Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma
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 tar...
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| Published in | Journal of thoracic oncology Vol. 7; no. 9; pp. 1440 - 1448 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.09.2012
International Association for the Study of Lung Cancer |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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.
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).
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.
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. |
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| AbstractList | 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.
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).
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.
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. BACKGROUNDPemetrexed-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. METHODSPretreatment 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). RESULTSMedian 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. CONCLUSIONFPGS 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. 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. |
| Author | Welter, Stefan Neumann, Volker Eberhardt, Wilfried E. Tran, Cindy Schuler, Martin Christoph, Daniel C. Gauler, Thomas C. Asuncion, Bernadette Reyna Stamatis, Georgios Hirsch, Fred R. Theegarten, Dirk Lu, Xian Hepp, Rodrigo Tannapfel, Andrea Wynes, Murry W. Mascaux, Celine Wohlschlaeger, Jeremias |
| AuthorAffiliation | Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; †Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ‡Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Anschutz Medical Campus, Aurora, Colorado; §Division of Thoracic Oncology, Ruhrlandklinik, University Duisberg-Essen, Essen, Germany, ‖Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ¶Institute of Pathology, Ruhr-University Bochum, Bochum, Germany; #Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, Division of Thoracic Surgery and Endoscopy, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; and ††Department of Pathology, University of Colorado, Anschutz Medical C |
| AuthorAffiliation_xml | – name: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; †Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ‡Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Anschutz Medical Campus, Aurora, Colorado; §Division of Thoracic Oncology, Ruhrlandklinik, University Duisberg-Essen, Essen, Germany, ‖Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ¶Institute of Pathology, Ruhr-University Bochum, Bochum, Germany; #Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, Division of Thoracic Surgery and Endoscopy, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany; and ††Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – name: 4 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – name: 5 Department of Pathology and Neuropathology, University Hospital Essen, University Duisburg-Essen, Essen, Germany – name: 8 Division of Thoracic Oncology, University Duisburg-Essen, Essen Germany – name: 3 Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA – name: 9 Division of Thoracic Surgery and Endoscopy, Ruhrlandklinik, University Duisburg-Essen, Essen Germany – name: 1 Department of Medicine, Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA – name: 2 Colorado School of Public Health, Department of Biostatistics and Informatics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA – name: 7 Institute of Pathology, Ruhr-University Bochum, Bochum, Germany – name: 6 Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany |
| Author_xml | – sequence: 1 givenname: Daniel C. surname: Christoph fullname: Christoph, Daniel C. organization: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – sequence: 2 givenname: Bernadette Reyna surname: Asuncion fullname: Asuncion, Bernadette Reyna organization: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – sequence: 3 givenname: Celine surname: Mascaux fullname: Mascaux, Celine organization: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – sequence: 4 givenname: Cindy surname: Tran fullname: Tran, Cindy organization: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – sequence: 5 givenname: Xian surname: Lu fullname: Lu, Xian organization: Department of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Anschutz Medical Campus, Aurora, Colorado – sequence: 6 givenname: Murry W. surname: Wynes fullname: Wynes, Murry W. organization: Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado – sequence: 7 givenname: Thomas C. surname: Gauler fullname: Gauler, Thomas C. organization: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 8 givenname: Jeremias surname: Wohlschlaeger fullname: Wohlschlaeger, Jeremias organization: Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 9 givenname: Dirk surname: Theegarten fullname: Theegarten, Dirk organization: Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 10 givenname: Volker surname: Neumann fullname: Neumann, Volker organization: Institute of Pathology, Ruhr-University Bochum, Bochum, Germany – sequence: 11 givenname: Rodrigo surname: Hepp fullname: Hepp, Rodrigo organization: Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 12 givenname: Stefan surname: Welter fullname: Welter, Stefan organization: Division of Thoracic Surgery and Endoscopy, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany – sequence: 13 givenname: Georgios surname: Stamatis fullname: Stamatis, Georgios organization: Division of Thoracic Surgery and Endoscopy, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany – sequence: 14 givenname: Andrea surname: Tannapfel fullname: Tannapfel, Andrea organization: Institute of Pathology, Ruhr-University Bochum, Bochum, Germany – sequence: 15 givenname: Martin surname: Schuler fullname: Schuler, Martin organization: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 16 givenname: Wilfried E. surname: Eberhardt fullname: Eberhardt, Wilfried E. organization: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany – sequence: 17 givenname: Fred R. surname: Hirsch fullname: Hirsch, Fred R. email: fred.hirsch@ucdenver.edu organization: Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado |
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| Keywords | Biomarker Folylpoly-γ-glutamate synthetase Malignant pleural mesothelioma Thymidylate synthase Pemetrexed |
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| Snippet | Pemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However, there are no... BACKGROUND:Pemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However,... BACKGROUNDPemetrexed-based chemotherapy represents the standard of care in first-line treatment of advanced malignant pleural mesothelioma (MPM). However,... |
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| SubjectTerms | Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarker Carboplatin - administration & dosage Cisplatin - administration & dosage Female Follow-Up Studies Folylpoly-γ-glutamate synthetase Glutamates - administration & dosage Guanine - administration & dosage Guanine - analogs & derivatives Humans Male Malignant pleural mesothelioma Mesothelioma - drug therapy Mesothelioma - enzymology Mesothelioma - pathology Middle Aged Neoplasm Staging Pemetrexed Peptide Synthases - metabolism Pleural Neoplasms - drug therapy Pleural Neoplasms - enzymology Pleural Neoplasms - pathology Prognosis Retrospective Studies Survival Rate Thymidylate synthase Thymidylate Synthase - metabolism |
| Title | Folylpoly-Glutamate Synthetase Expression Is Associated with Tumor Response and Outcome from Pemetrexed-Based Chemotherapy in Malignant Pleural Mesothelioma |
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