PURPOSE: There are multiple contemporary systemic therapy options for patients with HER2-positive advanced breast cancer. However, there are few longitudinal data regarding what proportion of patients go on to receive later lines of therapy, real-world outcomes and the impact of brain metastases. We therefore conducted a prospective, multicentre non-interventional study to describe the anti-cancer treatment regimens used and clinical outcomes in patients with HER2-positive advanced breast cancer across multiple lines of therapy undergoing treatment in routine clinical care. METHODS: Adult patients diagnosed with HER2-positive advanced breast cancer were recruited to a prospective, multicentre non-interventional study to observe treatment patterns and outcomes. RESULTS: Three hundred and eleven patients were recruited with median age 57 years. Of those patients initiating first, second-, and third-line treatment, 72 (23.2%), 59 (41.3%), and 20 (35%), respectively had passed away without advancing on to subsequent lines of therapy. The median progression-free survival in the first line was 25.8 months and overall survival 56.7 months. Over the course of the study 107 (34.4%) of participants were diagnosed with CNS metastases. Median overall survival from diagnosis of brain metastases was 15.4 months. CONCLUSIONS: Many patients treated in routine practice may not get to benefit from contemporary second and later line treatments, where brain metastases become increasingly common. These findings have implications for selection of optimal systemic therapy sequencing in advanced HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: This study was approved by Nottingham Research Ethics Committee on 29th December 2014. CLINICAL TRIAL REGISTRATION: NCT02393924.