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International Journal of Breast Cancer
Volume 2012, Article ID 415170, 13 pages
Review Article

Mechanisms of Resistance to Trastuzumab and Novel Therapeutic Strategies in HER2-Positive Breast Cancer

1Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore 119228
2Cancer Science Institute, National University of Singapore, Singapore 117599

Received 14 September 2011; Accepted 3 February 2012

Academic Editor: Mary Cianfrocca

Copyright © 2012 Andrea L. A. Wong and Soo-Chin Lee. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


HER2-positive breast cancers have poorer prognosis and are prime candidates for molecular-targeted therapy because they are driven by the unique mechanism of HER2 oncogene addiction. While anti-HER2 agents such as trastuzumab and lapatinib are integral to the treatment of HER2-positive breast cancer, intrinsic and secondary resistance pose a significant challenge, underscoring the need to develop novel anti-HER2 therapies. In recent years, an array of promising and novel anti-HER2 therapeutic agents and their combinations have entered various stages of clinical development. However, questions remain on the optimal sequences of HER2-directed therapies and selection of patients for the most appropriate drug or combinations; incompletely defined mechanisms of trastuzumab action and resistance have also dampened the progress of more successful biomarker-driven treatment approaches. This paper summarizes existing preclinical and clinical evidence on the mechanisms of trastuzumab action and resistance and provides an up-to-date overview of novel HER2-directed therapies in clinical development.