Emerging Targeted Therapies for HER2-Positive Breast Cancer

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.

A Cancer-Specific Monoclonal Antibody against HER2 for Breast Cancers

“…Based on the studies, T-DXd has been approved in not only HER2-positive breast cancer [20,21], but also HER2-mutant lung cancer [22] and HER2-low (IHC 1+ or IHC 2+ / ISH-non-amplified) advanced breast cancer [23]. Because approximately half of all breast cancers are classifiable as HER2-low [24], a greater number of patients may benefit from T-DXd therapy. Meanwhile, cardiotoxicity is the most significant toxicity associated with T-DXd [25].…”

“…Chimeric antigen receptor (CAR)-T cell therapy against HER2 has been evaluated in clinical studies [24]. Although the optimal epitope for HER2-targeting CAR-T has not been evaluated, it is worthwhile to investigate the cancer specificity of H2Mab-250 scFv and the efficacy of CAR-T against HER2-positive tumors.…”

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

“…This drug is composed of an anti-HER2 monoclonal antibody linked with mertansine (DM1) via a succinimidyl-4-(N-maleimidomethyl)cyclohexane-1carboxylate (SMCC) linker (73,74). TDM1 is now used in HER2positive tumors as both second-line and first-line treatment options, providing significant benefits, especially for patients with brain metastases (75).…”

Engineered Adoptive T-Cell Therapies for Breast Cancer: Current Progress, Challenges, and Potential

“…Unsurprisingly, the most common CAR T-cell target for breast cancer is HER2 (25%). Patients’ tumors are only considered HER2+ if they have a HER2 immunohistochemistry (IHC) score of 3+ or an IHC score of 2+ with positive fluorescence in-situ hybridization (FISH) [ 3 ]. Anti-HER2 CAR T-cells are an attractive alternative for HER2-low breast cancers, i.e., breast cancers with a HER2 IHC score of 2+ without a positive FISH or a score of 1+.…”

“…Clinically, it is divided into four molecular subtypes based on expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [ 2 ]. Various therapeutic modalities that target these receptors are utilized in the treatment of breast cancer, including anti-HER2 monoclonal antibodies and selective ER degraders (SERDs) [ 3 , 4 ]. Despite the great success of these therapies, there is a need for novel targeted treatments that can benefit a wider variety of breast cancer patients.…”