Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations

TY - JOUR

T1 - Pharmacogenetics of pemetrexed combination therapy in lung cancer

T2 - pathway analysis reveals novel toxicity associations

AU - Corrigan, A.

AU - Walker, J. L.

AU - Wickramasinghe, S.

AU - Hernandez, M. A.

AU - Newhouse, S. J.

AU - Folarin, A. A.

AU - Lewis, C. M.

AU - Sanderson, J. D.

AU - Spicer, J.

AU - Marinaki, A. M.

PY - 2014/10

Y1 - 2014/10

N2 - Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the II lumina Human Exome v1.1 Bead Chip. and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n = 136). GGH rs11545078 was associated with a reduced incidence of grade >= 3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade >= 3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade >= 3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.

AB - Identification of polymorphisms that influence pemetrexed tolerability could lead to individualised treatment regimens and improve quality of life. Twenty-eight polymorphisms within eleven candidate genes were genotyped using the II lumina Human Exome v1.1 Bead Chip. and tested for their association with the clinical outcomes of non-small cell lung cancer and mesothelioma patients receiving pemetrexed/platinum doublet chemotherapy (n = 136). GGH rs11545078 was associated with a reduced incidence of grade >= 3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P=0.018), as well as reduced grade >= 3 haematological toxicity (OR 0.13, P=0.048). DHFR rs1650697 conferred an increased risk of grade >= 3 toxicity (OR 2.14, P=0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P=0.023). Polymorphisms within SLC19A1 (rs3788189, rs1051298 and rs914232) were associated with overall survival. This study confirms previous pharmacogenetic associations and identifies novel markers of pemetrexed toxicity.

KW - REDUCED FOLATE CARRIER

KW - MULTITARGETED ANTIFOLATE LY231514

KW - MALIGNANT PLEURAL MESOTHELIOMA

KW - CHEMOTHERAPY-NAIVE PATIENTS

KW - PHASE-II TRIAL

KW - THYMIDYLATE SYNTHASE

KW - RECEPTOR-ALPHA

KW - GLUTAMYL HYDROLASE

KW - EXPRESSION

KW - CISPLATIN

U2 - 10.1038/tpj.2014.13

DO - 10.1038/tpj.2014.13

M3 - Article

SN - 1470-269X

VL - 14

SP - 411

EP - 417

JO - Pharmacogenomics journal

JF - Pharmacogenomics journal

IS - 5

ER -