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.

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

“…Specifically, blocking immune evasion and attracting more TILs and fewer Tregs (reactivating immunogenicity of BC) to the tumor microenvironment can improve the OS of BC patients [19,23,[115][116][117][118][119]. Sixteen percent of HER2 + subtypes are lymphocyte predominant (> 50-60% of TILs present) and are associated with improved outcome (EFS: event-free survival, OS) with many treatment modalities [19,[120][121][122][123][124]. The FinHER trial demonstrated the link between improved response to trastuzumab and higher levels of TILs among HER2 + BC patients [125].…”

“…As per available literature, potential predictive biomarkers that can be used to select patients who may benefit from combined treatment using HER2-targeted and PD-1/PD-L1 axis based therapeutic agents are (1) HER2 amplification/overexpression, (2) PD-1/PD-L1 expression, (3) presence of a greater number of TILs and fewer Tregs, (4) higher TMB (tumor mutation burden), (5) PTEN expression, and (6) expression of CD5, CD74, CD96, and CD226, to name only few [38,86,121,[131][132][133][134][135][136][137][138]. However, it is still not clear which combination of clinicopathological factors are most reliable predictive biomarkers to implement effective treatment protocols using anti-HER2 and/or PD-1/PD-L1 pathways [39,139].…”

“…Based on the knowledge of various HER2 signaling pathways (Figure 2), several HER2-targeted treatment options (Figure 3) are currently in use. However, even though PD-1/PD-L1 pathways are well discussed in literature, the exact mechanisms that lead to the overexpression of PD-L1 and their consequences in HER2 + BC patients are yet to be clearly understood [102,115,121,134,150,151]. Moreover, PD-1/PD-L1 signaling pathway-based therapeutic targets and agents for HER2 + BC patients are still under investigation.…”

Diffusion Weighted Imaging of Different Breast Cancer Molecular Subtypes. A Systematic Review and Meta Analysis.

“…This is also caused by the possibility of endocrine hormone therapy as a treatment option. Luminal B type is de ned by the presence of estrogen and progesterone receptors with additionally a high proliferation rate compared to Luminal A. Her2-enriched type is de ned by the expression of the oncogene human epidermal growth factor receptor, which stimulates proliferation and inhibits apoptosis [48]. Importantly, it can be targeted by an antibody treatment, namely trastuzumab, which shows the utter importance of this receptor [48].…”

“…Luminal B type is de ned by the presence of estrogen and progesterone receptors with additionally a high proliferation rate compared to Luminal A. Her2-enriched type is de ned by the expression of the oncogene human epidermal growth factor receptor, which stimulates proliferation and inhibits apoptosis [48]. Importantly, it can be targeted by an antibody treatment, namely trastuzumab, which shows the utter importance of this receptor [48]. Lastly, the triple negative type is de ned by the absence of any of these receptors, resulting in the worst prognosis and limited treatment options [10].…”