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

• Published in: Cancer chemotherapy and pharmacology 2012-11, Vol.70 (5), p.743-754
• Main Authors: Zimling, Zarah Glad, Sørensen, Jens Benn, Gerds, Thomas Alexander, Bech, Cecilia, Andersen, Claus Bøgelund, Santoni-Rugiu, Eric
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cancer Research; Cisplatin - administration & dosage; Disease-Free Survival; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm; Endonucleases - metabolism; Female; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Mesothelioma - drug therapy; Mesothelioma - pathology; Middle Aged; Multivariate Analysis; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pleural Neoplasms - drug therapy; Pleural Neoplasms - pathology; Pneumology; Predictive Value of Tests; Prognosis; Survival Rate; Treatment Outcome; Tubulin - metabolism; Tumors of the respiratory system and mediastinum; Vinblastine - administration & dosage; Vinblastine - analogs & derivatives
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1965-0

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.