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Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies

D Meulendijks, E A Rozeman, A Cats, K Sikorska, Markus Joerger, M J Deenen, J H Beijnen & J H M Schellens

abstract UNASSIGNED
The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3 R/3 R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3 R/3 R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation.The Pharmacogenomics Journal advance online publication, 20 December 2016; doi:10.1038/tpj.2016.81.
   
citation Meulendijks D, Rozeman E A, Cats A, Sikorska K, Joerger M, Deenen M J, Beijnen J H, Schellens J H M. Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. Pharmacogenomics J 2016;.
   
type journal paper/review (English)
date of publishing 20-12-2016
journal title Pharmacogenomics J
ISSN electronic 1473-1150
PubMed 27995989
DOI 10.1038/tpj.2016.81