Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma

Our plain-English summary of Thymidylate synthase and folyl-polyglutamate synthase are not clinically useful markers of response to pemetrexed in patients with malignant pleural mesothelioma, by D.E. Lustgarten, C. Deshpande, C. Aggarwal, et al (Journal of Thoracic Oncology, 2013).

The study

• Authors: D.E. Lustgarten, C. Deshpande, C. Aggarwal, L.C. Wang, V. Saloura, A. Vachani, L.P. Wang, L. Litzky, M. Feldman, J. Creaney, A.K. Nowak, C. Langer, S. Inghilleri, G. Stella, S.M. Albelda
• Journal: Journal of Thoracic Oncology
• Published: 2013;8(4):469-77
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly.

Methods: Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death.

Results: H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77, and 0.43, respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro.

Conclusions: Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.

In plain English

This retrospective study from three centers, with added laboratory experiments, tested whether tumor levels of two enzymes, thymidylate synthase (TS) and folyl-polyglutamate synthase (FPGS), predicted response to the chemotherapy drug pemetrexed in malignant pleural mesothelioma. The authors stained tissue from 85 patients treated in Pavia, Italy; Perth, Australia; and Philadelphia. Of these, 75 received pemetrexed with a platinum drug and 10 received pemetrexed alone. The median score of each test was used as the cutoff between high and low levels. Neither TS (78 samples) nor FPGS (74 samples), nor the ratio of the two, was significantly associated with disease control, time to progression or overall survival. Scores of patients whose disease was controlled overlapped widely with scores of those whose disease progressed. In nine mesothelioma cell lines, enzyme levels did not correlate with sensitivity to the drug. The authors noted the retrospective design and missing data on stage, performance status and weight loss. They concluded that these markers lack sufficient predictive value to guide treatment decisions for individual patients without prospective studies.

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: Multicenter retrospective observational study of patient tumor samples, plus in vitro experiments on mesothelioma cell lines
• Who was studied: 85 patients with malignant pleural mesothelioma (MPM) who received front-line pemetrexed-containing chemotherapy: 69 from Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 12 from Sir Charles Gairdner Hospital, Perth, Australia; 4 from the Hospital of the University of Pennsylvania, Philadelphia. Nine human mesothelioma cell lines were also tested. No study dates are given.
• Exposure: Treatment with pemetrexed: 75 patients with a platinum agent, 10 with pemetrexed alone. Tumor TS and FPGS levels were measured by immunohistochemistry (H-score). The study did not examine asbestos exposure.
• Main results:
  • In the whole group, the disease control rate was 69%, progressive disease occurred in 31%, median time to progression was 6.8 months and median overall survival was 13 months.
  • TS (78 samples, median H-score 105): patients with disease progression and patients with disease control had extensively overlapping scores, and both groups had the same median score of 105.
  • Disease control rate did not differ between high-TS and low-TS patients (68.6% below the median, n = 35, versus 72.1% above the median, n = 43; p = 0.73).
  • Low-TS patients had numerically longer median time to progression (8 versus 6 months; p = 0.93) and overall survival (14 versus 11.25 months; p = 0.59) than high-TS patients. These differences were not statistically significant.
  • FPGS (74 samples, median H-score 120): high versus low expression was not significantly associated with time to progression (p = 0.77), overall survival (p = 0.43) or disease control rate (p = 0.95).
  • FPGS-to-TS ratio (median 1.17): patients with a high ratio had longer time to progression (7.5 versus 6 months; p = 0.10), longer overall survival (13 versus 12 months; p = 0.43) and a higher disease control rate (76.3 versus 64.9%; p = 0.27). None of these differences was statistically significant.
  • In nine mesothelioma cell lines, TS levels did not correlate with sensitivity to pemetrexed. FPGS levels also showed no correlation, but those data were not shown.
  • Nonepithelioid tumor type was associated with shorter survival (hazard ratio 3.03; 95% confidence interval 1.64 to 5.62; p less than 0.001) but not with shorter time to progression.
  • Age above 65 years was associated with shorter time to progression (p = 0.02) but not with worse survival.
• The authors' conclusion: The authors concluded that TS and FPGS lack sufficient predictive value in individual patients and should not be used to guide treatment decisions in the absence of prospective studies.
• Limitations the authors state:
  • Retrospective observational design
  • Disease stage was unavailable for most patients and could not be included in the survival analysis as a possible confounder
  • No baseline data on performance status or weight loss
  • Radiographic response and time to progression came from routine clinical care, which made them less accurate
  • Second-line therapies given after progression could have influenced overall survival
  • Statistical significance might have been reached with more patients
  • Measuring TS by immunohistochemistry is imprecise and subjective

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, Biomarker, Overall Survival, Mesothelioma.

Related studies

• 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)
• Reduced folate carrier and folylpolyglutamate synthetase, but not thymidylate synthase predict survival in pemetrexed-treated patients suffering from malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)
• Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors — A.R. Hanauske, V. Chen, et al. (2001)
• ¹⁸F-FDG uptake on PET is a predictive marker of thymidylate synthase expression in patients with thoracic neoplasms — K. Kaira, N. Yamamoto, et al. (2014)
• The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma — F. Mairinger, C. Vollbrecht, et al. (2013)

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