title: Impact of ABCB1 variants on neutrophil depression: a pharmacogenomic study of paclitaxel in 92 women with ovarian cancer.
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.
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, Qld, AustraliaClinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, DenmarkDepartment of Clinical Genetics, Odense University Hospital, Odense, DenmarkClinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, SwedenScience for Life Laboratory, School of Biotechnology, Royal Institute of Technology, Solna, SwedenDepartment of Oncology, Odense University Hospital, Odense, DenmarkDepartment of Oncology, Herlev Hospital, Herlev, DenmarkDepartment of Oncology, Lund Hospital, Lund, SwedenDepartment of Oncology, Herning Hospital, Herning, DenmarkDepartment of Biochemistry & Pharmacology, Odense University Hospital, Odense, DenmarkClinical Epidemiology, Institute of Medical Biometry and Medical Informatics, University Medical Center, Freiburg, Germany.
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brasch-Andersen
authors.forename: Henrik
authors.initials: H
authors.lastname: Gréen
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.forename: Kristin
authors.initials: K
authors.lastname: Skougaard
authors.forename: Jessica
authors.initials: J
authors.lastname: Wihl
authors.forename: Nina
authors.initials: N
authors.lastname: Keldsen
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.forename: Werner
authors.initials: W
authors.lastname: Vach
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000209:etiology / Q000473:pathology; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics / Q000378:metabolism; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000633:toxicity*; D010349:Patient Compliance; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044465:White People
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel