Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Hassett MJ, O'Malley AJ, Pakes JR, Newhouse JP, Earle CC . Frequency and cost of chemotherapy-related serious adverse effects in a population sample of women with breast cancer. J Natl Cancer Inst 2006; 98: 1108–1117.

    Google Scholar 

  2. Shapiro CL, Recht A . Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344: 1997–2008.

    Google Scholar 

  3. Choi JY, Nowell SA, Blanco JG, Ambrosone CB . The role of genetic variability in drug metabolism pathways in breast cancer prognosis. Pharmacogenomics 2006; 7: 613–624.

    Google Scholar 

  4. Yao S, Maghsoudlou D, Ambrosone CB . Breast cancer pharmacogenetics in the era of personalized medicine. Curr Breast Cancer Rep 2012; 4: 271–281.

    Google Scholar 

  5. Sladek NE, Kollander R, Sreerama L, Kiang DT . Cellular levels of aldehyde dehydrogenases (ALDH1A1 and ALDH3A1) as predictors of therapeutic responses to cyclophosphamide-based chemotherapy of breast cancer: a retrospective study. Rational individualization of oxazaphosphorine-based cancer chemotherapeutic regimens. Cancer Chemother Pharmacol 2002; 49: 309–321.

    Google Scholar 

  6. Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD . Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet Genomics 2008; 18: 1009–1015.

    Google Scholar 

  7. Lal S, Mahajan A, Chen WN, Chowbay B . Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab 2010; 11: 115–128.

    Google Scholar 

  8. Sucheston LE, Zhao H, Yao S, Zirpoli G, Liu S, Barlow WE et al. Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). Breast Cancer Res Treat 2011; 130: 993–1002.

    Google Scholar 

  9. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 2006.

  10. Edlund CK, Lee WH, Li D, Van Den Berg DJ, Conti DV . Snagger: a user-friendly program for incorporating additional information for tagSNP selection. BMC Bioinformatics 2008; 9: 174.

    Google Scholar 

  11. The International HapMap Consortium. The International HapMap Project. Nature 2003; 426: 789–796.

    Google Scholar 

  12. Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

    Google Scholar 

  13. Luna A, Nicodemus KK . snp.plotter: an R-based SNP/haplotype association and linkage disequilibrium plotting package. Bioinformatics 2007; 23: 774–776.

    Google Scholar 

  14. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Google Scholar 

  15. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Google Scholar 

  16. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM . REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93: 387–391.

    Google Scholar 

  17. Caggiano V, Weiss RV, Rickert TS, Linde-Zwirble WT . Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy. Cancer 2005; 103: 1916–1924.

    Google Scholar 

  18. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205.

    Google Scholar 

  19. Levi BP, Yilmaz OH, Duester G, Morrison SJ . Aldehyde dehydrogenase 1a1 is dispensable for stem cell function in the mouse hematopoietic and nervous systems. Blood 2009; 113: 1670–1680.

    Google Scholar 

  20. Khoury T, Ademuyiwa FO, Chandraseekhar R, Jabbour M, Deleo A, Ferrone S et al. Aldehyde dehydrogenase 1A1 expression in breast cancer is associated with stage, triple negativity, and outcome to neoadjuvant chemotherapy. Modern Pathol 2012; 25: 388–397.

    Google Scholar 

  21. Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD . Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genomics 2008; 18: 515–523.

    Google Scholar 

  22. Gamazon ER, Zhang W, Konkashbaev A, Duan S, Kistner EO, Nicolae DL et al. SCAN: SNP and copy number annotation. Bioinformatics 2010; 26: 259–262.

    Google Scholar 

  23. Crabb DW, Matsumoto M, Chang D, You M . Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology. Proc Nutr Soc 2004; 63: 49–63.

    Google Scholar 

  24. Liu J, Zhou Z, Hodgkinson CA, Yuan Q, Shen PH, Mulligan CJ et al. Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations. Alcohol Clin Exp Res 2011; 35: 304–316.

    Google Scholar 

  25. Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ et al. Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci 2008; 99: 816–823.

    Google Scholar 

  26. Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 2005; 112: 3754–3762.

    Google Scholar 

  27. Simon RM, Paik S, Hayes DF . Ues of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101: 1–7.

    Google Scholar 

Download references

Acknowledgements

We thank Dr Frank L. Meyskens, Jr, M.D., Associate Chair for the Cancer Control & Prevention Committee of the Southwest Oncology Group, for his administrative support. This study was supported by NIH R01 CA116395, and the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA63844, CA63845, CA 20319, CA46282, CA46441, CA35261, CA63848, CA67575, CA14028, CA35281, CA128567, CA45560, CA58882, CA13612; CA46368, CA45808, CA58658, CA76447, CA37981, CA04919; CA95860; CA27057, CA42777, CA22433, CA74647, CA86780, CA68183, CA58861, CA45807, CA35192, CA35178, CA58416, CA35176, CA67663, CA35431, CA12644, CA16385, CA11083, CA45377, CA35128, CA35262, CA52654, CA76429, CA58723, CA46113, CA76132, CA45450, CA35119, CA45461, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and in part by Amgen. Support was also provided by the Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale (DFH), and Drs Ambrosone, Gralow, Hayes, Hershman and Hortobagyi are recipients of funding from the Breast Cancer Research Foundation. Funding agencies had no involvement in the study design, data collection, analysis and interpretation, or in the writing of the report and submission.

DISCLAIMER

Funding agencies had no involvement in the study design, data collection, analysis and interpretation, or in the writing of the report and submission.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Yao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yao, S., Sucheston, L., Zhao, H. et al. 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. Pharmacogenomics J 14, 241–247 (2014). https://doi.org/10.1038/tpj.2013.32

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2013.32

Keywords

This article is cited by

Search

Quick links