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Modeling precision treatment of breast cancer

Anneleen Daemen1132*, Obi L Griffith136*, Laura M Heiser14, Nicholas J Wang14, Oana M Enache1, Zachary Sanborn5, Francois Pepin114, Steffen Durinck1, James E Korkola14, Malachi Griffith6, Joe S Hur7, Nam Huh8, Jongsuk Chung8, Leslie Cope9, Mary Jo Fackler9, Christopher Umbricht9, Saraswati Sukumar9, Pankaj Seth10, Vikas P Sukhatme10, Lakshmi R Jakkula1, Yiling Lu11, Gordon B Mills11, Raymond J Cho12, Eric A Collisson12, Laura J van’t Veer2, Paul T Spellman13 and Joe W Gray14*

Author affiliations

1 Department of Cancer & DNA Damage Responses, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

2 Laboratory Medicine, University of California San Francisco, San Francisco, CA 94115, USA

3 Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA

4 Department of Biomedical Engineering, Center for Spatial Systems Biomedicine, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA

5 Five3 genomics, 101 Cooper St, Santa Cruz, CA 95060, USA

6 The Genome Institute, Washington University School of Medicine, St Louis, MO 63105, USA

7 Samsung Electronics Headquarters, Seocho-gu, Seoul 137-857, Korea

8 Emerging Technology Research Center, Samsung Advanced Institute of Technology, Kyunggi-do 446-712, Korea

9 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

10 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

11 Department of Systems Biology, MD Anderson Cancer Center, Houston, TX 77030, USA

12 Department of Dermatology, University of California, San Francisco, CA 94115, USA

13 Present address: Department of Bioinformatics & Computational Biology, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA

14 Present address: Sequenta Inc, South San Francisco, CA 94080, USA

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Citation and License

Genome Biology 2013, 14:R110  doi:10.1186/gb-2013-14-10-r110

Published: 31 October 2013

Abstract

Background

First-generation molecular profiles for human breast cancers have enabled the identification of features that can predict therapeutic response; however, little is known about how the various data types can best be combined to yield optimal predictors. Collections of breast cancer cell lines mirror many aspects of breast cancer molecular pathobiology, and measurements of their omic and biological therapeutic responses are well-suited for development of strategies to identify the most predictive molecular feature sets.

Results

We used least squares-support vector machines and random forest algorithms to identify molecular features associated with responses of a collection of 70 breast cancer cell lines to 90 experimental or approved therapeutic agents. The datasets analyzed included measurements of copy number aberrations, mutations, gene and isoform expression, promoter methylation and protein expression. Transcriptional subtype contributed strongly to response predictors for 25% of compounds, and adding other molecular data types improved prediction for 65%. No single molecular dataset consistently out-performed the others, suggesting that therapeutic response is mediated at multiple levels in the genome. Response predictors were developed and applied to TCGA data, and were found to be present in subsets of those patient samples.

Conclusions

These results suggest that matching patients to treatments based on transcriptional subtype will improve response rates, and inclusion of additional features from other profiling data types may provide additional benefit. Further, we suggest a systems biology strategy for guiding clinical trials so that patient cohorts most likely to respond to new therapies may be more efficiently identified.