, 1.31, and 1.90, ps < 0.001); respectively). After receiving NACT, multivariable logistic regression analyses confirmed that SPAG5+ mRNA and protein expression were independently associated with higher pCR (OR: 1.90; p = 0.041 and 23.03; p < 0·0001; respectively). Downregulation of SPAG5 has been observed after 2-weeks on NECT and this predicted the dynamic clinical response (p < 0.01). In patients received Tamoxifen alone with either lymph node positive (LN+) or LN negative disease, SPAG5+ BC (mRNA, protein) exhibited a two-fold increase in DRR compared to patients with SPAG5- disease (ps < 0·0001). In contrast, in patients received CT+Tamoxifen with LN+ or LN-disease, SPAG5+ (mRNA, protein) exhibited a similar DRR to that with SPAG5- disease. ER+ patients with SPAG5+ mRNA tumours receiving CT+Tamoxifen has improved 5-year-DRFS by 28% for those with LN- disease (89% vs., 67%; p < 0·001) and 22% for those with LN+ disease (76% vs., 54%; p < 0·001), as compared to receiving Tamoxifen alone. Conclusions: SPAG5 could be used as a prognostic and predictive tool for selecting systemic therapies and monitoring response to the selected therapy in patients with ER+ BC.