Predicting paclitaxel-induced neutropenia using the DMET platform.
OBJECTIVE
The use of paclitaxel in cancer treatment is limited by paclitaxel-induced neutropenia. We investigated the ability of genetic variation in drug-metabolizing enzymes and transporters to predict hematological toxicity.


METHODS
Using a discovery and validation approach, we identified a pharmacogenetic predictive model for neutropenia. For this, a drug-metabolizing enzymes and transporters plus DNA chip was used, which contains 1936 SNPs in 225 metabolic enzyme and drug-transporter genes.


RESULTS
Our 10-SNP model in 279 paclitaxel-dosed patients reached 43% sensitivity in the validation cohort. Analysis in 3-weekly treated patients only resulted in improved sensitivity of 79%, with a specificity of 33%. None of our models reached statistical significance.


CONCLUSIONS
Our drug-metabolizing enzymes and transporters-based SNP-models are currently of limited value for predicting paclitaxel-induced neutropenia in clinical practice. Original submitted 9 March 2015; Revision submitted 20 May 2015.
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Annemieke J M
AJ
Nieuweboer
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Marcel
M
Smid
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Anne-Joy M
AJ
de Graan
Department of Clinical Chemistry, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Samira
S
Elbouazzaoui
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Peter
P
de Bruijn
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
John W
JW
Martens
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Ron H J
RH
Mathijssen
Department of Clinical Chemistry, Erasmus University Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Ron H N
RH
van Schaik
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D055815:Young Adult
D000972:Antineoplastic Agents, Phytogenic; D026901:Membrane Transport Proteins; D017239:Paclitaxel
DMET™ platform; drug-metabolizing enzymes and transporters; genetic variation; leukopenia; neutropenia; paclitaxel; polymorphisms