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Beyond Trastuzumab: Small Molecule Tyrosine Kinase Inhibitors in HER-2–Positive Breast Cancer

Mayo Clinic, Jacksonville, Florida, USA

Key Words. HER-2 • Breast cancer • Tyrosine kinase inhibitors • Trastuzumab • Lapatinib

Correspondence: Correspondence: Vivek Roy, M.D., Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. Telephone: 904-953-7291; Fax: 904-953-2315; e-mail: roy.vivek{at}mayo.edu

Received July 7, 2009; accepted for publication September 28, 2009.

Vivek Roy: None; Edith A. Perez: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers.

HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti–HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood–brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti–HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available.