Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival

Our plain-English summary of Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival, by Z.G. Zimling, J.B. Sørensen, T.A. Gerds, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: Z.G. Zimling, J.B. Sørensen, T.A. Gerds, C. Bech, C.B. Andersen, E. Santoni-Rugiu
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(1):249-56
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: The relationship between excision repair cross-complementation group 1 (ERCC1) expression and outcome, in patients with malignant pleural mesothelioma (MPM), treated with cisplatin/vinorelbine combination-therapy, was retrospectively evaluated in a patient population from a previously published phase II clinical trial.

Methods: The study population consisted of 54 inoperable patients with MPM enrolled between 2003 and 2006. ERCC1 expression was evaluated by immunohistochemistry (IHC) on the formalin-fixed paraffin-embedded diagnostic biopsies. The immunoreaction was quantified using an H-score (staining intensity multiplied by a proportion score based on the percentage of stained tumor cells). The cutoff point was chosen as the median H-score in a cohort of non-neoplastic pleural samples from patients with benign thoracic diseases. The tumor samples were separated according to this cutoff point into ERCC1-negative (H-score ≤ median) and ERCC1-positive (H-score > median) cases.

Results: Fifty patients had tumor tissue available for IHC. There were 20 ERCC1-positive and 30 ERCC1-negative tumors. There was a significant correlation between negative ERCC1 status and long progression-free survival (PFS). Median PFS was 10.9 months in the ERCC1-negative group, opposed to 6.7 months in the ERCC1-positive group (p = 0.053). Multivariate Cox regression showed ERCC1 to be the only variable significantly associated with PFS, and ERCC1-positive patients had a significantly shorter time to progression compared with ERCC1-negative patients (hazard ratios, 2.24; 95% confidence interval, 1.16-4.34; p = 0.0163). We found no association between ERCC1 status and overall survival.

Conclusion: Our retrospective study in MPM patients treated with cisplatin/vinorelbine suggests that low ERCC1 expression, evaluated by IHC, may predict longer PFS, a result that warrants further validation.

In plain English

This Danish study looked back at 50 patients with inoperable malignant pleural mesothelioma. They had been treated with cisplatin and vinorelbine in an earlier phase II trial. Asbestos exposure was not studied. The authors stained the patients' diagnostic biopsies for ERCC1, a DNA-repair protein. The cutoff was the median score in 34 non-cancerous pleural samples. By that cutoff, 20 tumors were ERCC1-positive and 30 were ERCC1-negative. Median progression-free survival was 10.9 months in the ERCC1-negative group and 6.7 months in the ERCC1-positive group (p = 0.053). In an analysis that also took age, gender, histology, performance status and stage into account, ERCC1-positive patients had a significantly shorter time to progression or death (hazard ratio 2.24; 95% CI 1.16 to 4.34). ERCC1 status was not significantly linked to overall survival or response rate. The authors concluded that low ERCC1 may predict longer progression-free survival with cisplatin-based chemotherapy, but that this needs confirmation. They noted the study was not originally designed for this question. They also noted that 44% of patients later received pemetrexed, which might have obscured effects on overall survival.

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 analysis of archived diagnostic biopsies from patients in a previously published, uniformly treated phase II clinical trial
• Who was studied: 54 consecutive inoperable patients with malignant pleural mesothelioma were enrolled February 2003 to September 2006 at a Copenhagen hospital. Tumor tissue was available for 50 of them, with biopsies obtained from pathology departments throughout Denmark. A comparison group of 34 non-neoplastic pleural samples came from patients with relapsing pneumothorax or cystic fibrosis.
• Exposure: No asbestos exposure was studied. The factor studied was tumor ERCC1 protein expression, measured by immunohistochemistry (H-score), in patients treated with cisplatin plus vinorelbine.
• Main results:
  • The cutoff was the median H-score of 2 in the non-neoplastic pleural samples. Using it, the 50 tumors split into 20 ERCC1-positive and 30 ERCC1-negative.
  • Median progression-free survival was 10.9 months (95% CI, 5.6 to 16.7) in the ERCC1-negative group and 6.7 months (95% CI, 4.4 to 7.2) in the ERCC1-positive group (p = 0.053).
  • In multivariate Cox regression adjusting for age, gender, histology, performance status and stage, ERCC1-positive patients had a significantly shorter time to progression or death than ERCC1-negative patients (HR 2.24; 95% CI, 1.16 to 4.34; p = 0.0163). The other factors were not significant.
  • Overall survival did not differ significantly by ERCC1 status (HR 1.29; 95% CI, 0.7 to 2.36; p = 0.4). Median overall survival was 16.5 months in ERCC1-negative and 17.4 months in ERCC1-positive patients, and 16.8 months overall.
  • The overall response rate was 35.7%, with no significant difference by ERCC1 status (p = 0.7).
  • Performance status was significantly associated with overall survival (HR 2.15; 95% CI, 1.04 to 4.42).
  • As a predictor of progression, ERCC1 status had sensitivity below 50% throughout the study period. Its specificity was high during the first 3 years.
• The authors' conclusion: The authors concluded that low ERCC1 expression may predict longer progression-free survival in inoperable mesothelioma patients treated with cisplatin-based chemotherapy. They said these results should be further validated to confirm them or refute them as false positive.
• Limitations the authors state:
  • The original trial was not designed to address whether this marker is useful for guiding treatment decisions.
  • 44% of patients received second-line pemetrexed after progression, which might have affected overall survival and obscured any effect of ERCC1 on it.
  • Immunohistochemistry scoring is subject to variability between observers and laboratories. The scoring method also differed slightly from that of earlier mesothelioma studies.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Vinorelbine, Progression-Free Survival, Clinical Trial, Immunohistochemistry, Hazard Ratio, confidence interval.

Related studies

• A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma — Z.G. Zimling, J.B. Sørensen, et al. (2012)
• 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)
• 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)
• 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)
• Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052) — M.E. O'Brien, R.M. Gaafar, et al. (2013)

Browse more research in Journal of Thoracic Oncology, or return to medical research.