HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

Abstract

Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20-25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

Fig. 1. Mechanism of action of HER2 tyrosine kinase inhibitors.

There are four members of the HER2 receptor family, these are the targets of lapatinib, neratinib, pyrotinib and tucatinib. The HER2 extracellular domain has no known ligand and is activated by the formation of homo or heterodimers (exemplified by a HER2-HER3 heterodimer in the figure). These dimers lead to phosphorylation of tyrosine kinase residues in the cytoplasmic domain which function as docking sites for proteins that activate the PI3K and MAPK signaling pathways downstream leading to cell cycle progression and proliferation.

Fig. 2. United States Food and Drug Administration and Approval History of HER2-targeted tyrosine kinase inhibitors.

This shows the time of approval and indications of the currently tyrosine kinase inhibitors approved by the United States Food and Drug Administration.

Fig. 3. Proposed treatment algorithm for HER2+Breast Cancer.

This is a suggested treatment algorithm for early stage and advanced human epidermal growth factor 2 positive BC, based on the current United States Food and Drug Administration approvals. Radiation therapy and endocrine therapy should be incorporated when appropriate. There are multiple options for metastatic disease beyond second line, tucatinib can be considered in the third line setting based on the results of the phase 3 HER2CLIMB study. Other agents can be considered as fourth line or beyond, based on prior therapies, toxicity profile and comorbidities. *Subgroup analysis of APHINITY showed that patients with node positive disease have a greater benefit from adjuvant dual HER2 blockade. **Benefit seen in patients with hormone receptor positive and HER2 positive disease. There are no data about the use of neratinib after treatment with pertuzumab and/or ado-trastuzumab emtansine. ***Tucatinib is FDA approved in the second line setting after treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine. Can be considered for patients with CNS involvement.