Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer

BMC Pulmonary Medicine

Juan Madoz-Gúrpide¹  Federico Rojo¹  Jesús García-Foncillas²  Ion Cristóbal²  Manuel Dómine²  Sandra Zazo¹  Cristina Chamizo¹ 

[1] Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, Madrid, Spain;Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, Madrid, Spain

关键词: Pemetrexed;    NSCLC;    Thymidylate synthase;   

Others  :  1231055
DOI  :  10.1186/s12890-015-0132-x

 received in 2015-03-05, accepted in 2015-10-19,  发布年份 2015

【 摘 要 】

Background

Although it has been suggested that a high level of thymidylate synthase (TYMS) gene expression in malignant tumors is related to reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with the drug. The purpose of this study was to quantitatively assess the impact of TYMS gene expression in tumor cells as a predictor of the efficacy of pemetrexed therapy in patients with advanced non-small cell lung cancer (NSCLC) treated at our institution.

Methods

Sixty-two NSCLC patients were included in this study: 16 patients received platins-pemetrexed as first-line NSCLC, and 46 pemetrexed in monotherapy as second- or subsequent-line treatment. Total mRNA was isolated and the expression of TYMS was analyzed by RT-qPCR. TYMS levels were calibrated against expression in normal lung tissue.

Results

TYMS overexpression was detected in 61 % of patients and low expression in 39 %. The response rate for patients with low TYMS expression was 0.29 compared with 0.03 in patients with overexpression (P = 0.025). A significant benefit was observed in patients with low expression both in time to progression (average TTP = 56 vs. 23 months, P = 0.001) and in overall survival (average OS = 60 vs. 25 months, P = 0.002).

Conclusions

TYMS overexpression in tumor cells correlated with a reduced response to pemetrexed-containing chemotherapy and might be used as a predictive biomarker in advanced NSCLC patients.

【 授权许可】

   
2015 Chamizo et al.

【 图 表 】

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【 参考文献 】

• [1]Shih C, Chen VJ, Gossett LS, Gates SB, MacKellar WC, Habeck LL, Shackelford KA, Mendelsohn LG, Soose DJ, Patel VF et al.. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 1997; 57(6):1116-1123.
• [2]Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T et al.. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004; 22(9):1589-1597.
• [3]Shimizu T, Nakanishi Y, Nakagawa Y, Tsujino I, Takahashi N, Nemoto N, Hashimoto S. Association between expression of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase and efficacy of pemetrexed in advanced non-small cell lung cancer. Anticancer Res. 2012; 32(10):4589-4596.
• [4]Buque A, Aresti U, Calvo B, Sh Muhialdin J, Munoz A, Carrera S, Azkona E, Rubio I, Lopez-Vivanco G. Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells. PLoS ONE. 2013; 8(5):e63338.
• [5]Ozasa H, Oguri T, Uemura T, Miyazaki M, Maeno K, Sato S, Ueda R. Significance of thymidylate synthase for resistance to pemetrexed in lung cancer. Cancer Sci. 2010; 101(1):161-166.
• [6]Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C et al.. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006; 12(3 Pt 1):832-838.
• [7]Rose MG, Farrell MP, Schmitz JC. Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer. 2002; 1(4):220-229.
• [8]Johnston PG, Mick R, Recant W, Behan KA, Dolan ME, Ratain MJ, Beckmann E, Weichselbaum RR, Allegra CJ, Vokes EE. Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer. J Natl Cancer Inst. 1997; 89(4):308-313.
• [9]Righi L, Papotti MG, Ceppi P, Bille A, Bacillo E, Molinaro L, Ruffini E, Scagliotti GV, Selvaggi G. Thymidylate synthase but not excision repair cross-complementation group 1 tumor expression predicts outcome in patients with malignant pleural mesothelioma treated with pemetrexed-based chemotherapy. J Clin Oncol. 2010; 28(9):1534-1539.
• [10]Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M 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(21):3543-3551.
• [11]Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, Lo Iacono M, Cappia S, Papotti M, Scagliotti GV. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006; 107(7):1589-1596.
• [12]Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45.
• [13]Tanaka F, Wada H, Fukui Y, Fukushima M. Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population. Ann Oncol. 2011; 22(8):1791-1797.
• [14]Wang L, Wang R, Pan Y, Sun Y, Zhang J, Chen H. The pemetrexed-containing treatments in the non-small cell lung cancer is -/low thymidylate synthase expression better than +/high thymidylate synthase expression: a meta-analysis. BMC cancer. 2014; 14:205. BioMed Central Full Text
• [15]Liu Q, Yu Z, Xiang Y, Wu N, Wu L, Xu B, Wang L, Yang P, Li Y, Bai L. Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: a systematic review and meta-analysis. Cancer Biomark. 2015; 15(1):65-78.
• [16]Wang T, Chuan Pan C, Rui Yu J, Long Y, Hong Cai X, De Yin X, Qiong Hao L, Li Luo L. Association between TYMS expression and efficacy of pemetrexed-based chemotherapy in advanced non-small cell lung cancer: a meta-analysis. PLoS ONE. 2013; 8(9):e74284.
• [17]Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer. 2011; 104(10):1594-1601.
• [18]Zucali PA, Giovannetti E, Destro A, Mencoboni M, Ceresoli GL, Gianoncelli L, Lorenzi E, De Vincenzo F, Simonelli M, Perrino M et al.. Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin. Clin Cancer Res. 2011; 17(8):2581-2590.