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

Our plain-English summary of 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, by L. Frischknecht, M. Meerang, A. Soltermann, et al (The Journal of Thoracic and Cardiovascular Surgery, 2015).

The study

• Authors: L. Frischknecht, M. Meerang, A. Soltermann, R. Stahel, H. Moch, B. Seifert, W. Weder, I. Opitz
• Journal: The Journal of Thoracic and Cardiovascular Surgery
• Published: 2015;149(6):1539-46.e1
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Survival and response to platinum-based induction chemotherapy are heterogeneous among patients with malignant pleural mesothelioma. The aim of the present study was to assess the prognostic role of DNA repair markers, such as excision repair cross-complementation group 1 and ribonucleotide reductase M1, in multimodally treated patients with malignant pleural mesothelioma.

Methods: Tumor tissue of a malignant pleural mesothelioma cohort (n = 107) treated with platinum/gemcitabine (n = 46) or platinum/pemetrexed (n = 61) induction chemotherapy followed by extrapleural pneumonectomy was assembled on a tissue microarray. Immunohistochemical expression of excision repair cross-complementation group 1 (nuclear) and ribonucleotide reductase M1 (nuclear and cytoplasmic) was assessed for its prognostic impact (association with overall survival or freedom from recurrence).

Results: Patients with high nuclear ribonucleotide reductase M1 expression before chemotherapy showed significantly longer freedom from recurrence (P = .03). When specifically analyzed in the subgroup of patients receiving platinum/gemcitabine followed by extrapleural pneumonectomy, high nuclear ribonucleotide reductase M1 was associated with prolonged freedom from recurrence (P = .03) and overall survival (P = .02). Low excision repair cross-complementation group 1 expression in prechemotherapy tumor tissues was associated with significantly longer freedom from recurrence (P = .04). Nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 were independent prognosticators of freedom from recurrence in addition to pT stage in multivariate analysis.

Conclusions: In the present study, nuclear ribonucleotide reductase M1 and excision repair cross-complementation group 1 expression were identified as independent prognosticators for freedom from recurrence of malignant pleural mesothelioma in patients undergoing induction chemotherapy followed by extrapleural pneumonectomy.

Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

In plain English

This study from University Hospital Zurich examined tumor tissue from 107 patients with malignant pleural mesothelioma treated between 1999 and 2009. All received induction chemotherapy (platinum/gemcitabine, 46 patients; platinum/pemetrexed, 61) followed by extrapleural pneumonectomy. The authors measured two DNA repair proteins, ERCC1 and RRM1, and tested whether their levels were linked with time free from recurrence and overall survival. Asbestos exposure was not studied. Among 71 patients with pre-chemotherapy samples, median freedom from recurrence was 19 months (95% CI 15-22) in the 35 with nuclear RRM1 expression and 13 months (95% CI 10-16) in the 36 without it. In the platinum/gemcitabine subgroup (32 patients), nuclear RRM1 was linked with longer freedom from recurrence and longer overall survival. No such link was seen in the platinum/pemetrexed subgroup. Low ERCC1 before chemotherapy was associated with longer freedom from recurrence. In a combined analysis, nuclear RRM1, ERCC1 and tumor (pT) stage were independent prognostic factors for freedom from recurrence. The authors concluded that nuclear RRM1 was an independent prognostic factor that needs confirming in a larger cohort. They noted small subgroups and limited tissue sampling.

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: Cohort study of archived tumor tissue: immunohistochemical staining of tissue microarrays from patients uniformly treated with induction chemotherapy and surgery, with survival analysis
• Who was studied: 107 patients with malignant pleural mesothelioma treated 1999 to 2009 at University Hospital Zurich, Switzerland: 46 received platinum/gemcitabine and 61 platinum/pemetrexed induction chemotherapy, all followed by extrapleural pneumonectomy. Patient numbers varied between analyses because some tissue spots were unusable.
• Exposure: Not an asbestos exposure study. The factors studied were tumor levels of the DNA repair proteins ERCC1 (nuclear) and RRM1 (nuclear and cytoplasmic), measured before and after platinum-based chemotherapy. Asbestos exposure is not reported.
• Main results:
  • All patients with pre-chemotherapy samples (n = 71): median freedom from recurrence was 19 months (95% CI 15-22) with nuclear RRM1 expression (n = 35) versus 13 months (95% CI 10-16) without it (n = 36); log-rank p = 0.03.
  • Platinum/gemcitabine subgroup (n = 32): with nuclear RRM1 (n = 11), median freedom from recurrence was 24 months (95% CI 6-41) versus 14 months (95% CI 8-19) without it (n = 21), p = 0.02. Median overall survival was 32 months (95% CI 13-51) versus 20 months (95% CI 16-25), p = 0.03.
  • No association was found between nuclear RRM1 and survival in the platinum/pemetrexed subgroup. Cytoplasmic RRM1 was not associated with freedom from recurrence or overall survival, and RRM1 was not associated with response to chemotherapy.
  • Low nuclear ERCC1 before chemotherapy (H-score 2.00 or below) was associated with longer freedom from recurrence (n = 87): median 16 months (95% CI 12-20) versus 15 months (95% CI 11-19) for high ERCC1; p = 0.04.
  • Multivariate analysis of freedom from recurrence: nuclear RRM1 expression versus none had a hazard ratio of 0.4 (95% CI 0.2-0.8, p = 0.005). High versus low nuclear ERCC1 had a hazard ratio of 2.2 (95% CI 1.2-4.0, p = 0.01). pT stage was also an independent prognostic factor; pT4 versus pT1 had a hazard ratio of 13.3 (95% CI 2.8-62.2).
  • In 64 paired samples, cytoplasmic RRM1 increased and nuclear RRM1 decreased significantly after induction chemotherapy. Nuclear ERCC1 did not change significantly (84 paired samples, p = 0.07).
• The authors' conclusion: The authors concluded that nuclear RRM1 was an independent prognostic factor in patients with malignant pleural mesothelioma receiving induction chemotherapy followed by extrapleural pneumonectomy. They said the finding should be validated in a larger patient cohort, and that their study supports ERCC1 as a prognostic factor in platinum-treated patients.
• Limitations the authors state:
  • The platinum/gemcitabine group was small compared with the platinum/pemetrexed group.
  • Only 2 tissue cores (before chemotherapy) and 4 cores (after chemotherapy) were sampled per patient, which may not represent protein levels in tumors that vary from area to area.
  • No prognostic significance was seen in nonepithelioid tumors, which the authors said may be due to small sample size.
  • Tumor volume was available for only a small subset of patients, so it was not included in the multivariate model (stated in the published discussion).

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: Biomarker, Pleural Mesothelioma, Chemotherapy, Gemcitabine, Pemetrexed (Alimta), Extrapleural Pneumonectomy (EPP), Overall Survival, Multivariate Analysis.

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• ¹⁸F-FDG uptake on PET could be a predictive marker of excision repair cross-complementation group 1 (ERCC1) expression in patients with thoracic neoplasms? — K. Kaira, M. Endo, et al. (2012)
• 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)
• The mesothelioma enigma — R.M. Flores (2015)
• Discussion — (2015)
• 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)

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