We observed that high SPAG5 expression was associated with a significant increase in risk of relapse among ER+ (HR = 1.77, 95% CI 1.55–2.03, p < 0.001), but not ER- breast cancer patients (HR = 1.03, 95% CI 0.82–1.28, p = 0.81). This evidence concerns the gene ESR1 and breast cancer.