Human epidermal growth factor receptor-2-positive breast cancer: Current management of early, advanced, and recurrent disease

Abstract

Purpose of review: This review describes the current treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer with a focus on recently reported clinical trials.Treatment of resistant disease and central nervous system metastases will be reviewed as will new agents that are being developed to target HER2-amplified breast cancers.

Recent findings: Recent studies evaluating trastuzumab-resistant breast cancer have shown a benefit of continuing trastuzumab with chemotherapy or with another HER2-targeted agent.Targeting the vascular endothelial growth factor, mammalian target of rapamycin, and PI3 kinase pathways in addition to HER2 may enhance efficacy compared with individual agents. Several novel anti-HER2 compounds are being evaluated with promising early data.

Summary: HER2-positive breast cancer has traditionally been associated with poor prognosis.However, treatment with HER2-targeted therapies has changed the natural history of this disease. Greater success depends on elucidating mechanisms of resistance and exploring new methods of blocking signal transduction via HER2 and related pathways.

Figure 1. The HER2 Signaling Pathway

Ligand binding induces dimerization, leading to activation of the intracellular tyrosine kinase. On auto- and cross-phosporylation of the receptor complex, key downstream effectors are recruited. This figure illustrates a HER2-HER3 heterodimer, but HER2 can also form homodimers or heterodimerize with other members of the HER2 family. FKHR, forkhead in rhabdomyosarcoma; Grb2, growth factor receptor-bound protein 2; GSK-3, glycogen kinase synthase-3; MAPK, mitogen-activated protein kinase; mTOR, molecular target of rapamycin; PI3K, phospatidyl-inositol 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SOS, son-of-sevenless guanine nucleotide exchange factor.