Emerging Targeted Therapies for HER2-Positive Breast Cancer

SIMPLE SUMMARY: HER2-positive breast cancer (BC), which accounts for ~20% of BC, is one of the more aggressive and has the worst overall survival rate among them. These patients are treated with trastuzumab, a monoclonal antibody targeting the HER2 molecule. Even though trastuzumab is an effective therapy, resistance events hamper its clinical benefit, making the development of new therapies a constantly growing area of interest. In this review, we will summarize the current therapies for HER2-positive BC and review the therapeutic approaches effective in preclinical models and clinical trials which could contribute to the therapeutic landscape. We will investigate the development of novel HER2-therapies such as antibodies, inhibitors, and bispecific antibodies, which is a burgeoning field in oncology. Furthermore, we will summarize the most recent developments in CAR-T, CAR-NK, and CAR-M therapies for the treatment of HER2-positive tumors, as well as a brief review of cancer vaccines. ABSTRACT: Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.