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. Key points HER2-targeted therapies function by blocking activation of the oncogenic tyrosine kinase signalling pathways downstream of HER2 and inducing immune-mediated cell death. Dual HER2 inhibition can overcome resistance to single-agent blockade through several mechanisms, including more potent inhibition of downstream signalling pathways, overcoming limited HER2 binding, and augmenting HER2 receptor downregulation and degradation. Regimens including trastuzumab plus pertuzumab improve pathological complete response and long-term event rates in patients with stage II–III HER2 + breast cancer receiving neoadjuvant or adjuvant therapy, respectively, compared with trastuzumab monotherapy. Compared with single-agent HER2 inhibition, dual inhibition improves the outcomes of patients with HER2 + metastatic breast cancer in both the first-line and treatment-refractory settings, thus underscoring the importance of oncogenic HER2 signalling throughout the course of disease. HER2 + breast cancer is a biologically heterogen