TY - JOUR

T1 - A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma

AU - Zimling, Zarah Glad

AU - Sørensen, Jens Benn

AU - Gerds, Thomas Alexander

AU - Bech, Cecilia

AU - Andersen, Claus Bøgelund

AU - Santoni-Rugiu, Eric

PY - 2012/11

Y1 - 2012/11

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Biomarkers, Tumor/metabolism

KW - Cisplatin/administration & dosage

KW - DNA-Binding Proteins/metabolism

KW - Disease-Free Survival

KW - Drug Resistance, Neoplasm

KW - Endonucleases/metabolism

KW - Female

KW - Humans

KW - Male

KW - Mesothelioma/drug therapy

KW - Middle Aged

KW - Multivariate Analysis

KW - Pleural Neoplasms/drug therapy

KW - Predictive Value of Tests

KW - Prognosis

KW - Survival Rate

KW - Treatment Outcome

KW - Tubulin/metabolism

KW - Vinblastine/administration & dosage

KW - Vinorelbine

U2 - 10.1007/s00280-012-1965-0

DO - 10.1007/s00280-012-1965-0

M3 - Journal article

C2 - 22960937

VL - 70

SP - 743

EP - 754

JO - Cancer Chemotherapy and Pharmacology, Supplement

JF - Cancer Chemotherapy and Pharmacology, Supplement

SN - 0943-9404

IS - 5

ER -