Association between expression of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase and efficacy of pemetrexed in advanced non-small cell lung cancer.
BACKGROUND
Pemetrexed inhibits three key folate enzymes: thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The relationship between the clinical efficacy of pemetrexed and the expression of folate enzymes in lung cancer cells is unknown. The purpose of this study was to determine whether TYMS, DHFR, and GARFT expression affect the therapeutic efficacy of pemetrexed.


METHODS
Participants (n=50) were patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed. Samples were obtained by tumor biopsy before treatment. We isolated cancer cells from formalin-fixed paraffin-embedded tissues using laser microdissection, and mRNA levels were analyzed using real-time reverse transcription polymerase chain reaction. Protein expression was evaluated using immunohistochemistry. We assessed the association between TYMS, DHFR, and GARFT expression and the therapeutic efficacy of pemetrexed.


RESULTS
The median age was 66.8 years. Compared to healthy tissues, the relative TYMS mRNA expression ranged from 0.001 to 41.613 (mean 4.638 ± 1.357), and was significantly lower in responders compared to non-responders (1.671 ± 0.844 versus 5.978 ± 1.895, p=0.0142). Progression-free survival was prolonged in patients with lower TYMS mRNA expression compared to those with higher TYMS mRNA expression, but the difference was not statistically significant (18.0 versus 13.3 weeks, p=0.3001). DHFR and GARFT mRNA expression did not correlate with the efficacy of pemetrexed.


CONCLUSIONS
We specifically analyzed TYMS, DHFR, and GARFT mRNA expression levels in lung cancer cells from biopsy specimens using laser microdissection. TYMS mRNA expression affected the therapeutic efficacy of pemetrexed and could therefore constitute a useful predictive biomarker for NSCLC patients receiving pemetrexed.
Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan. shimizu.tetsuo@nihon-u.ac.jp
Tetsuo
T
Shimizu
Yoko
Y
Nakanishi
Yoshiko
Y
Nakagawa
Ichiro
I
Tsujino
Noriaki
N
Takahashi
Norimichi
N
Nemoto
Shu
S
Hashimoto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005971:Glutamates / Q000627:therapeutic use*; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed; D051026:Phosphoribosylglycinamide Formyltransferase / Q000032:analysis / Q000096:biosynthesis*; D011859:Radiography; D012720:Severity of Illness Index; D013762:Tetrahydrofolate Dehydrogenase / Q000032:analysis / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000032:analysis / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D051026:Phosphoribosylglycinamide Formyltransferase