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

Abstract

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. 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. 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 6.7months in the treatment-resistant group, 15.3months in the treatment-responsive group, and 8.1months 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. Combined negative ERCC1 and class III β-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.