Plasma Biomarker Enrichment of Clinical Prognostic Indices in Malignant Pleural Mesothelioma

Our plain-English summary of Plasma Biomarker Enrichment of Clinical Prognostic Indices in Malignant Pleural Mesothelioma, by H.I. Pass, C. Goparaju, O. Espin-Garcia, et al (Journal of Thoracic Oncology, 2016).

The study

• Authors: H.I. Pass, C. Goparaju, O. Espin-Garcia, J. Donington, M. Carbone, D. Patel, Z. Chen, R. Feld, J. Cho, S. Gadgeel, A. Wozniak, A. Chachoua, N. Leighl, M.S. Tsao, M. de Perrot, W. Xu, G. Liu
• Journal: Journal of Thoracic Oncology
• Published: 2016;11(6):900-9
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: Prognostic models for malignant pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 patients with MPM improved.

Methods: Individuals were recruited from three different centers: a discovery cohort (83 patients with MPM) created by combining patients from two U.S. centers and a separate, independent cohort from Canada (111 patients with MPM). Univariable and multivariable analyses were performed on the initial discovery and independent cohorts separately. In the multivariable analyses, prognostic factors were adjusted for the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (PI) of mesothelioma. The prognostic significance of adding plasma biomarker data to the PI was determined by using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell's C-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI.

Results: Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell's C-statistic. In the final prognostic model, log-osteopontin, EORTC clinical prognostic index, and hemoglobin remained as independently significant predictors and the entire prognostic model improved the optimism-corrected Harrell's C-index significantly, from 0.718 (0.67-0.77) to 0.801 (0.77-0.84).

Conclusions: These data suggest a possible role for preoperative plasma biomarkers to improve the prognostic capability of the EORTC PI of MPM.

Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This study asked whether blood tests could improve survival prediction in malignant pleural mesothelioma beyond an existing score, the EORTC prognostic index. The authors tested pre-treatment plasma from 83 patients at two US centers (discovery group) and 111 at a Canadian center (separate group). They measured osteopontin, mesothelin and fibulin-3. In the discovery group, higher osteopontin and mesothelin, but not fibulin-3, were each linked to worse survival after accounting for the index. In the Canadian group, adding either marker to the index significantly improved prediction. There, adding osteopontin to the EORTC index raised the c-index, which measures how well a model ranks patients by outlook, from 0.596 (95% CI 0.55-0.64) to 0.811 (0.76-0.86). In a combined model of 154 patients, osteopontin, the EORTC index and hemoglobin remained significant predictors. Adding both osteopontin and mesothelin to this model raised its optimism-corrected c-index from 0.718 (0.67-0.77) to 0.801 (0.77-0.84). The authors concluded that pre-treatment plasma biomarkers have a possible role in improving the index. They noted that the combined model lacked external validation and that treatments differed between centers. The study did not examine asbestos exposure.

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 patients recruited prospectively at diagnosis at three centers, with a discovery cohort and a separate, blinded validation cohort, followed by a pooled prognostic model
• Who was studied: 194 patients with malignant pleural mesothelioma. Discovery cohort of 83: 44 from NYU Langone Medical Center, New York (treated 2007 to 2012) and 39 from Karmanos Cancer Institute, Detroit (treated 1998 to 2006). Independent cohort of 111 from Princess Margaret Cancer Centre, Toronto (treated 2004 to 2012). The pooled model used 154 patients with complete data.
• Exposure: Not an asbestos exposure study. The factors studied were plasma levels of osteopontin, mesothelin and fibulin-3, measured before therapy, alongside the EORTC and CALGB clinical prognostic indices and laboratory values.
• Main results:
  • In the discovery (NYU/KCI) cohort, higher log-osteopontin and log-mesothelin, but not fibulin-3, were each associated with worse prognosis after adjusting for the clinical prognostic indices.
  • In the discovery cohort, adjusted for the EORTC index, the hazard ratio for log-osteopontin was 2.70 (95% CI 1.8-4.0). The hazard ratio for log-mesothelin was 1.94 (1.4-2.8).
  • In the independent PMCC cohort, adding either log-osteopontin or log-mesothelin to the clinical index significantly improved the c-statistic. With the EORTC index, the c-index went from 0.596 (0.55-0.64) alone to 0.811 (0.76-0.86) with osteopontin, and to 0.650 (0.58-0.72) with mesothelin.
  • In the pooled model (n=154), log-osteopontin, the EORTC index and hemoglobin remained independently significant predictors. The optimism-corrected c-index improved from 0.718 (0.67-0.77) for the model without log-osteopontin and log-mesothelin to 0.801 (0.77-0.84) for the model with both.
  • Median overall survival was 11 months (95% CI 8-14) in the discovery cohort and 18 months (95% CI 14-22) in the PMCC cohort. Survival was better in the validation cohort (P=0.04).
• The authors' conclusion: The authors concluded that the data suggest a possible role for pre-treatment plasma biomarkers in improving the prognostic capability of the EORTC prognostic index. They described the combined model as one for future validation.
• Limitations the authors state:
  • Pooling the data for the final model meant that no external validation was available for it.
  • The components and timing of multimodality treatment were not uniform across the cohorts.
  • The number of patients was small compared with a large international database.
  • Only 8% of the Canadian cohort had early-stage (Stage I/II) disease.

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, Discovery, Mesothelioma, Osteopontin, Mesothelin, Prognosis.

Related studies

• Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma — H.I. Pass, S.M. Levin, et al. (2012)
• Lung volume measurements as a surrogate marker for patient response in malignant pleural mesothelioma — Z.E. Labby, S.G. Armato, et al. (2013)
• A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma — B.C. Cho, R. Feld, et al. (2014)
• Inflammation-based prognostic indices in malignant pleural mesothelioma — D.J. Pinato, F.A. Mauri, et al. (2012)
• External validation of prognostic indices for overall survival of malignant pleural mesothelioma — Y. Kataoka, Y. Yamamoto, et al. (2017)
• The homeobox gene EMX2 is a prognostic and predictive marker in malignant pleural mesothelioma — E. Giroux Leprieur, T. Hirata, et al. (2014)

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