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Pharmacogenetics of Pemetrexed Combination Therapy in Lung Cancer: Pathway Analysis Reveals Novel Toxicity Associations

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Pharmacogenetics of Pemetrexed Combination Therapy in Lung Cancer: Pathway Analysis Reveals Novel Toxicity Associations The Pharmacogenomics Journal (2014) 14, 411–417 & 2014 Macmillan Publishers Limited All rights reserved 1470-269X/14 www.nature.com/tpj ORIGINAL ARTICLE Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations A Corrigan1,6, JL Walker2,6, S Wickramasinghe1, MA Hernandez1, SJ Newhouse3, AA Folarin3, CM Lewis2, JD Sanderson4, J Spicer5 and AM Marinaki1 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 ¼ 136). GGH rs11545078 was associated with a reduced incidence of grade X3 toxicity within the first four cycles of therapy (odds ratio (OR) 0.25, P ¼ 0.018), as well as reduced grade X3 haematological toxicity (OR 0.13, P ¼ 0.048). DHFR rs1650697 conferred an increased risk of grade X3 toxicity (OR 2.14, P ¼ 0.034). Furthermore, FOLR3 rs61734430 was associated with an increased likelihood of disease progression at mid-treatment radiological evaluation (OR 4.05, P ¼ 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. The Pharmacogenomics Journal (2014) 14, 411–417; doi:10.1038/tpj.2014.13; published online 15 April 2014 INTRODUCTION (FPGS).16 Polyglutamation serves for both prolongation of cellular Pemetrexed is a folate antimetabolite approved for the treatment retention of pemetrexed and also increases the affinity of the 5,17 of advanced non-small cell lung cancer (NSCLC) both in drug for its cellular targets. Gamma-glutamyl hydrolase (GGH) combination with a platinum agent in the first-line setting and catalyses the removal of these glutamic acid residues from as single agent maintenance or second line therapy.1 In addition, pemetrexed, facilitating extrusion from the cell and reducing the 18 it has proven efficacy in the treatment of mesothelioma.2,3 activity of the drug. Of interest, polymorphic variants within GGH Cytotoxicity is achieved through simultaneous inhibition of three are reported to be associated with significant pemetrexed toxicity, 9,10 key enzymes, which results in the disturbance of nucleotide pools as well as altered response and survival rates (Table 1). and disruption of DNA and RNA synthesis. Pemetrexed is primarily Although high rates of pemetrexed resistance have driven a a potent inhibitor of thymidylate synthetase and to a lesser extent number of pharmacogenetic studies investigating the predictive of glycinamide ribonucleotide formyltransferase and dihydrofolate or prognostic influence of polymorphisms within the enzymatic reductase (DHFR).4,5 targets and drug metabolic pathway, few have focussed on the Several transporters are known to be involved in the intracel- impact on treatment tolerability (Table 1). Pemetrexed therapy lular uptake of pemetrexed. Reduced folate carrier 1 (RFC1, can be complicated by dose-limiting haematological and gastro- 19,20 SLC19A1) has a high affinity for pemetrexed6 and the importance intestinal toxicity, with subsequent dose reductions and treat- of this transport mechanism is illustrated by studies that demon- ment delays potentially impairing treatment efficacy. Identification strate a complex interplay between alterations in SLC19A1 gene of powerful pharmacogenetic markers would enable informed expression and sensitivity to pemetrexed cytotoxicity.7,8 Further- treatment choices, which maximise efficacy and maintain quality more, a number of polymorphic SLC19A1 variants have been of life through avoidance of side effects. shown to influence pemetrexed tolerability and survival after Response to pemetrexed therapy and the incidence of adverse therapy (Table 1).9–11 More recently, the proton-coupled folate drug reactions (ADRs) are likely to be due to a complex interplay transporter has been shown to possess high affinity for peme- between variation in genes encoding pemetrexed targets, as well trexed and has been confirmed as an important mechanism of as those involved in the metabolism of the drug. To reflect this cellular influx.12,13 A third route of cellular uptake of uncertain complex situation, Illumina Human Exome v1.1 chip genotyping significance, is mediated by folate receptors (FR) -a and -b, which was used to assess the influence of single nucleotide polymorph- are anchored to the cellular membrane, transporting folate isms (SNPs) within 11 genes involved in the pemetrexed pathway derivatives via a complex endocytotic mechanism.6,14,15 including SLC19A1, FOLR3 (FR-g), FPGS, GGH, DHFR, GART (GARFT), Upon entering the cytoplasm, pemetrexed is rapidly polygluta- MTHFR, MTHFD1, MTR, SHMT2 and ERCC2 (Table 2).21 We predicted mated in a process mediated by folylpolyglutamate synthetase that variation within these genes, involved in pemetrexed uptake 1Purine Research Laboratory, GSTS Pathology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London, UK; 2Department of Medical and Molecular Genetics, King’s College London, 8th Floor Tower Wing, Guy’s Hospital, London, UK; 3National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and (Institute of Psychiatry) King’s College London, London, UK; 4Department of Gastroenterology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, College House, St Thomas’ Hospital, London, UK and 5Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK. Correspondence: Dr AM Marinaki, Purine Research Laboratory, GSTS Pathology, Guy’s and St Thomas’ Hospital NHS Foundation Trust, 4th Floor, North Wing, St Thomas Hospital, Lambeth Palace Road, London SE1 7EH, UK. E-mail: [email protected] 6These authors contributed equally to this work. Received 21 November 2013; revised 17 January 2014; accepted 19 February 2014; published online 15 April 2014 Pharmacogenetics of pemetrexed combination therapy A Corrigan et al 412 Table 1. Previously reported pharmacogenetic associations influencing pemetrexed outcomes Gene dbSNP ID Change Association Study participants P-value Evidence (n) SLC19A1 rs914232 c.190–688A4G GG genotype have increased grade 48 0.05 9 X3 leukopaenia rs2838958 c.1151 þ 2117C4T TT genotype have longer OS 54 0.03 10 rs3788189 c.1294–1517A4C AA genotype have longer OS 54 0.03 10 rs1051298 3’-UTR: c.*64C4T CC genotype have longer OS 54, 45 0.03, 0.022 10,11 FPGS rs138322374 c. À 327G4A GA genotype risk of high ALT 54 0.07 10 GGH rs3780126 c.109 þ 1307C4T T allele causative of increased grade 48 0.03, 0.04 9 X3 lymphopaenia, TT genotype have shorter OS rs7010484 c.500–930G4A GA genotype better response rates and 54 0.06, 0.03 10 decreased risk grade 4 ADRs DHFR rs442767 c. À 1188C4A CC genotype increased fatigue 90 0.008 28 MTHFR rs1801133 c.665C4T; p.Ala222Val TT genotype longer PFS and OS 208 0.012, 26 0.026 rs1801131 c.1286A4C; AC/CC genotype associated with shorter OS and 65 0.001, 27 p.Glu429Ala PFS 0.019 ERCC2 rs13181 c.2251A4C; CC genotypes associated with shorter PFS and 208 0.021, 26 p.Lys751Gln OS 0.044 Abbreviations: ADRs, adverse drug reactions; ALT, alanine transaminase; DHFR, dihydrofolate reductase; ERCC2, excision repair cross-complementing rodent repair deficiency, complementation group 2; FPGS, folylpolyglutamate synthase; GGH, gamma-glutamyl hydrolase; MTHFR, methylenetetrahydrofolate reductase; OS, overall survival; PFS, progression-free survival; SLC19A1, solute carrier family 19 (folate transporter), member 1. and metabolism, would affect treatment tolerability, response and Analysis Software v1.0 clustering algorithm in Genome Studio v2011.1 survival in this mixed NSCLC and mesothelioma cohort. (Illumina). This clustering data was further refined to improve rare variant genotype call rates using the zCall algorithm.22 Finally, data underwent quality control for sex mismatch, individual call rate of 497%, SNP call rate of 499%, Hardy–Weinberg Equilibrium P-value o10 À 6, cryptic relatedness MATERIALS AND METHODS and minor allele frequency 40.02. Variants with a minor allele frequency Patients and methods o0.02 are unlikely to be genuinely informative of true associations. 136 Subjects were recruited to a retrospective pharmacogenetic study at The selection of candidate genes was based on previously reported Guy’s and St Thomas’ Hospitals NHS Foundation Trust. Appropriate ethical pharmacogenetic studies (Table 1) and additionally, included genes identi- approval was obtained and written consent was provided by all fied as potentially influencing pemetrexed transport and metabolism.21 participants. Patients with cytological or histological confirmation of After quality control, of the 192 SNPs within 19 genes selected for malignant mesothelioma (n ¼ 42) or advanced NSCLC at stage XIIIB investigation, 20 SNPs within 11 genes remained for association tests (n ¼ 94) were eligible for inclusion. All patients had received at least one (Table 2). The majority of SNPs were omitted from the analysis on the basis cycle of pemetrexed therapy at a standard dose of 500 mg m À 2 in of low minor allele frequency and this is reflective of the chip design, combination
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