Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish Randomised Trial in Ovarian Cancer.
OBJECTIVE
Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane, which has a 5-year survival rate of approximately 45%. The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.


METHODS
We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery.


RESULTS
No reproducible significant associations between genotype and outcome or toxicity were found for any of the genes analyzed. Previously reported genotype associations could not be replicated in this large study of a well-defined patient population within one specific clinical trial.


CONCLUSIONS
There are no clear candidates for taxane/platinum pharmacogenetic markers. This study highlights the need for validation of putative genetic markers in large, well-defined clinical sample sets.
Marsh
Sharon
S
Washington University School of Medicine, Division of Oncology, St Louis, MO 63110, USA. smarsh@im.wustl.edu
Paul
Jim
J
King
Cristi R
CR
Gifford
Gillian
G
McLeod
Howard L
HL
Brown
Robert
R
D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D016190:Carboplatin / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D000089762:Multidrug Resistance-Associated Protein 2; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic
C000715087:ABCC2 protein, human; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin