A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma

Our plain-English summary of A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma, by Z.G. Zimling, J.B. Sørensen, T.A. Gerds, et al (Cancer Chemotherapy and Pharmacology, 2012).

The study

• Authors: Z.G. Zimling, J.B. Sørensen, T.A. Gerds, C. Bech, C.B. Andersen, E. Santoni-Rugiu
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2012;70(5):743-54
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III β-tubulin in a cohort of MPM patients treated with cisplatin-vinorelbine. We further explored the possibility of combining markers into a treatment-response profile to increase the predictive power.

Methods: Formalin-fixed paraffin-embedded tumor specimens from 54 MPM patients included in a phase II trial were evaluated for ERCC1, BRCA1, and class III β-tubulin by immunohistochemistry (IHC). Immunostaining was quantified by an H-score and dichotomized according to upper quartile values. The ERCC1- and class III β-tubulin-status classified patients as treatment resistant (ERCC1 positive + class III β-tubulin positive) or treatment responsive (ERCC1 negative + class III β-tubulin negative). The remaining marker combinations were considered inconclusive.

Results: Fifty patients had tumor tissue available for IHC. Eleven had a responsive profile, and nine had a resistant profile. Thirty patients had an inconclusive profile. Median progression-free survival (PFS) was 6.7 months in the treatment-resistant group, 15.3 months in the treatment-responsive group, and 8.1 months in the inconclusive group (log-rank p = 0.03). Multivariate analysis revealed that treatment-resistant patients had a decreased PFS and overall survival (OS) compared with the treatment-responsive patients (HR 6.45, CI 95 % [2.02-20.64] p = 0.002 and HR 4.64, CI 95 % [1.56-13.79], p = 0.006, respectively). BRCA1 status was associated with neither PFS nor OS.

Conclusion: Combined negative ERCC1 and class III β-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.

In plain English

This study used archived tumor samples from an earlier phase II trial in Copenhagen that enrolled 54 patients with inoperable malignant pleural mesothelioma, treated with cisplatin and vinorelbine between 2003 and 2006. Tissue was available for 50 patients for class III beta-tubulin staining and 49 for BRCA1. ERCC1 results came from the authors' earlier study of the same patients. Combining ERCC1 and class III beta-tubulin, 11 patients were 'responsive' (negative for both), nine 'resistant' (positive for both) and 30 'inconclusive'. Median progression-free survival (time until worsening or death) was 6.7 months in the resistant group, 15.3 months in the responsive group and 8.1 months in the inconclusive group. After adjustment for age, sex, stage, tumor type and performance status, the resistant group had shorter progression-free survival (hazard ratio 6.45, 95% confidence interval 2.02 to 20.64) and overall survival (hazard ratio 4.64, interval 1.56 to 13.79) than the responsive group. Response-rate differences were not statistically significant. BRCA1 was not associated with survival. The authors noted that the study was small and not randomized, so the markers might mark slower-growing tumors rather than predict treatment benefit.

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: Laboratory biomarker study (immunohistochemistry) on archived tumor tissue from patients treated in an earlier single-arm, non-randomized phase II trial, with survival analysis. ERCC1 data came from the authors' earlier publication.
• Who was studied: 54 consecutive patients with inoperable malignant pleural mesothelioma enrolled in a phase II trial at the authors' institution in Copenhagen, Denmark, between 2003 and 2006. Tumor tissue was available for 50 patients for class III beta-tubulin analysis and 49 for BRCA1. Patients were 84% male, with a median age of 64 years.
• Exposure: Not asbestos. The study looked at levels of the tumor proteins ERCC1, BRCA1 and class III beta-tubulin in patients treated with vinorelbine 25 mg per square meter weekly and cisplatin 100 mg per square meter every 4 weeks. The article gives no asbestos exposure data for the patients.
• Main results:
  • Of the 50 patients with tissue, 11 had a treatment-responsive profile (ERCC1 negative and class III beta-tubulin negative), 9 had a treatment-resistant profile (both positive) and 30 had an inconclusive profile.
  • Median progression-free survival (time from start of treatment until documented progression or death from any cause) was 6.7 months (95% CI 1.9 to 6.7) in the treatment-resistant group, 15.3 months (95% CI 5.1 to 22.2) in the treatment-responsive group and 8.1 months in the inconclusive group (log-rank p = 0.03).
  • In multivariate Cox regression, treatment-resistant patients had shorter progression-free survival than treatment-responsive patients (HR 6.45, 95% CI 2.02 to 20.64, p = 0.002).
  • For overall survival, the difference between profiles was not significant in univariate analysis (log-rank p = 0.08). After adjustment for age, gender, stage, histology and performance status, treatment-resistant patients had shorter overall survival than treatment-responsive patients (HR 4.64, 95% CI 1.56 to 13.79, p = 0.006).
  • All 9 of 9 patients with a resistant profile progressed or died within the first year of treatment. This compared with 4 of 11 (36%) with a responsive profile and 21 of 30 (70%) with an inconclusive profile (Fisher's exact p = 0.008).
  • The response rate was 14% in the treatment-resistant group (1 partial response among 7 evaluable patients), 33% in the treatment-responsive group (3 of 9 evaluable) and 42% in the inconclusive group. These differences were not statistically significant.
  • BRCA1 status was not associated with overall survival (multivariate HR 0.97, 95% CI 0.49 to 1.93, p = 0.93) or with progression-free survival (log-rank p = 0.9).
  • Considered alone, class III beta-tubulin-positive patients had shorter overall survival than negative patients after adjustment (HR 2.64, 95% CI 1.24 to 5.61, p = 0.01). The difference was not significant in univariate analysis (log-rank p = 0.2), and class III beta-tubulin status was not significantly linked to progression-free survival.
• The authors' conclusion: The authors concluded that combining ERCC1 and class III beta-tubulin can identify a group of mesothelioma patients, negative for both markers, whose disease stayed stable longer on cisplatin-vinorelbine. They said this needs confirmation in larger studies.
• Limitations the authors state:
  • The study was not randomized, so the authors could not say whether the markers truly predict response to therapy or only mark slower-growing tumors.
  • The small number of patients may explain why differences in response rate were not statistically significant.
  • The H-score method used to grade staining is a research tool. Clinical use would require standardized detection and a validated cut-off point.
  • Cisplatin-vinorelbine is not the preferred first-line treatment for mesothelioma, which limits the immediate clinical applicability of the results.

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, Cisplatin, Vinorelbine, Pleural Mesothelioma, Prognosis, Immunohistochemistry, Progression-Free Survival, Multivariate Analysis.

Related studies

• 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)
• 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)
• 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)
• Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma — R. Maruyama, F. Shoji, et al. (2005)
• 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)
• Successful salvage chemotherapy with gemcitabine and vinorelbine in a malignant pleural mesothelioma patient previously treated with pemetrexed — T. Agatsuma, T. Koizumi, et al. (2010)

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