Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for around 15% of all breast cancers and was historically associated with a worse prognosis compared with other breast cancer subtypes. With the development of HER2-directed therapies, the outcomes of patients with HER2-positive disease have improved dramatically; however, many patients present with de novo or acquired resistance to these therapies, which leads to early recurrences or progression of advanced disease. In this narrative review, we discuss the mechanisms of resistance to different HER2-targeted therapies, including monoclonal antibodies, small tyrosine kinase inhibitors, and antibody-drug conjugates. We review mechanisms such as impaired binding to HER2, incomplete receptor inhibition, increased signaling from other receptors, cross-talk with estrogen receptors, and PIK3CA pathway activation. We also discuss the role of the tumor immune microenvironment and HER2-heterogeneity, and the unique mechanisms of resistance to novel antibody-drug conjugates. A better understanding of these mechanisms and the potential strategies to overcome them will allow us to continue improving outcomes for patients with breast cancer.

The Role of Tumor-Associated Antigen HER2/neu in Tumor Development and the Different Approaches for Using It in Treatment: Many Choices and Future Directions

“…However, and despite all the advancements in this field, many patients still suffer from recurrences and disease progression on treatment, suggesting that tumors can develop resistance to these therapies. Furthermore, a growing body of evidence shows that the vast majority of patients do not respond to these therapies, and those who initially respond eventually develop resistance to treatment [ 144 , 145 , 146 ]. This is particularly relevant in the case of trastuzumab, as studies have indicated that the majority of patients who respond to treatment based on trastuzumab acquire resistance within a year.…”

“…Since HER2 is involved in a range of biological processes such as proliferation, survival, angiogenesis, and metastasis, resistance to HER2-targeted therapies can develop due to various mechanisms. A deeper understanding of these mechanisms, as well as the possible strategies to overcome them, will help improve the outcomes for patients with HER2-positive cancers [ 144 , 147 ]. Table 3 outlines the mechanisms of resistance to HER2-targeted therapies with the suggested strategies to overcome it.…”

“…In line with that and since the immune check point inhibitors (ICIs) have achieved great success in the treatment of tumors, it is only logical to use a combination of HER2-targeted therapies and ICIs for the treatment of resistant tumors as the ICIs will help overcome the immuno-inhibitory effect of the TME. In fact, in preclinical models, ICIs have been shown to improve the therapeutic efficacy of HER2-targeted therapies [ 144 , 156 ]. However, in clinical studies, the benefits of combining ICIs with HER2-targeted therapies have been modest, not to mention that this treatment modality was associated with increased toxicities.…”

“…However, in clinical studies, the benefits of combining ICIs with HER2-targeted therapies have been modest, not to mention that this treatment modality was associated with increased toxicities. Nonetheless, certain clinical trials are being conducted to determine whether patients with advanced HER2-positive breast cancer can benefit from ICIs treatment (NCT04740918 and NCT03199885) [ 144 ].…”

Engineering a HER2-CAR-NK cell secreting soluble programmed cell death protein with superior anti- tumor efficacy

“…Several classes of HER2-targeted agents have been developed for the treatment of HER2-positive (HER2+) breast cancer, including monoclonal antibodies (Trastuzumab and Pertuzumab), small molecule tyrosine kinase inhibitors (Lapatinib and Neratinib) and antibody-drug conjugates (trastuzumab emtansine T-DM1) [2,3]. Although the outcomes of patients with HER2-positive disease have improved dramatically, the diseases will inevitably relapse because of de novo or acquired resistance to HER2-targeted therapies [4]. How to improve the therapeutic e cacy to relapse patient remains an urgent problem to be solved.…”