Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma

Our plain-English summary of Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma, by F. Mairinger, C. Vollbrecht, I. Halbwedl, et al (Journal of Thoracic Oncology, 2013).

The study

• Authors: F. Mairinger, C. Vollbrecht, I. Halbwedl, M. Hatz, E. Stacher, C. Gülly, F. Quehenberger, S. Stephan-Falkenau, J. Kollmeier, A. Roth, T. Mairinger, H. Popper
• Journal: Journal of Thoracic Oncology
• Published: 2013;8(5):644-53
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma is a highly aggressive tumor arising from mesothelial-lined surfaces, most often in the pleura cavities. Antifolates belong to the most effective cytotoxic drugs for malignant pleural mesothelioma (MPM) treatment. Pemetrexed is an antifolate inhibiting different folate pathway genes (thymidylate synthase [TS], dihydrofolate reductase, glycinamide ribonucleotide formyltransferase [GARFT], and aminoimidazole carboxamide ribonucleotide formyltransferase, [AICARFT]). Increased activity of pemetrexed occurs by folylpolyglutamate synthetase (FPGS), intracellular transport by reduced folate carrier (RFC). The aim of the study was to explore potential correlations between TS, GARFT, AICARFT, RFC, and FPGS levels in MPM and associations with clinical benefit from pemetrexed treatment.

Methods: Samples from 63 patients were tested using immunohistochemistry (IHC) and quantitative polymerase chain reaction(qPCR) for expression levels of TS, GARFT, AICARFT, RFC, and FPGS. Clinical data were evaluated to determine associations between efficacy of pemetrexed and enzyme expression levels. Evaluation of expression levels was done through TaqMan-based qPCR, and IHC was evaluated semiquantitatively by using the H-score.

Results: qPCR analysis showed no difference in expression pattern of GARFT and AICARFT. IHC analysis revealed a heterogeneous staining pattern for all the enzymes. No significant association was found between TS expression and survival or objective response of the tumors after pemetrexed treatment. FPGS (p = 0.0111) and RFC (p = 0.0088) mRNA expression levels were strongly associated with overall survival in these patients.

Conclusions: Our results reveal that in pemetrexed-treated MPMs TS expression levels have no influence on patient outcome. Furthermore, GARFT and AICARFT were homogeneously expressed in the patient samples. Folate uptake mechanisms by RFC and activation by FPGS were associated with clinical benefit from pemetrexed treatment.

In plain English

This study used archived tumor samples from 63 patients with malignant pleural mesothelioma treated with the chemotherapy drug pemetrexed, alone or with platinum drugs, at a hospital in Berlin, Germany. The samples dated from 2002 to 2009. The authors measured five enzymes or carrier proteins linked to how pemetrexed works (TS, GARFT, AICARFT, RFC and FPGS), both as gene activity and as protein staining. They then compared these levels with survival and tumor response. Survival data were available for 58 patients, and median survival was 16.2 months. TS levels were not significantly associated with survival. Gene activity of FPGS (p = 0.011) and RFC (p = 0.0088) was significantly associated with overall survival. No significant association was found between FPGS, RFC or TS and tumor response. Only GARFT protein showed a significant but weak correlation with response. The authors concluded that TS and other folate-pathway enzymes had no critical influence on benefit from pemetrexed. They noted that disease stage and progression-free survival could not be studied, and that only patients collected after 2007 received standardized first-line pemetrexed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory analysis of archived tumor samples (gene-expression testing by qPCR and protein staining by immunohistochemistry) linked to patients' clinical outcomes; the authors describe it as retrospective
• Who was studied: 63 patients with malignant pleural mesothelioma (46 men, 12 women, 5 of unknown sex) from the mesothelioma database of the Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany; samples from 2002 to 2009; survival data available for 58 patients
• Exposure: Treatment with pemetrexed, alone or with platinum compounds; the study measured tumor levels of TS, GARFT, AICARFT, RFC and FPGS. Asbestos exposure was not studied.
• Main results:
  • Among the 58 patients with survival data, median survival was 16.2 months
  • TS gene expression was not significantly associated with survival on either a linear scale (p = 0.6611) or a logarithmic scale (p = 0.3187); TS protein staining was also not significantly associated with survival (linear p = 0.1199; logarithmic p = 0.0804)
  • Gene expression levels of FPGS and RFC were significantly associated with overall survival time (FPGS p = 0.011; RFC p = 0.0088)
  • No significant association was found between FPGS, RFC or TS and objective tumor response to pemetrexed-based therapy (FPGS p = 0.0834; RFC p = 0.1393; TS p = 0.5919); the authors wrote that these markers 'do not seem to be associated' with response
  • Only GARFT protein expression showed a significant but weak correlation with response (p = 0.0382)
  • GARFT and AICARFT gene expression was consistently low across samples, with no difference detected
• The authors' conclusion: The authors concluded that TS levels and levels of the other folate-pathway enzymes had no critical influence on clinical benefit from pemetrexed. They also concluded that the transport and activation enzymes FPGS and RFC seem to be associated with improved survival time.
• Limitations the authors state:
  • Because of sample age and lack of clinical documentation, the link between expression levels and disease stage (IMIG stage) could not be examined
  • Exact dates of tumor progression were unavailable, so progression-free survival could not be calculated
  • Only patients collected after 2007 had standardized first-line pemetrexed; the others received it as second- or third-line therapy
  • Protein staining was scored by eye rather than by an automated method, which the authors say leads to high variation between and within observers

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Mesothelioma, Pleura, Antifolate, Immunohistochemistry, Overall Survival.

Related studies

• Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma — D.E. Lustgarten, C. Deshpande, et al. (2013)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• New tricks for old biomarkers: thymidylate synthase expression as a predictor of pemetrexed activity in malignant mesothelioma — P.A. Zucali, E. Giovannetti, et al. (2010)
• Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma — D.C. Christoph, B.R. Asuncion, et al. (2012)
• Survey and biological insights of pemetrexed-related therapeutic improvement in mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort — F. Vlastos, G. Hillas, et al. (2009)
• Adaptation of a chemosensitivity assay to accurately assess pemetrexed in ex vivo cultures of lung cancer — S.L. Suchy, R.J. Landreneau, et al. (2013)

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