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

Didier Meulendijks; E A Rozeman; A Cats; K Sikorska; M Joerger; M J Deenen; J H Beijnen; J H M Schellens

doi:10.1038/tpj.2016.81

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

Didier Meulendijks
, E A Rozeman
, A Cats
, K Sikorska
, M Joerger
, M J Deenen
, J H Beijnen
, J H M Schellens

Antoni van Leeuwenhoek-The Netherlands Cancer Institute
Cantonal Hospital St. Gallen

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	441-451
Number of pages	10
Journal	Pharmacogenomics Journal
Volume	17
Early online date	20 Dec 2016
DOIs	https://doi.org/10.1038/tpj.2016.81
Publication status	Published - Oct 2017

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Meulendijks, D., Rozeman, E. A., Cats, A., Sikorska, K., Joerger, M., Deenen, M. J., Beijnen, J. H., & Schellens, J. H. M. (2017). 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 Journal, 17, 441-451. https://doi.org/10.1038/tpj.2016.81

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title = "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",

abstract = "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.",

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Meulendijks, D, Rozeman, EA, Cats, A, Sikorska, K, Joerger, M, Deenen, MJ, Beijnen, JH & Schellens, JHM 2017, '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 Journal, vol. 17, pp. 441-451. https://doi.org/10.1038/tpj.2016.81

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. / Meulendijks, Didier; Rozeman, E A; Cats, A et al.
In: Pharmacogenomics Journal, Vol. 17, 10.2017, p. 441-451.

Research output: Contribution to journal › Article › Academic › peer-review

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Meulendijks D, Rozeman EA, Cats A, Sikorska K, Joerger M, Deenen MJ et al. 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 Journal. 2017 Oct;17:441-451. Epub 2016 Dec 20. doi: 10.1038/tpj.2016.81