AbstractIntroductionThe cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early‐stage breast cancer patients using the Nottingham (n= 1094) and METABRIC (n= 1980) cohorts, respectively.ResultsHigh expression of ezrin was significantly associated with larger tumour size (p= 0.027), higher tumour grade (p< 0.001), worse Nottingham Prognostic Index prognostic group (p= 0.011) and HER2‐positive status (p= 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p< 0.001) and remained associated with survival in multivariate Cox‐regression analysis (p= 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051–1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p< 0.001) in comparison to those categorised as triple‐negative breast cancer (p= 0.889). High expression of ezrin mRNA (VIL2)in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p< 0.001).ConclusionRetrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor‐positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early‐stage breast cancer.