Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma

Our plain-English summary of Folylpoly-glutamate synthetase expression is associated with tumor response and outcome from pemetrexed-based chemotherapy in malignant pleural mesothelioma, by D.C. Christoph, B.R. Asuncion, C. Mascaux, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: D.C. Christoph, B.R. Asuncion, C. Mascaux, C. Tran, X. Lu, M.W. Wynes, T.C. Gauler, J. Wohlschlaeger, D. Theegarten, V. Neumann, R. Hepp, S. Welter, G. Stamatis, A. Tannapfel, M. Schuler, W.E. Eberhardt, F.R. Hirsch
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(9):1440-8
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However, there are no established predictors of clinical benefit. Pemetrexed inhibits multiple enzymes involved in pyrimidine and purine synthesis, but the main target is thymidylate synthase (TS). After cellular uptake pemetrexed is converted into more effective polyglutamated forms by folylpoly-γ-glutamate synthetase (FPGS). We hypothesized that FPGS and TS protein expressions are associated with clinical outcome after pemetrexed-based chemotherapy.

Methods: Pretreatment tumor samples from 84 patients with histologically confirmed MPM, who received pemetrexed combined with platinum (79 of 84) or single-agent pemetrexed (5 of 84) as first-line treatment, were retrospectively analyzed. FPGS and TS protein expressions were semiquantitatively assessed by using the Hybrid (H)-scoring system (range, 0-300). H-scores were correlated with radiological response according to modified Response Evaluation Criteria in Solid Tumors, progression-free survival (PFS) and overall survival (OS).

Results: Median H-score of the entire cohort was 230 for FPGS (range, 100-300), and 210 for TS (range, 100-300). High FPGS protein expression was significantly associated with longer PFS (pCOX = 0.0337), better objective tumor response (partial response versus stable disease + progressive disease; pKW = 0.003), and improved disease-control rate (partial response + stable disease versus progressive disease; pKW = 0.0208), but not with OS. In addition, high TS protein expression was associated with progressive disease under pemetrexed-based therapy (p = 0.0383), and shorter OS (pCOX = 0.0071), but no association with PFS was observed.

Conclusion: FPGS and TS expressions were associated with clinical response and outcome to pemetrexed-based first-line chemotherapy in MPM. Prospective evaluation of FPGS and TS expressions and their prognostic/predictive power in MPM patients is warranted.

In plain English

This retrospective study examined tumor biopsies taken before treatment from 84 patients with malignant pleural mesothelioma. All received pemetrexed-based chemotherapy as first-line treatment at the West German Cancer Center in Essen, Germany, between 2003 and 2010. Most received pemetrexed with cisplatin, carboplatin or both, and 5 received pemetrexed alone. The article does not discuss asbestos exposure. The authors stained the tumors for two proteins, FPGS and TS, scored each on a 0 to 300 scale (TS could be scored in 79 cases), and compared the scores with tumor response and survival. Higher FPGS was associated with tumor shrinkage and with disease control. Patients with high FPGS had longer median progression-free survival than those with low FPGS (9.1 versus 6.1 months), but FPGS was not significantly linked to overall survival. Higher TS was associated with disease progression during treatment and with shorter overall survival (median 20.8 versus 28.8 months), but not with progression-free survival. The authors described their results as exploratory and hypothesis-generating, needing confirmation in larger, 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: Retrospective study of tumor protein markers (immunohistochemistry) in relation to chemotherapy response and survival; it also included laboratory staining of mesothelioma cell lines
• Who was studied: 84 patients with advanced malignant pleural mesothelioma (70 men, 14 women; median age 67) treated at the West German Cancer Center, Essen, Germany, 2003 to 2010, out of 104 patients whose samples were reviewed; 27 also had samples taken after treatment
• Exposure: No asbestos exposure is reported. What was studied was first-line pemetrexed-based chemotherapy: pemetrexed plus cisplatin (66), plus carboplatin (10), plus cisplatin switched to carboplatin (3), or pemetrexed alone (5)
• Main results:
  • Median pretreatment scores in the whole cohort were 230 for FPGS (range 100 to 300) and 210 for TS (range 100 to 300)
  • FPGS scores were higher in patients with partial response (n = 36; mean 248, median 255) than in non-responders (n = 45; mean 221, median 220), p = 0.0030
  • FPGS scores were higher in patients with disease control (n = 72; median 240) than in those with progressive disease (n = 9; mean 209, median 200), p = 0.0208
  • High FPGS expressors had longer median progression-free survival than low expressors (9.1 versus 6.1 months, p = 0.0233, univariate)
  • Adjusted for IMIG stage and sex, each 30-unit increase in FPGS score had a hazard ratio for progression of 0.773 (95% CI 0.618 to 0.970), pCOX = 0.0337
  • FPGS expression was not significantly associated with overall survival (p = 0.7043, univariate)
  • High TS expression was associated with progressive disease during chemotherapy and with shorter median overall survival (20.8 versus 28.8 months)
  • Adjusted for IMIG stage and sex, each 30-unit increase in TS score had a hazard ratio for death of 1.386 (95% CI 1.093 to 1.762), pCOX = 0.0071
  • TS expression was not significantly associated with progression-free survival (p = 0.1412)
  • In the 27 patients with samples before and after treatment, FPGS scores before and after were moderately correlated (r = 0.537, p = 0.0039)
• The authors' conclusion: The authors concluded that in these patients high FPGS expression was associated with better objective response, disease control and progression-free survival, but not with longer overall survival, and that TS expression was associated with disease control and overall survival
• Limitations the authors state:
  • Because the study was retrospective, all p values and test results should be regarded as exploratory
  • The study generates hypotheses, and its findings need validation in a larger cohort and in prospective studies
  • Only immunohistochemistry was used to measure FPGS and TS
  • Glutamyl hydrolase, an enzyme that may also affect pemetrexed resistance, was not measured
  • There was no control group of patients who did not receive pemetrexed, and the patients were not treated uniformly
  • Small subgroup sizes limited further analyses, including of the 5 patients given pemetrexed alone
  • ERCC1, an enzyme involved in resistance to cisplatin and carboplatin, was not analyzed
  • Progression-free survival is a weak endpoint that can be affected by assessment schedules

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), Chemotherapy, Pleural Mesothelioma, Modified RECIST (mRECIST), Progression-Free Survival, 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)
• ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma — S. Ting, F.D. Mairinger, et al. (2013)
• Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients — T. Powrózek, D.M. Kowalski, 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)
• 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)
• Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma — K. Hollevoet, K. Nackaerts, et al. (2011)

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