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:

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

The Pharmacogenomics Journal volume 16, pages 243–248 (2016)Cite this article

Subjects

Abstract

Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A . Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9–29.

    Google Scholar 

  2. Brown ML, Riley GF, Schussler N, Etzioni R . Estimating health care costs related to cancer treatment from SEER-Medicare data. Med Care 2002; 40: 104–117.

    Article  Google Scholar 

  3. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY et al. Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 1996; 23: 40–47.

    CAS  PubMed  Google Scholar 

  4. du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–1329.

    Article  CAS  PubMed  Google Scholar 

  5. Guastalla JP 3rd, Dieras V . The taxanes: toxicity and quality of life considerations in advanced ovarian cancer. Br J Cancer 2003; 89: S16–S22.

    Article  CAS  PubMed  Google Scholar 

  6. Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004; 96: 1682–1691.

    Article  CAS  PubMed  Google Scholar 

  7. Schnell FM . Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist 2003; 8: 187–198.

    Article  CAS  PubMed  Google Scholar 

  8. McWhinney-Glass S, Winham SJ, Hertz DL, Revollo JY, Paul J, He Y et alScottish Gynaecological Clinical Trials Group. Cumulative genetic risk predicts platinum/taxane-induced neurotoxicity. Clin Cancer Res 2013; 19: 5769–5776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hardy GH . Mendelian proportions in a mixed population. Science 1908; 28: 49–50.

    Article  CAS  PubMed  Google Scholar 

  10. Akaike H . A new look at the statistical model identification. IEEE Transactions on Automatic Control 1974; 19: 716–723.

    Google Scholar 

  11. Team RDC. R: a language and environment for statistical computing; 2007.

  12. Kim HS, Kim MK, Chung HH, Kim JW, Park NH, Song YS et al. Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: a Korean population-based study. Gynecol Oncol 2009; 113: 264–269.

    Article  CAS  PubMed  Google Scholar 

  13. Marsh S, King CR, McLeod HL, Paul J, Gifford G, Brown R . ABCB1 2677G&gt;T/A genotype and paclitaxel pharmacogenetics in ovarian cancer. Clin Cancer Res 2006; 12: 4127.

    Article  CAS  PubMed  Google Scholar 

  14. Pillot GA, Read WL, Hennenfent KL, Marsh S, Gao F, Viswanathan A et al. A phase II study of irinotecan and carboplatin in advanced non-small cell lung cancer with pharmacogenomic analysis: final report. J Thorac Oncol 2006; 1: 972–978.

    Article  PubMed  Google Scholar 

  15. Chang H, Rha SY, Jeung HC, Im CK, Ahn JB, Kwon WS et al. Association of the ABCB1 gene polymorphisms 2677G&gt;T/A and 3435C&gt;T with clinical outcomes of paclitaxel monotherapy in metastatic breast cancer patients. Ann Oncol 2009; 20: 272–277.

    Article  CAS  PubMed  Google Scholar 

  16. Sissung TM, Baum CE, Deeken J, Price DK, Aragon-Ching J, Steinberg SM et al. ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel. Clin Cancer Res 2008; 14: 4543–4549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cascorbi I . P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations. Handb Exp Pharmacol 2011; 201: 261–283.

    Article  CAS  Google Scholar 

  18. Aszalos A . Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects. Drug Discov Today 2007; 12: 838–843.

    Article  CAS  PubMed  Google Scholar 

  19. Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K et al. A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. Pharmacogenomics J 2009; 10: 191–199.

    Article  PubMed  Google Scholar 

  20. Zhang G, Skorokhod OA, Khoo SK, Aguilar R, Wiertsema S, Nhabomba AJ et al. Plasma advanced oxidative protein products are associated with anti-oxidative stress pathway genes and malaria in a longitudinal cohort. Malar J 2014; 13: 134.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cater MA, Forbes J, La Fontaine S, Cox D, Mercer JF . Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. Biochem J 2004; 380: 805–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fatemi N, Sarkar B . Molecular mechanism of copper transport in Wilson disease. Environ Health Perspect 2002; 110: 695–698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kreiner-Moller E, Chawes BL, Vissing NH, Koppelman GH, Postma DS, Madsen JS et al. VEGFA variants are associated with pre-school lung function, but not neonatal lung function. Clin Exp Allergy 2013; 43: 1236–1245.

    Article  CAS  PubMed  Google Scholar 

  24. Sitohy B, Nagy JA, Dvorak HF . Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res 2012; 72: 1909–1914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484–2496.

    Article  CAS  PubMed  Google Scholar 

  26. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473–2483.

    Article  CAS  PubMed  Google Scholar 

  27. Hansen TF, Garm Spindler KL, Andersen RF, Lindebjerg J, Brandslund I, Jakobsen A . The predictive value of genetic variations in the vascular endothelial growth factor A gene in metastatic colorectal cancer. Pharmacogenomics J 2011; 11: 53–60.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was partially supported by T32GM081057 from the National Institute of General Medical Sciences and the National Institute of Health. Dr McLeod is a 1000 Talent Scholar of the People’s Republic of China.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiang-Ya Hospital, Central South University, Changsha, China

    Y J He & H L McLeod

  2. Pharmacogenetics Research institute, Central South University, Changsha, China

    Y J He & H L McLeod

  3. Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA

    Y J He, J M Hoskins, S Glass & H L McLeod

  4. Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA

    Y J He & H L McLeod

  5. Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA

    S J Winham & A Motsinger-Reif

  6. Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    S J Winham

  7. Cancer Research UK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    J Paul

  8. Department of Surgery and Cancer, Imperial College London, London, UK

    R Brown

Authors
  1. Y J He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S J Winham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J M Hoskins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Glass
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Motsinger-Reif
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H L McLeod
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Scottish Gynaecological Cancer Clinical Trials Group

Corresponding author

Correspondence to H L McLeod.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, Y., Winham, S., Hoskins, J. et al. Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial. Pharmacogenomics J 16, 243–248 (2016). https://doi.org/10.1038/tpj.2015.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2015.52

This article is cited by

Search

Advanced search

Quick links