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. 2020 Dec;12(12):7313-7319.
doi: 10.21037/jtd-20-3185.

Plasma thymidylate synthase and dihydrofolate reductase mRNA levels as potential predictive biomarkers of pemetrexed sensitivity in patients with advanced non-small cell lung cancer

Tao Li  1 , Jin-Bo Huang  2 , Jun-Guo Lu  1 , Rong Li  3 , Yan Wang  1 , Xiang-Rong Shi  1 , Min-Xin Shi  4 , Xiao-Dong Zhang  1
Affiliations

Plasma thymidylate synthase and dihydrofolate reductase mRNA levels as potential predictive biomarkers of pemetrexed sensitivity in patients with advanced non-small cell lung cancer

Tao Li et al. J Thorac Dis. 2020 Dec.

Abstract

Background: High levels of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) expression in tumour tissues are an indicator of ineffective responses to pemetrexed-based chemotherapy in various tumours, including non-small cell lung cancer (NSCLC). However, tumour tissues are highly heterogeneous, so a single biopsy may not reflect genetic alterations during disease progression. This study investigated the potential use of plasma TS and DHFR mRNA levels as biomarkers for predicting sensitivity to pemetrexed-based chemotherapy.

Methods: Plasma samples were obtained from 245 patients with advanced NSCLC and 30 healthy donors. Total RNA was extracted from the plasma samples, and TS and DHFR mRNA levels were determined via real-time PCR. TS and DHFR mRNA levels between cancer patients and healthy controls were compared. The association between plasma TS and DHFR mRNA levels and tumour response to pemetrexed/cisplatin chemotherapy was analysed.

Results: The plasma TS and DHFR mRNA levels decreased in patients with advanced NSCLC compared with healthy controls. Moreover, plasma TS and DHFR mRNA levels negatively correlated with tumour response to pemetrexed/cisplatin chemotherapy in patients with advanced NSCLC. Overall survival time was prolonged in patients with low TS mRNA expression compared with those with high TS mRNA expression, although the difference was not statistically significant.

Conclusions: Low expression levels of plasma TS and DHFR mRNA confer increased tumour sensitivity to pemetrexed/cisplatin chemotherapy in patients with advanced NSCLC. The results suggested that plasma TS and DHFR mRNA levels are promising biomarkers for choosing patients who are likely to respond and benefit the most from pemetrexed-based chemotherapy.

Keywords: Thymidylate synthase (TS); dihydrofolate reductase (DHFR); mRNA; non-small cell lung cancer (NSCLC).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-3185). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Plasma thymidylate synthase (TS) and dihydrofolate reductase (DHFR) mRNA levels. (A) TS and (B) DHFR mRNA expression levels in plasma samples of patients with non-small cell lung cancer (NSCLC) and heathy controls (HC). Relative mRNA levels were calculated relative to β-actin. Lines inside the boxes denote the medians. **, P<0.01; ***, P<0.001. (C) Plasma TS and DHFR mRNA expression levels were significantly correlated in patients with NSCLC (R2=0.4531, P<0.0001).
Figure 2
Figure 2
Association between plasma thymidylate synthase (TS) and dihydrofolate reductase (DHFR) mRNA levels and response to pemetrexed/cisplatin chemotherapy of patients with advanced NSCLC. Tumour response assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) v.1.0. Response was defined as complete response (CR) + partial response (PR); non-response was defined as stable disease (SD) + progressive disease (PD). Lines inside the boxes denote the medians. **, P<0.01; ****, P<0.0001.
Figure 3
Figure 3
Kaplan-Meier survival curves of overall survival after pemetrexed/cisplatin chemotherapy. Median levels of (A) thymidylate synthase (TS) and (B) dihydrofolate reductase (DHFR) mRNA expressions used as the cut-off values for assigning patients into low/high mRNA groups.
See this image and copyright information in PMC

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