Progression and treatment of HER2-positive breast cancer

Abstract

Purpose: Approximately 20-30% of breast cancer tumors overexpress or amplify human epidermal growth factor receptor 2 (HER2). The role of this receptor in the progression of HER2+ breast cancer and resistance to certain anticancer monotherapies was investigated. The results of several pre-clinical and clinical trials, with the aim of determining the most safe and effective course of treatment for HER2+ breast cancer, were also thoroughly examined.

Methods: A thorough search of databases including Pubmed, Springer, and The American Society of Clinical Oncology was performed, and pertinent studies were identified. The most relevant studies were preclinical, phase II, and III clinical trials identifying the function of the HER2 receptor in HER2+ breast cancer progression, as well as studies assessing the efficacy of monotherapy and combination therapy in the treatment of this aggressive form of cancer.

Results: The HER2 receptor belongs to a family of receptors that consists of four cell-surface receptors (HER1-4) that share strong homology with the epidermal growth factor receptor (EGFR). All HER receptors interact with specific types of ligands to induce receptor activation, except for HER2, for which no known ligand has yet been identified. HER2 is activated by forming dimers with other HER receptors, and this results in a stronger and more prolonged signal transduction event. When expressed at normal levels, HER2 regulates cell growth, differentiation, and survival. However, under pathological conditions of HER2 overexpression, numerous HER2 heterodimers are formed resulting in aggressive tumor growth. Therefore, the prognosis associated with HER2-positive breast cancer is usually poor. A specific cohort of patients with breast cancer whose tumors test both hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 positive have been found to be resistant to targeted hormone therapy. Studies investigating the etiology of this resistance have found that the cell membrane estrogen receptor communicates with HER2 in promoting the release of ER coactivators that cause the endocrine drug and selective estrogen receptor modulator, tamoxifen, to act as an agonist rather than an antagonist of the hormone estrogen. Thus, research has directed its inquiry toward the development of therapies specifically targeting HER2. The development of trastuzumab, a recombinant monoclonal antibody against HER2, initially proved to be a well-tolerated first line of treatment. However, in the long-term patients, trastuzumab was shown to develop resistance to this monotherapy. Therefore, research on HER2 positive breast cancer has focused on the study of different anti-HER2 combination therapies over the past decade.

Conclusions: While the development and approval of the HER2-targeted recombinant monoclonal antibody trastuzumab (Herceptin) has been efficacious in slowing HER2 cancer progression, combining this and other anti-HER2 therapy with either chemotherapy or endocrine therapy has proven more effective in improving overall and progression free survival.