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Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.

Methods

The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients’ toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.

Results

Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.

Conclusion

CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

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Acknowledgments

We wish to acknowledge the AGO Ovarian Cancer study group in Wiesbaden, Germany, and The Nordic Society of Gynecologic Oncology, Clinical Trial Unit, Odense, Denmark, for making available the clinical data from the AGO-OVAR-9 study and the NSGO-OC9804 (TEC) study. We wish to acknowledge the work and invaluable help of lab technicians Ingrid Jakobsen Falk and Karin Skoglund in Linköping and Pernille Jordan in Odense. The work was financially supported by grants from the European Commission (CHEMORESLSHC-CT-2007-037665), the Swedish Cancer Society, the Swedish Medical Society–Linköping branch, the County Council in Östergötland, the Danish Ministry of Interior Affairs and Health (2001–2007) (J.nr 2006-12103-276), the Danish Research Agency (J.nr 271-05-0266), Borgholm Rotary Club, Sweden, and Roche Denmark, Hvidovre, Denmark.

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, J.B. Winsleows vej 19, 2nd floor, Odense, Denmark

    Troels K. Bergmann, Charlotte Brasch-Andersen & Kim Brosen

  2. Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

    Henrik Gréen & Curt Peterson

  3. Department of Oncology, Odense University Hospital, Odense, Denmark

    Mansoor R. Mirza & Jørn Herrstedt

  4. Department of Pathology, Odense University Hospital, Odense, Denmark

    Berit Hølund

  5. Gynecology & Gynecological Oncology, Dr. Horst Schmidt Clinic, Wiesbaden, Germany

    Andreas du Bois

  6. Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark

    Charlotte Brasch-Andersen & Per Damkier

  7. Clinical Epidemiology, Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg, Freiburg, Germany

    Werner Vach

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  1. Troels K. Bergmann
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  2. Henrik Gréen
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  3. Charlotte Brasch-Andersen
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  9. Werner Vach
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  10. Kim Brosen
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Corresponding author

Correspondence to Troels K. Bergmann.

Additional information

Henrik Gréen and Troels K. Bergmann contributed equally to the work.

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Bergmann, T.K., Gréen, H., Brasch-Andersen, C. et al. Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer. Eur J Clin Pharmacol 67, 693–700 (2011). https://doi.org/10.1007/s00228-011-1007-6

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  • DOI: https://doi.org/10.1007/s00228-011-1007-6

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