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Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance)

The Pharmacogenomics Journal volume 14, pages 336–342 (2014)Cite this article

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Abstract

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

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Acknowledgements

The research for CALGB 60202 and 40101 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M Bertagnolli, MD, Chair) and to the Alliance Statistics and Data Center (Daniel J Sargent, PhD, CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. This work was also supported, in part, by the NIH Grants U01 GM61390, U01 GM61393 and U01 HL065962 and the Biobank Japan Project funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology. The genotyping used for this work was generated as part of the NIH Pharmacogenomics Research Network-RIKEN Center for Genomic Medicine Global Alliance. AC and ML were supported, in part, by the NIH Training Grant T32 GM007175.

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  1. E A Stahl

    Present address: 14Current address: Division of Psychiatric Genomics, Mt Sinai School of Medicine, New York, NY, USA.,

Authors and Affiliations

  1. Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA

    A Chhibber, R M Baldwin, M Li & D L Kroetz

  2. Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA

    A Chhibber, J Mefford, R M Baldwin, M Li, J S Witte & D L Kroetz

  3. Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA

    J Mefford & J S Witte

  4. Division of Rheumatology, Division of Genetics, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    E A Stahl & R M Plenge

  5. Medical and Population Genetics Program, Chemical Biology Program, Broad Institute, Cambridge, MA, USA

    E A Stahl & R M Plenge

  6. Department of Biochemistry and Molecular Biology, Center for Systems Genomics, The Pennsylvania State University, Eberly College of Science, The Huck Institutes of the Life Sciences, University Park, PA, USA

    S A Pendergrass & M D Ritchie

  7. Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, USA

    K Owzar

  8. Dana-Farber Cancer Institute, Boston, MA, USA

    E P Winer & L N Shulman

  9. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    C A Hudis

  10. Laboratory of Molecular Medicine, University of Tokyo, Tokyo, Japan

    H Zembutsu & Y Nakamura

  11. Center for Integrative Medical Sciences, Riken Center, Yokohama, Japan

    M Kubo & Y Nakamura

  12. Department of Medicine, University of Chicago, Chicago, IL, USA

    Y Nakamura & M J Ratain

  13. Department of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    H L McLeod

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  1. A Chhibber
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Correspondence to D L Kroetz.

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Chhibber, A., Mefford, J., Stahl, E. et al. Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance). Pharmacogenomics J 14, 336–342 (2014). https://doi.org/10.1038/tpj.2014.2

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