The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma

Our plain-English summary of The issue of studies evaluating biomarkers which predict outcome after pemetrexed-based chemotherapy in malignant pleural mesothelioma, by F. Mairinger, C. Vollbrecht, T. Mairinger, et al (Journal of Thoracic Oncology, 2013).

The study

• Authors: F. Mairinger, C. Vollbrecht, T. Mairinger, H. Popper
• Journal: Journal of Thoracic Oncology
• Published: 2013;8(8):e80-2
• Type of article: Letter, Comment
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Summary of the article

This letter was the authors' reply to a letter by Giovannetti, Peters and Zucali criticizing the authors' earlier study of folate pathway markers as predictors of survival after pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM). The authors noted that Zucali and colleagues' own study of 99 MPM patients treated with carboplatin and pemetrexed had examined only thymidylate synthase (TS) and ERCC1, and that earlier studies had reported either a correlation between TS and pemetrexed response or none. They stated that some previous studies had immunohistochemical sections evaluated by inexperienced researchers rather than pathologists. They agreed that the whole thymidylate pathway must be investigated and that a multi-institutional prospective trial was probably needed. On FPGS, they wrote that no validated antibodies against splice variants were available for formalin-fixed paraffin-embedded tissue, so they chose polyclonal antibodies expected to detect several isoforms, and their mRNA assay covered both known physiological isoforms. They described their validation: immunohistochemistry on whole-tissue sections and tissue microarrays with negative and positive controls, and quantitative PCR following MIQE guidelines with two reference genes, controls, small amplicons and exon-spanning assays. They agreed that drug metabolites and uptake mechanisms should be studied. They argued that repeat biopsies for research were uncommon and would not be approved, and said they had used at least three tissue cores per tumor to address heterogeneity.

PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

In plain English

This is a letter to the editor, not a new study. The authors replied to criticism from another research group (Zucali and colleagues) of the authors' earlier article on markers that might predict how patients with malignant pleural mesothelioma respond to pemetrexed chemotherapy. The authors noted that the critics' own study had examined only two markers, TS and ERCC1. They wrote that results from studies in which inexperienced researchers scored stained tissue should be viewed with caution. They explained that they had used polyclonal antibodies to pick up at least some FPGS splice variants. They said their tissue staining was checked using normal lung tissue as a negative control and lung squamous cell carcinomas as positive controls. Their mRNA tests followed the MIQE guidelines, used two reference genes and control samples, and measured short stretches of 75 to 100 base pairs. They argued that repeat biopsies for research would not be approved by ethics committees, and said they had taken at least three cores from each tumor. They suggested that total FPGS protein levels might be a suitable marker. Asbestos was not discussed.

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: Letter to the editor: the original authors' reply to a critical letter about their earlier study. No new data were presented.
• Who was studied: No new patients. The letter defends the authors' earlier study of predictors of pemetrexed response in malignant pleural mesothelioma.
• Exposure: Pemetrexed-based chemotherapy and tissue markers (TS, FPGS) thought to predict response to it. Asbestos exposure is not discussed.
• Main results:
  • The authors stated that the critics' own study investigated only TS and ERCC1.
  • The authors wrote that studies in which inexperienced researchers evaluated the stained sections should raise caution.
  • The authors chose polyclonal antibodies to detect at least some FPGS splice variants. They noted that only two physiological splice variants are known.
  • Immunohistochemical staining was checked using normal lung tissue as a negative control and lung squamous cell carcinomas with known TS and FPGS overexpression as positive controls.
  • The qPCR analyses of mRNA followed the MIQE guidelines and included two reference genes, positive controls and nontemplate controls.
  • The qPCR analyses used small amplicons of 75 to 100 base pairs to deal with mRNA degradation in archived tissue.
  • The authors' FPGS assay covered both known physiological isoforms.
  • The authors argued that repeat biopsies for research purposes alone would not be approved by an ethics committee.
  • To address variation within a tumor, the authors used a tissue microarray with at least three cores per tumor.
• The authors' conclusion: The authors suggested that total FPGS protein levels might be an appropriate marker for predicting response or resistance to pemetrexed-based chemotherapy in malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors acknowledged that mRNA levels can differ from protein levels, especially for enzymes such as FPGS that undergo extensive mRNA splicing.

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Pemetrexed (Alimta), Chemotherapy, Pleural Mesothelioma, Carboplatin, Immunohistochemistry.

Related studies

• 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)
• 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)
• Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery — L. Frischknecht, M. Meerang, et al. (2015)
• 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)
• 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)

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