Association between response to brief trastuzumab exposure in cell lines and early stage HER2+ breast tumors

Emmett Sprecher, Sudipa Sarkar, Steven H. Kleinstein, Murli Narayan, Eric Winer, David Tuck, Kimberly Lezon-Geyda, Ian Krop, Lyndsay Harris

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Human epidermal growth factor receptor 2 amplified (HER2+) breast cancer is common and aggressive. Trastuzumab is a targeted therapy to the HER2 cell surface receptor and has greatly improved prognosis for HER2+ breast cancer patients, but trastuzumab-resistance is a significant problem. Few biomarkers of trastuzumab resistance of response have been found, and there has been tremendous difficulty identifying in vitro biomarkers that transfer to the in vivo HER2+ breast cancer setting. We identified gene expression signatures of trastuzumabresponse and trastuzumab-resistance in HER2+ breast cancer cell lines across 24-hour exposure to trastuzumab. A set of 180-genes changed significantly in a trastuzumab-sensitive HER2+ cell line (BT474) and 58 genes changed significantly across treatment in a trastuzumab-resistant HER2+ cell line (UACC812). To demonstrate that these signatures have clinical relevance, we applied them in vivo to gene expression profiles from early stage HER2+ breast tumors treated with a single dose of trastuzumab. We found that the BT474 trastuzumabresponsive signature was enriched among the changes in expression across treatment for responsive patients. The expression change for the BT474 signature genes was also able to partially cluster responsive and resistant breast tumors by outcome. A subset of the UACC812 trastuzumab-resistance signature was also enriched in the differential between responsive and resistant tumors prior to trastuzumab treatment. These results show for the first time that cell line-derived gene signatures can be useful in identifying whether breast cancer patients will ultimately benefit from trastuzumab treatment. This approach might one day be applied to enhance clinical treatment decisions.

Original languageEnglish (US)
Title of host publication2011 ACM Conference on Bioinformatics, Computational Biology and Biomedicine, BCB 2011
Pages446-450
Number of pages5
DOIs
StatePublished - Dec 1 2011
Externally publishedYes
Event2011 ACM Conference on Bioinformatics, Computational Biology and Biomedicine, ACM-BCB 2011 - Chicago, IL, United States
Duration: Aug 1 2011Aug 3 2011

Publication series

Name2011 ACM Conference on Bioinformatics, Computational Biology and Biomedicine, BCB 2011

Other

Other2011 ACM Conference on Bioinformatics, Computational Biology and Biomedicine, ACM-BCB 2011
CountryUnited States
CityChicago, IL
Period8/1/118/3/11

Keywords

  • Breast cancer
  • Drug resistance
  • Gene expression
  • HER2
  • Trastuzumab

ASJC Scopus subject areas

  • Biomedical Engineering
  • Health Informatics
  • Health Information Management

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