Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches

Abstract

Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor–immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy.

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…Out of all different subtypes of BC, TNBC and HER2 + BCs are identified to have a significant association with the immune surveillance of the host [19,22]. These studies also highlight the significance of immunomodulation, the number of tumor-infiltrating lymphocytes, and the expression of programmed death-ligand (PD-L1) to the disease prognosis and treatment outcome pertaining to human BC [16,[22][23][24]. All these findings emphasize the importance of further investigating the applicability of immunotherapy for HER2 + BC.…”

“…This drug is particularly effective against the most potent HER2-HER3 heterodimer. Notably, the combination of pertuzumab, trastuzumab, and docetaxel can substantially improve the treatment outcomes of HER2 + BC patients [16,47,48]. While targeted therapy agents work from outside the cell, small molecule agents such as lapatinib and neratinib, tyrosine kinase inhibitors, HER2 + targeting drugs such as ado-trastuzumab emtansine (T-DM1) use trastuzumab as a drug-targeting agent to deliver emtansine to the HER2 + BC cells [46].…”

“…In some cancers, even if cancer cells are immunogenic, they are also identified to have many receptors (e.g., PD-L1, PD-L2) to stimulate immune checkpoint targets (e.g., PD-1) and block the immune response. Other immune checkpoint targets include cytotoxic T lymphocyte antigen (CTLA-4), glucocorticoid-induced TNFR-related protein (GITR), OX40, 4-1BB, T-cell immunoglobulin (TIM-3), and lymphocyte-activation gene (LAG-3) [16]. Several co-inhibitory and co-stimulatory pathways that are regulated by the immune system mediate the selective attack on external invaders (pathogens) while sparing the host cells [94].…”

“…However, only 50-80% of patients with HER2 + BC benefit from this drug, while 20-50% either do not respond from the beginning of the treatment or develop resistance after treatment [10,11]. Moreover, with currently available treatment options, the overall disease-free survival (DFS) statistics of patients with the HER2 + subtype of BC are not adequate [12][13][14][15][16][17][18]. Hence, intense research is ongoing to determine new therapeutic targets or agents to improve the treatment of HER2 + BC patients.…”

“…The immunogenicity of BC and the applicability of immunogenic pathways to enhance the treatment outcome of BC patients were not explored much in earlier days. However, in light of the motivating success rates of immunotherapy in other types of cancers, there is an increased interest in this area of research [16]. Out of all different subtypes of BC, TNBC and HER2 + BCs are identified to have a significant association with the immune surveillance of the host [19,22].…”