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

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 Illumina Human Exome v1.1 BeadChip 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 [greater than or equal to] 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. doi: 10.1038/tpj.2014.13; published online 15 April 2014 32 44 TaqMan 31 TaqMan 1 12 61 TaqMan 50 Chip 88 Chip 66 TaqMan 1 1 3 130 Chip 21 81 Chip 67 Chip 44 (32.4) 20.9 31 (22.8) 12.1 1.99 1.21-3.27 0.007