Immunotherapy in HER2-positive breast cancer: state of the art and future perspectives

Abstract

Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

Keywords: Breast cancer; Early; HER2+; Immunotherapy; Metastatic; Vaccine.

Fig. 1

Graphic representation of anti-cancer immune response in HER2+ breast cancer. The anti-cancer immune response is composed by two phases: in the first phase (early phase), DCs sample, process, and present TAAs (such as HER2) generating T cell triggering (both CD4 and CD8) with consequent specific antibody production and cytotoxic cell activation. The process involved in the first phase is responsible for the development of vaccines. The second phase takes place in peripheral areas where specific anti-HER2 antibodies and activated cytotoxic cells explicit their functions. The second phase is the main target of other anti-tumor drugs such as anti-HER2 antibody, antibody-drug conjugate, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Legend: Ab-HER2= anti-HER2 antibody; APC= antigen-presenting cell; B7= B7 protein; CD28= T cell costimulatory molecule CD28; CTLA-4= cytotoxic T-lymphocyte–associated antigen 4; DC= dendritic cell; HER2= human epidermal growth factor 2; MHC= major histocompatibility complex; PD-1= Programmed cell death protein 1; PDL-1= Programmed death-ligand 1; TAAs= tumor-associated antigens; TCR= T-cell receptor; Tregs= regulatory T cells; T CD8= CD8+ cytotoxic T cell; T CD4=CD4+ T cell