Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer |
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| Authors: | Troels K. Bergmann Charlotte Brasch‐Andersen Henrik Gréen Mansoor R. Mirza Kristin Skougaard Jessica Wihl Nina Keldsen Per Damkier Curt Peterson Werner Vach Kim Brøsen |
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| Affiliation: | 1. School of Pharmacy, University of Queensland, Brisbane, Qld, Australia;2. Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark;3. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;4. Clinical Pharmacology, Department of Medical and Health Sciences, Link?ping University, Link?ping, Sweden;5. Science for Life Laboratory, School of Biotechnology, Royal Institute of Technology, Solna, Sweden;6. Department of Oncology, Odense University Hospital, Odense, Denmark;7. Department of Oncology, Herlev Hospital, Herlev, Denmark;8. Department of Oncology, Lund Hospital, Lund, Sweden;9. Department of Oncology, Herning Hospital, Herning, Denmark;10. Department of Biochemistry & Pharmacology, Odense University Hospital, Odense, Denmark;11. Clinical Epidemiology, Institute of Medical Biometry and Medical Informatics, University Medical Center, Freiburg, Germany |
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| Abstract: | Abstract: The standard treatment for ovarian cancer in advanced stages is post‐surgery treatment with taxane–platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose‐limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter‐individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p‐value 0.03). A similar association was found for G2677T/A, p‐value 0.02. For C1236T, there was a trend with p‐value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy. |
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