Among highly proliferative ER+/HER2− breast cancers, tumours with low ER-related signalling, hereafter referred to as MKShi/ERSlo, exhibit the highest risk of recurrence despite adjuvant endocrine therapy, show poor response to neoadjuvant letrozole endocrine therapy, and account for most of early recurrences during adjuvant tamoxifen treatment [9]. Here, ESR1 is linked to breast carcinoma.