Yonsei Med J.  2013 Jul;54(4):854-864. 10.3349/ymj.2013.54.4.854.

Pharmacogenomic Assessment of Outcomes of Pemetrexed-Treated Patients with Adenocarcinoma of the Lung

• Jung M
• Lee CH
• Park HS
• Lee JH
• Kang YA
• Kim SK
• Chang J
• Kim DJ
• Rha SY
• Kim JH
• Cho BC

• KMID: 2158218
• DOI: http://doi.org/10.3349/ymj.2013.54.4.854

Abstract

PURPOSE
The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed.
MATERIALS AND METHODS
We assessed polymorphisms at 8 sites in 4 genes [thymidylate synthase (TS), dihydrofolate reductase (DHFR; 1610, 680, 317, intron 1), methylenetetrahydrofolate reductase (MTHFR; 677, 1298), glycinamide ribonucleotide formyl transferase (GARFT; 2255)] associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung.
RESULTS
Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes of pemetrexed.
CONCLUSION
The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.

Keyword

Polymorphism; lung neoplasms; pemetrexed

MeSH Terms

Adenocarcinoma/*drug therapy/*genetics/mortality
Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic/pharmacology/*therapeutic use/toxicity
Female
Glutamates/pharmacology/*therapeutic use/toxicity
Guanine/*analogs & derivatives/pharmacology/therapeutic use/toxicity
Humans
Lung Neoplasms/*drug therapy/*genetics/mortality
Male
Methylenetetrahydrofolate Reductase (NADPH2)/genetics
Middle Aged
Pharmacogenetics
Phosphoribosylglycinamide Formyltransferase/genetics
*Polymorphism, Single Nucleotide
Tetrahydrofolate Dehydrogenase/genetics
Thymidylate Synthase/genetics
Antimetabolites, Antineoplastic
Glutamates
Guanine
Methylenetetrahydrofolate Reductase (NADPH2)
Tetrahydrofolate Dehydrogenase
Thymidylate Synthase
Phosphoribosylglycinamide Formyltransferase

Figure

• 

  Fig. 1 Kaplan-Meier curve estimates for patients treated with pemetrexed. Progression-free survival (PFS) and overall survival (OS) were plotted against the expression of thymidylate synthase. Low expression group: 2RCC/2RGC, 2RGC/3RGCC, 3RGCC/3RGCC; high expression group: 2RGC/3RGGC, 3RGCC/3RGGC, 3RGGC/3RGGC. (A) PFS. (B) OS. TS, thymidylate synthase.

• 

  Fig. 2 Kaplan-Meier curve estimates for patients treated with pemetrexed. Progression-free survival (PFS) and overall survival (OS) were plotted by genotype. Dotted line-2RCC/2RGC, 2RGC/3RGCC, 2RGC/3RGGC, 3RGCC/3RGGC; straight line-3RGCC/3RGCC and 3RGGC/3RGGC. (A) PFS. (B) OS. TS, thymidylate synthase.

Reference

1. Curtin NJ, Hughes AN. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol. 2001; 2:298–306.

2. Adjei AA. Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res. 2004; 10(12 Pt 2):4276s–4280s.

3. Kaneda S, Nalbantoglu J, Takeishi K, Shimizu K, Gotoh O, Seno T, et al. Structural and functional analysis of the human thymidylate synthase gene. J Biol Chem. 1990; 265:20277–20284.

4. Jakobsen A, Nielsen JN, Gyldenkerne N, Lindeberg J. Thymidylate synthase and methylenetetrahydrofolate reductase gene polymorphism in normal tissue as predictors of fluorouracil sensitivity. J Clin Oncol. 2005; 23:1365–1369.

5. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004; 50:2766–2774.

6. Berkun Y, Levartovsky D, Rubinow A, Orbach H, Aamar S, Grenader T, et al. Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Ann Rheum Dis. 2004; 63:1227–1231.

7. Schultz RM, Chen VJ, Bewley JR, Roberts EF, Shih C, Dempsey JA. Biological activity of the multitargeted antifolate, MTA (LY231514), in human cell lines with different resistance mechanisms to antifolate drugs. Semin Oncol. 1999; 26:2 Suppl 6. 68–73.

8. Sigmond J, Backus HH, Wouters D, Temmink OH, Jansen G, Peters GJ. Induction of resistance to the multitargeted antifolate Pemetrexed (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Biochem Pharmacol. 2003; 66:431–438.

9. Smit EF, Burgers SA, Biesma B, Smit HJ, Eppinga P, Dingemans AM, et al. Randomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27:2038–2045.

10. Ulrich CM, Robien K, Sparks R. Pharmacogenetics and folate metabolism--a promising direction. Pharmacogenomics. 2002; 3:299–313.

11. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological typing of lung and pleural tumours. 1999. 3rd ed. Berlin: Springer-Verlag.

12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000; 92:205–216.

13. Boom R, Sol CJ, Salimans MM, Jansen CL, Wertheim-van Dillen PM, van der Noordaa J. Rapid and simple method for purification of nucleic acids. J Clin Microbiol. 1990; 28:495–503.

14. Nief N, Le Morvan V, Robert J. Involvement of gene polymorphisms of thymidylate synthase in gene expression, protein activity and anticancer drug cytotoxicity using the NCI-60 panel. Eur J Cancer. 2007; 43:955–962.

15. Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006; 107:1589–1596.

16. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008; 26:3543–3551.

17. Dulucq S, St-Onge G, Gagné V, Ansari M, Sinnett D, Labuda D, et al. DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood. 2008; 111:3692–3700.

18. Wu MF, Hsiao YM, Huang CF, Huang YH, Yang WJ, Chan HW, et al. Genetic determinants of pemetrexed responsiveness and nonresponsiveness in non-small cell lung cancer cells. J Thorac Oncol. 2010; 5:1143–1151.

19. Uramoto H, Onitsuka T, Shimokawa H, Hanagiri T. TS, DHFR and GARFT expression in non-squamous cell carcinoma of NSCLC and malignant pleural mesothelioma patients treated with pemetrexed. Anticancer Res. 2010; 30:4309–4315.

20. Graziano F, Kawakami K, Ruzzo A, Watanabe G, Santini D, Pizzagalli F, et al. Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer. 2006; 118:628–632.

21. Shannon B, Gnanasampanthan S, Beilby J, Iacopetta B. A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability. Gut. 2002; 50:520–524.

22. Boccia S, Boffetta P, Brennan P, Ricciardi G, Gianfagna F, Matsuo K, et al. Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer. Cancer Lett. 2009; 273:55–61.