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

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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.

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Acknowledgments

Thanks to Lone Svendstrup, Anne Jørgensen, and Margit Bæksted for excellent technical assistance. Thanks to N.Z. Sroczynski, TopoTarget, Copenhagen, Denmark, for the kind donation of the A2780 cell pellet. Thanks to Heidi R. Hudlebusch, BRIC, Copenhagen Biocenter, Denmark, for kindly providing the SH-SY5Y cell pellet. This work was funded by The Danish Cancer Society, the Harboe foundation, the Danielsen foundation, and the Danish Lung Association.

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Authors and Affiliations

  1. Department of Oncology, National University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Zarah Glad Zimling, Jens Benn Sørensen & Cecilia Bech

  2. Department of Pathology, 5444 National University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen East, Denmark

    Zarah Glad Zimling, Claus Bøgelund Andersen & Eric Santoni-Rugiu

  3. Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

    Thomas Alexander Gerds

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  1. Zarah Glad Zimling
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Correspondence to Zarah Glad Zimling.

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Zimling, Z.G., Sørensen, J.B., Gerds, T.A. et al. A biomarker profile for predicting efficacy of cisplatin–vinorelbine therapy in malignant pleural mesothelioma. Cancer Chemother Pharmacol 70, 743–754 (2012). https://doi.org/10.1007/s00280-012-1965-0

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  • DOI: https://doi.org/10.1007/s00280-012-1965-0

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