Dual HER2 inhibition: mechanisms of synergy, patient selection, and resistance

HER2-targeted therapies for patients with HER2+ breast cancer are rapidly evolving, offering a range of more complex and personalized treatment options. Currently, an array of anti-HER2 monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates are administered, sometimes alongside chemotherapy or endocrine therapy, both in curative and palliative contexts. However, the heterogeneous nature of HER2+ breast cancer demands a deeper understanding of disease biology and its role in responsiveness to novel HER2-targeted agents, as well as non-HER2-targeted therapies, in order to optimize patient outcomes. In this Review, we revisit the mechanisms of action of HER2-targeted agents, examine the evidence supporting the use of dual HER2 blockade in patients with HER2-amplified tumours, and explore the role of biomarkers in guiding future treatment strategies. We also discuss potential implications for the future treatment of patients with HER2+ breast cancer. Patients with HER2+ breast cancer often respond to trastuzumab, although acquired resistance is common and can involve a range of mechanisms. reflecting the highly heterogeneous biology of this breast cancer subtype. In this Review, the authors describe the role of dual HER2 blockade, involving the co-administration of two HER2-targeted therapies (including monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates) in patients with HER2+ breast cancer.