The studies about relationship between TYMS expression and effect of pemetrexed-based chemotherapy were comparatively few, and reports about prognostic significance of TYMS expression in advanced NSCLC non-small cell lung cancer are controversial. So it is necessary to combine and analyze these data to find a result. Our purpose was to prove the hypothesis that low TYMS expression is associated with higher response rate and longer survival in advanced NSCLC non-small cell lung cancer patients. Our study may provide a theoretical evidence for individualized chemotherapy in advanced NSCLC and supports the use of detecting lung cancer tissue for TYMS expression to help us chose chemotherapy regimens.
To our knowledge there is no published meta-analysis about the predictive value of TYMS expression for pemetrexed-based chemotherapy in NSCLC patients. In this meta-analysis 11 studies were included, and they were most retrospective studies. TYMS expression was detected by immunohistochemistry and RT-PCR. Six of included studies compared the response rate between two groups. Nine studies reported the PFS and were included in analysis. Eight studies compared the OS but only six studies reported enough data to carry out the analysis. No study reported treatment related adverse effect between groups. This meta-analysis included a total of 798 cases of patients and demonstrated that the response rate was significantly higher and median survival (PFS and OS) were significantly longer in patients with low/negative TYMS expression.
Most of the included studies used IHC to detest the TYMS expression, while only two studies used RT-PCR. IHC and RT-PCR detects TYMS expression at protein level and mRNA level respectively. We all know that the expression of TYMS protein may influenced by many factors during several step, such as transcription, post-transcriptional regulation, translation and post-translation modification. The mRNA expression may be quite different from protein expression. In our meta-analysis one study published by Shimizu T compared the IHC and RT-PCR method in the detection effect of TYMS expression and reported that there was a significant correlation between the two detection methods [26
]. However, most studies utilized IHC to detect the TYMS expression. Our analysis showed that TYMS expression detected by both IHC and RT-PCR was associated with higher response rate, longer PFS and longer OS. According to the results and available evidence, IHC is more preferable than RT-PCR when used to predict the sensitivity of pemetrexed-based regimens in patients with advanced NSCLC. Furthermore, the TYMS staining within the tumors varies a lot among studies and there’s lack of a standardized scoring system in NSCLC. These reasons may contribute to the heterogeneity. The reported TYMS positivity rate ranges from 29.6% to 72.5% [34
This study has several other limitations. Heterogeneity is a potential problem to affect the results. We didn’t observed significant heterogeneity among studies in the analysis of response rate and PFS, but in OS analysis and subgroup analysis significant heterogeneity was observed among the studies of IHC subgroup. Many factors might cause significant heterogeneity, such as different stage, previous treatments, pathological subtype, treatment regimens, treatment cycles and performance status. Most study included the patients with stage III/IV while one study included relapsed patients. The relapsed patients may have longer survival than the advanced patients. The concurrent treatment regimens (radiotherapy, chemotherapy) and previous treatment (surgery, radiotherapy or chemotherapy) will influence the response rate and survival outcome a lot. What’s more, the combined treatment, especially with radiotherapy, will be more attend to achieve better response rate than single agent pemetrexed therapy.
Besides, another contributing factor might be ethnic differences, which may also affect the result. Most included studies were from Asia, and two studies were performed in Caucasian (). So, based on data from two retrospective studies, the result was not very representative and convincing in Caucasian patients until more evidence exists. Publication bias is also a possible limitation. However, in our study we didn’t find significant publication bias that might influence the result of meta-analysis.
In conclusion, despite the limitations of this meta-analysis, our study still demonstrated that low/negative TYMS expression was significantly associated with higher response rate, longer median overall survival and longer progression free survival for advanced NSCLC patients receiving pemtrexed-containing chemotherapy. Hence, TYMS may be a potential predictor of sensitivity to pemtrexed-based chemotherapy in advanced NSCLC. However, nearly all of the available information regarding the predictive value of TYMS was derived from retrospective studies. Large scale prospective clinical trials are still warranted to validate the prospective utility of TYMS in clinical decision making and appropriate marker evaluation methodology.