Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Current and Future Trends

SIMPLE SUMMARY: Therapeutic advances in the treatment of HER2-positive metastatic breast cancer have dramatically improved the natural history of these patients. Although double anti-HER2 blockade associated with a taxane currently remains the best option in the first line, recently, T-DXd has positioned itself as the new standard in the second line. Eventually, most patients progress and develop resistance. In response to this need, new treatments and combinations are being developed. The aim of this paper was to review the new strategies that are in development for the treatment of these patients, the mechanisms of action and toxicities. Treatments are expected in the near future to change the treatment paradigm. ABSTRACT: Approximately 20% of breast cancers (BC) overexpress human epidermal growth factor receptor 2 (HER2). This subtype of BC is a clinically and biologically heterogeneous disease that was associated with an increased risk for the development of systemic and brain metastases and poor overall survival before anti-HER2 therapies were developed. The standard of care was dual blockade with trastuzumab and pertuzumab as first-line followed by TDM-1 as second-line. However, with the advent of new HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors and antibody- drug conjugates, the clinical outcomes of patients with HER2-positive BC have changed dramatically in recent years, leading to a paradigm shift in the treatment of the disease. Notably, the development of new-generation ADCs has led to unprecedented results compared with T-DM1, currently establishing trastuzumab deruxtecan as a new standard of care in second-line. Despite the widespread availability of HER2-targeted therapies, patients with HER2-positive BC continue to face the challenges of disease progression, treatment resistance, and brain metastases. Response rate and overall life expectancy decrease with each additional line of treatment, and tumor heterogeneity remains an issue. In this review, we update the new-targeted therapeutic options for HER2-positive BC and highlight the future perspectives of treatment in this setting.