ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma

Our plain-English summary of ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma, by S. Ting, F.D. Mairinger, T. Hager, et al (Clinical Lung Cancer, 2013).

The study

• Authors: S. Ting, F.D. Mairinger, T. Hager, S. Welter, W.E. Eberhardt, J. Wohlschlaeger, K.W. Schmid, D.C. Christoph
• Journal: Clinical Lung Cancer
• Published: 2013;14(5):558-567.e3
• Cited by: 39 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Platinum-based chemotherapy is besides the standard antifolate therapy with pemetrexed, the cornerstone for treatment of patients with malignant pleural mesothelioma (MPM), and its efficacy depends on several DNA repair enzymes. Therefore, these enzymes could be biomarkers for "tailoring" chemotherapy. This study evaluated enzymes involved in repair of platinum-caused DNA damage, potentially resulting in a biomarker panel associated with patient response and outcome to platinum-based chemotherapy.

Material And Methods: Pre- or posttreatment specimens from a total of 103 patients with MPM who were undergoing first-line chemotherapy were tested separately. Immunohistochemistry for ERCC1 (endonuclease excision repair cross-complementing 1), MLH1 (MutL homologue 1), MutS homologue (MSH) 2, MSH6, and βIII-tubulin protein expression, and pyrosequencing for ERCC1 codon 118 and C8092A polymorphisms were performed, and their results were correlated to clinicopathologic data.

Results: ERCC1, MLH1, MSH2, MSH6, and βIII-tubulin were expressed in human MPM specimens at different intensities. When considering only pretreatment specimens, MSH6 protein levels were correlated to progression during chemotherapy (P = .0281). MLH1 protein levels (P = .0205), and ERCC1 codon 118 polymorphisms (P ≤ .0001) were significantly associated with progression-free survival. A significant association between ERCC1 protein levels and overall survival was noted (P = .032). Analyses of posttreatment specimens revealed significant associations between βIII-tubulin protein levels and progression-free survival (P = .0066). ERCC1 C8092A polymorphisms were significantly associated with progression-free survival and overall survival (P = .0463 and P = .0080, respectively) in this group.

Conclusions: Enzymes involved in DNA repair mechanisms are associated with patient response and outcome to platinum-based chemotherapy. Their assessment may be a helpful tool to tailor platinum-based chemotherapy of MPM patients who might expect the largest clinical benefit. Prospective validation of this biomarker panel is warranted.

Copyright © 2013 Elsevier Inc. All rights reserved.

In plain English

This retrospective study examined tumor samples from patients with advanced malignant pleural mesothelioma who received first-line chemotherapy at the West German Cancer Center between 2003 and 2010. It did not report on asbestos exposure. Of 103 patients, usable samples taken before treatment were available for 79 and samples taken after treatment for 41. The authors measured five DNA-repair or resistance proteins (ERCC1, MLH1, MSH2, MSH6 and beta-III tubulin) and two ERCC1 gene variants, and compared them with outcomes of platinum-based chemotherapy. In pretreatment samples, MSH6 levels were related to disease progression during chemotherapy, lower MLH1 levels were associated with longer progression-free survival, higher ERCC1 levels with worse overall survival, and the ERCC1 codon 118 variant with progression-free survival. In posttreatment samples, higher beta-III tubulin levels were associated with shorter progression-free survival, and the ERCC1 C8092A variant with both progression-free and overall survival. The authors noted that the study lacked a comparison group of patients not given platinum chemotherapy. They concluded that the results should be confirmed by independent 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 archived tumor specimens, with protein staining (immunohistochemistry) and gene-variant testing (pyrosequencing), plus preliminary testing in mesothelioma cell lines
• Who was studied: 103 patients with advanced malignant pleural mesothelioma (16 women, 87 men; median age 67). Adequate pretreatment specimens were available from 79 patients and posttreatment specimens from 41. These two groups were analyzed separately.
• Exposure: No asbestos exposure is reported. The treatment studied was first-line chemotherapy, given at the West German Cancer Center between 2003 and 2010. Outcomes were analyzed for platinum-based chemotherapy; the 4 patients without platinum-based chemotherapy were excluded from the response and survival analyses.
• Main results:
  • Pretreatment group: MSH6 protein levels correlated with progression during platinum-based chemotherapy (P = .0281). This was the only significant correlation with response in this group.
  • Pretreatment group: lower MLH1 protein levels were significantly associated with prolonged progression-free survival (hazard ratio 1.248, P = .0205).
  • ERCC1 protein levels were significantly associated with overall survival in the pretreatment group: higher levels went with worse survival (HR 1.122, P = .032). The association was not found in the posttreatment group (P = .8248).
  • Pretreatment group: ERCC1 codon 118 variants were associated with progression-free survival (P = .0002 comparing the three genotypes). The C/C genotype was associated with shortened progression-free survival (HR 9.453, P = .0001).
  • Posttreatment group: higher beta-III tubulin protein levels were associated with reduced progression-free survival (P = .0066; HR printed as 0.671).
  • Posttreatment group: ERCC1 C8092A variants were significantly associated with worse progression-free survival (P = .0463). The A/A genotype had the shortest progression-free survival (HR 6.341, P = .0140).
  • Posttreatment group: ERCC1 C8092A variants were also associated with overall survival (P = .0080).
  • The authors reported that levels of the DNA-repair enzymes correlated with one another; for example, ERCC1 and MSH2 in the posttreatment group (r = 0.7757, P < .0001).
  • No association was found between the ERCC1 gene variants and ERCC1 protein levels in either group.
• The authors' conclusion: The authors concluded that ERCC1 variants and MLH1 levels were associated with progression-free survival, ERCC1 protein levels with overall survival, and MSH6 levels with progression. They also concluded that currently available antibodies do not discriminate well enough to guide decisions on platinum treatment, and that the results should be confirmed by independent prospective studies focusing on ERCC1 variants.
• Limitations the authors state:
  • Response and survival data came from a retrospective review of medical records and images, not a prospective clinical trial.
  • Progression-free survival is a weak endpoint that can be affected by assessment schedules.
  • Only protein staining was used; mRNA levels were not analyzed because not enough tissue remained.
  • There is debate over whether the ERCC1 antibody (clone 8F1) binds only ERCC1.
  • There was no control group of patients who did not receive platinum-based chemotherapy, and the cohort was not homogeneously treated.
  • Small numbers in some subgroups, such as the non-epithelioid subtype, limited further statistical analysis.

Topics

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

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Antifolate, Pemetrexed (Alimta), Biomarker, Immunohistochemistry, Progression-Free Survival, Overall Survival.

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)
• 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)
• Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• 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)
• Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients — S. Cedrés, S. Ponce-Aix, et al. (2020)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)

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