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

Wang, Lei; Wang, Rui; Pan, Yunjian; Sun, Yihua; Zhang, Jie; Chen, Haiquan

doi:10.1378/chest.1832401

Cited by 6 publications

(8 citation statements)

References 41 publications

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“…Furthermore, meta-analyses have reported associations between low TS expression levels and higher objective response to TS-targeted treatments and better prognosis in patients with lung cancer (Liu et al 2013;Wang et al 2013;Wang et al 2014). In the present study, lower TS expression levels were associated with favorable prognosis in the cohort of patients treated with UFT (Table 7).…”

Section: Discussionsupporting

confidence: 56%

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Shiina

Saito

Sakaizawa

et al. 2017

Tohoku J. Exp. Med.

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Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues.

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Section: Discussionsupporting

confidence: 56%

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Shiina

Saito

Sakaizawa

et al. 2017

Tohoku J. Exp. Med.

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“…With regard to cytotoxic anticancer drugs for lung cancer, although few reliable predictors have been identified, recent meta-analyses have reported TS expression as a predictor of the sensitivity to pemetrexed-based chemotherapy in advanced NSCLC patients [17][18][19][20][21] . Similarly, polymorphisms of the TS gene have been shown to be correlated with the objective response rate in European patients with advanced NSCLC treated with pemetrexedbased regimens [25] .…”

Section: Discussionmentioning

confidence: 99%

“…Results of meta-analyses have indicated that low/ negative TS expression was associated with a significantly higher response rate and longer PFS in advanced NSCLC patients receiving pemetrexed-based chemotherapy. Accordingly, TS expression has been recognized as a potential predictor of the sensitivity to pemetrexed-based chemotherapy in patients with advanced NSCLC [17][18][19][20][21] . However, it is difficult to widely perform TS immunohistochemistry using small biopsy specimens obtained from advanced NSCLC patients in many institutions, and this test has not been applied in clinical practice.…”

Section: Smoking History As a Predictor Of Pemetrexed Monotherapy In mentioning

confidence: 99%

Smoking History as a Predictor of Pemetrexed Monotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer

Igawa¹,

Sasaki²,

Otani³

et al. 2016

Oncology

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Background: Pemetrexed monotherapy has come to be recognized as the standard of care for second-line therapy of non-squamous non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) expression is recognized as a potential predictor of the response to pemetrexed-based chemotherapy in patients with advanced NSCLC. The purpose of this study was to identify useful predictors of the response to pemetrexed other than TS expression. Methods: The records of non-squamous NSCLC patients without driver mutations who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2009 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated. Results: In the 116 patients with non-squamous NSCLC, the overall response rate and progression-free survival (PFS) were 10.3% and 2.1 months, respectively. The disease control rate and PFS differed significantly among current smokers and never-smokers/former light smokers (44.9 vs. 65.8%, and 1.8 vs. 4.0 months, respectively). Furthermore, multivariate analysis identified Eastern Cooperative Oncology Group Performance Status and smoking status as independent predictors of the PFS. Conclusion: The clinical data obtained in this study may provide a valuable basis for the use of smoking status as a predictor of pemetrexed monotherapy in wild-type NSCLC patients.

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“…These data have been corroborated by a recent meta-analysis in a total of 526 patients from the eight studies, showing that objective response rate for pemetrexed-containing chemotherapy was significantly higher in patients with TS low expression. However, although patients with low expression of TS have a longer median OS, this difference was not statistically significant [38]. These conflicting results might be due to relatively small/heterogeneous sample size, different methodologies, treatment heterogeneity, and retrospective nature of most studies.…”

Section: Pharmacogenetics Of Pemetrexedmentioning

confidence: 92%

On the pharmacogenetics of non-small cell lung cancer treatment

Santarpía

Rolfo

Peters

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/ acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches. ARTICLE HISTORY

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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

Cited by 6 publications

References 41 publications

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Smoking History as a Predictor of Pemetrexed Monotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer

On the pharmacogenetics of non-small cell lung cancer treatment

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