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Int J Breast Cancer. 2012;2012:415170. doi: 10.1155/2012/415170. Epub 2012 May 9.

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

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  • 1Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore 119228.


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.

TRIAL REGISTRATION: NCT01097460 NCT00444587 NCT00710736 NCT00878709 NCT00679341 NCT00553358 NCT00452140 NCT01358877 NCT01288092 NCT00625898 NCT00567190 NCT00567554 NCT00736970 NCT00684983 NCT01283789 NCT00431067 NCT01111825 NCT00347919 NCT00127192 NCT00398567 NCT00876395 NCT00391092 NCT00301899 NCT00773344 NCT00558103 NCT00788333 NCT01196052 NCT01137994 NCT01125566 NCT00426566 NCT01007942 NCT00829166 NCT01271920 NCT00777101 NCT00667251 NCT01008150 NCT00374322 NCT00490139 NCT00520975 NCT00915018 NCT01132664 NCT01120184 NCT00650572 NCT00448279.

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