Thymidylate synthase expression as a predictive biomarker of pemetrexed sensitivity in advanced non-small cell lung cancer.
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.
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, Madrid, Spain. cristina.chamizo@fjd.es.
Cristina
C
Chamizo
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, Madrid, Spain. SZazo@fjd.es.
Sandra
S
Zazo
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, Madrid, Spain. MDomine@fjd.es.
Manuel
M
Dómine
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, Madrid, Spain. ion.cristobal@fjd.es.
Ion
I
Cristóbal
Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, Madrid, Spain. jgfoncillas@fjd.es.
Jesús
J
García-Foncillas
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, Madrid, Spain. FRojo@fjd.es.
Federico
F
Rojo
Cancer Biomarkers Research Group, Fundacion Jimenez Diaz University Hospital Health Research Institute, UAM, Madrid, Spain. JMadoz@fjd.es.
Juan
J
Madoz-Gúrpide
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013940:Thymidylate Synthase / Q000235:genetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D000068437:Pemetrexed; C000600377:TYMS protein, human; D013940:Thymidylate Synthase; D002945:Cisplatin