Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics.
Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.<mean clearance) was identified in 80% of cases. These models however did not reach statistical significance. To improve the predictive value of these models, the addition of non-genetic influencing factors is needed.
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
A J M
AJ
Nieuweboer
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
M
M
Smid
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
A-J M
AM
de Graan
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
S
S
Elbouazzaoui
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
P
P
de Bruijn
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
F A L M
FA
Eskens
Department of Internal Medicine, St. Franciscus Gasthuis, Rotterdam, The Netherlands.
P
P
Hamberg
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
J W M
JW
Martens
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
A
A
Sparreboom
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
R
R
de Wit
Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
R H N
RH
van Schaik
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
R H J
RH
Mathijssen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D030541:Databases, Genetic; D000077143:Docetaxel; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics*; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012720:Severity of Illness Index; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
D000970:Antineoplastic Agents; D026901:Membrane Transport Proteins; D043823:Taxoids; D000077143:Docetaxel