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Correlation of genetic polymorphisms with clinical outcomes in pemetrexed-treated advanced lung adenocarcinoma patients
Aim: Pemetrexed is a commonly used chemotherapeutic agent for lung adenocarcinoma patients. We investigated the impact of the genetic polymorphisms on the therapeutic efficacy of pemetrexed in lung adenocarcinoma patients. Materials & methods: We performed genotying of 51 polymorphisms of 13 genes in 243 lung adenocarcinoma patients treated with pemetrexed as a single agent for second or more line of therapy. Results: Total 12 polymorphisms in six genes were showed statistical significances in univariate analysis. After a false-discovery rate correction, the associations between GGH rs16930092 (p = 0.034) and rs10464903 (p = 0.034), and progression-free survival (PFS) were still conserved. Two polymorphisms in ATIC and GGH genes were associated with therapeutic efficacy in multivariate analysis: ATIC rs12995526 for tumor response (p = 0.014) and for overall survival (p = 0.006), and GGH rs16930092 (p = 0.009) for PFS. Conclusion: This study shows that polymorphisms on genes related to the metabolic pathway of pemetrexed, especially, ATIC and GGH genes, would have a therapeutic implication in pemetrexed-treated patients with lung adenocarcinoma. Original submitted 10 May 2013; Revision submitted 27 June 2014 Keywords: ATIC • GGH • NSCLC • pharmacogenetics • prognosis • SNPs
Pemetrexed is an antifolate agent that has been approved as a first- and second-line chemotherapeutic agent in the treatment of advanced lung adenocarcinoma  . Although the clinical benefits along with diminished drug toxicity were demonstrated after introduction of pemetrexed [2–5] , differences in the therapeutic response and clinical outcome according to each patient have been observed. Despite extensive work on pemetrexed predictive markers, no definitive biomarker for the prediction of therapeutic efficacy of pemetrexed in lung adenocarcinoma has been established [2,3,6] . Pemetrexed is a multitargeted folate analog like methotrexate (MTX) that enters the cell through SLC19A1 (Figure 1) . Intracellular pemetrexed is activated by FPGS to become polyglutamate derivatives that inhibit multiple enzymes including TYMS, DHFR, GART, ATIC and PPAT. Reversely,
10.2217/PGS.15.14 © 2015 Future Medicine Ltd
GGH removes glutamyl residues from polyglutamate derivatives, resulting in the inactivation of pemetrexed [7–11] . TYMS is the primary target of polyglutamated pemetrexed, 30–200 times more potent to TYMS than ATIC and GART [7,12] . In addition, MTHFR and SHMT1 are involved in the folate pathway which is related to the process of metabolites produced by prior enzymes  . Previous studies have reported that nonsmall-cell lung cancer (NSCLC) cell lines with an overexpression of TYMS showed reduced sensitivity to pemetrexed  . It has been demonstrated that polymorphisms on SLC19A1, GGH, MTHFR and XPD genes are associated with the progression-free survival (PFS) and overall survival (OS) [2,3,15] , and polymorphisms on SLC19A1, FPGS and GGH genes with drug toxicity in NSCLC patients treated with pemetrexed-based
Pharmacogenomics (2015) 16(4), 383–391
Hye In Woo‡,1, Jung A Kim‡,2, Hyun Ae Jung3, Ka-Kyung Kim4, Ji Yean Lee5, Jong-Mu Sun3, Jin Seok Ahn3, Keunchil Park3, Soo-Youn Lee*,§ ,1,6 & Myung-Ju Ahn § ,3 Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Division of Hematology-Oncology, Department of Medicine, Seoul Paik Hospital, Inje University School of Medicine, Seoul, Korea 3 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Health Sciences & Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea 5 Department of Internal Medicine, G SAM Hospital, Gunpo, Korea 6 Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea *Author for correspondence: Tel.: +82 2 3410 1834 Fax: +82 2 3410 2719 [email protected]
samsung.com ‡ Authors contributed equally § Authors contributed equally 1
Research Article Woo, Kim, Jung et al.
ABC transporters Pyrimidine synthesis DNA incorporation
De novo purine synthesis
Figure 1. The metabolism and action sites of pemetrexed. DHF: Dihydrofolate; THF: Tetrahydrofolate.
chemotherapy  . On the other hand, negative findings of these correlations have been also reported  . Until now, there have still been only a few reports about the relationship between genetic polymorphisms and the therapeutic efficacy of pemetrexed-based chemot herapy in NSCLC, especially in lung adenocarcinoma. Moreover, most studies are involved in patients treated with pemetrexed in combination with other various agents, and only a small number of polymorphisms. In this respect, we evaluated the association between the genetic polymorphisms in genes related to the metabolic pathway of pemetrexed and the therapeutic efficacy in a large number of advanced lung adenocarcinoma patients treated with pemetrexed as a single agent. Materials & methods Patients eligibility criteria, treatment & evaluation
Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC who had been treated with pemetrexed alone as second or more line of therapy at Samsung Medical Center between April 2007 and February 2010 were included. Other eligible criteria included: 18 years-of-age or older; a measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST); an ECOG performance status of 0–2; adequate function of the bone marrow (absolute neutrophil count >1.5 × 109 /l, platelet count >100 × 109 /l), kidney (serum creatinine 60 ml/min) and liver (total bilirubin