Clinical Impact of New Treatment Strategies for HER2-Positive Metastatic Breast Cancer Patients with Resistance to Classical Anti-HER Therapies

SIMPLE SUMMARY: HER2-positive metastatic breast cancer remains a nearly incurable disease. In this sense, new treatments have been developed in recent years. On the one hand, drug conjugates have been reformulated and, on the other hand, the combination of anti-HER2 therapies with new drugs has been also tested. CDK4/6 inhibitors, tyrosine kinase inhibitors, and immunotherapy treatments have also been evaluated. Despite these advances, it is still urgent to continue deepening the biological knowledge of the disease and improving the therapeutic design of pharmacologic drugs in order to select the best available option for each patient. ABSTRACT: HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.