Systemic Therapies for HER2-Positive Advanced Breast Cancer

Simple Summary HER2-positive breast cancer is an aggressive subtype of breast cancer which used to be associated with a poor prognosis, however this has been transformed by treatment advances over the past two decades. Patients with HER2-positive breast cancer are normally treated with a combination of two or more chemotherapy drugs and targeted agents which block the HER2 receptor, followed by surgery, radiotherapy and sometimes hormonal therapies. However, if the cancer is too extensive to be removed by surgery and/or has spread to other sites in the body, it is known as HER2-positive advanced breast cancer and regrettably is normally incurable. In this situation, sequential drug treatments, aiming to control the cancer for as long as possible and maintain quality of life are advised. The anti-HER2 drug, trastuzumab, was the first targeted agent developed for HER2-positive breast cancer and remains a key component of treatment for both early, curable and advanced incurable disease. Progress including the development of new targeted agents which synergise with trastuzumab and novel antibody-drug conjugates where chemotherapy is bound to the trastuzumab allowing selective delivery to cancer cells are discussed in this review.Abstract Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately unavoidable for all but a small minority of patients who achieve an enduring remission and possibly cure. Over the past two decades, significant advances in our understanding of the underlying molecular mechanisms of HER2-driven oncogenesis have translated into pharmaceutical advances, with the developing of increasingly sophisticated therapies directed against HER2. These include novel, more potent selective HER2 tyrosine kinase inhibitors (TKIs); new anti-HER2 antibody-drug conjugates; and dual epitope targeting antibodies, with more advanced pharmacological properties and higher affinity. With the introduction of adjuvant T-DM1 for incomplete responders to neoadjuvant therapy, fewer patients are relapsing, but for those who do relapse, disease that may be resistant to standard first- and second-line therapies requires new approaches. Furthermore, the risk of CNS relapse has not been abrogated by current (neo)adjuvant strategies; therefore, current research efforts are being directed towards this challenging site of metastatic disease. In this article, we review the currently available clinical data informing the effective management of HER2-positive breast cancer beyond standard first-line therapy with pertuzumab, trastuzumab, and taxanes, and the management of relapse in patients who have already been exposed to both these agents and T-DM1 for early breast cancer (EBC). We additionally discuss novel anti-HER2 targeted agents and combinations in clinical trials, which may be integrated into standard treatment paradigms in the future.