TY - JOUR
T1 - Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer
AU - Bergmann, Troels Korshøj
AU - Gréen, Henrik
AU - Brasch-Andersen, Charlotte
AU - Mirza, Mansoor R
AU - Skougaard, Kristin
AU - Wihl, Jessica
AU - Keldsen, Nina
AU - Damkier, Per
AU - Peterson, Curt
AU - Vach, Werner
AU - Brøsen, Kim
N1 - © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
U2 - 10.1111/j.1742-7843.2011.00802.x
DO - 10.1111/j.1742-7843.2011.00802.x
M3 - Journal article
C2 - 21955855
SN - 1742-7835
VL - 110
SP - 199
EP - 204
JO - Basic & clinical pharmacology & toxicology
JF - Basic & clinical pharmacology & toxicology
IS - 2
ER -