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Pharmacogenomics J. 2014 Jun;14(3):241-7. doi: 10.1038/tpj.2013.32. Epub 2013 Sep 3.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Author information

  • 1Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • 2Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3SWOG Statistical Center, Seattle, WA, USA.
  • 4Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH, USA.
  • 5Columbia University Medical Center, Columbia University, New York, NY, USA.
  • 6Department of medicine, Baystate Medical Center, Springfield, MA, USA.
  • 7Lombardi Comprehensive Cancer Center, Washington, DC, USA.
  • 8Mayo Clinic, Rochester, MN, USA.
  • 9Allan Blair Cancer Centre, Regina, SK, Canada.
  • 10Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • 11Seattle Cancer Care Alliance, Seattle, WA, USA.
  • 12College of Medicine, Arizona Cancer Center, Tucson, AZ, USA.
  • 13Loyola University Chicago Cardinal Bernardin Cancer Center, Maywood, IL, USA.
  • 14Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Abstract

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

PMID:
23999597
[PubMed - in process]
PMCID:
PMC3940691
[Available on 2014/12/1]

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