An Intersection Between the Immune System and Cellular Signaling Pathways - The Impact of Anti-HER2 Monoclonal Antibodies on Individualized Approaches to Patients with Breast Cancer

Abstract

1. Abstract Overexpression or gene amplification of Human Epidermal Growth Factor Receptor 2 (HER2) is present in approximately 20% of breast cancers, and indicates an aggressive tumor behavior. Activated HER homo and heterodimers orchestrate a downstream signaling network that regulates cell growth, proliferation and malignant spread. Trastuzumab, as a monoclonal antibody that inhibits the HER2, has immensely improved the outcome of patients with HER2-positive breast cancer. Since trastuzumab targets abnormal expression of HER2 in tumors, which are ‘addicted’ to HER2 activation, its therapeutic effects have been attributed to blocking of the intracellular signaling pathways. Moreover, the immune system is involved in the therapeutic impact of trastuzumab or similar anti-HER2 monoclonal antibodies. Various molecular pathways are relevant to HER2 overexpression, as well as the expression of other members of the Epithelial Growth Factor Receptor (EGRF) family. In addition, the estrogen and progesterone activity can interfere with the effects of trastuzumab and/or Chemotherapy (CHT) regimen, especially in patients with metastatic, HER2-positive malignancy. This article presents some insights to the signaling pathways, relevant to progression of breast cancer. It explains molecular characteristics that play a key role in affecting tumor response and resistance to HER2-targeted treatments. It also highlights the need for patient stratification, to develop the most reasonable de-escalation approaches, using HER2-targeted monoclonal antibodies. In addition, some practical strategies to overcome the resistance to trastuzumab, via targeting the main signaling pathways, in the context of HER2-positive and Hormone Receptor (HR)-positive metastatic or locally advanced breast cancer have been discussed, based on evidence from recent clinical trials. 2. Keywords: <span style=font-size:10.0pt;mso-ansi-language:EN-US;mso-fareast-language: PL>Breast Cancer; Estrogen Receptor (ER); Human Epidermal Growth Factor Receptor 2 (HER2) Monoclonal Antibodies; Trastuzumab; Signaling Pathways