title: A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Combined negative ERCC1 and class III β-tubulin immunostaining is associated with significantly prolonged PFS and OS in MPM patients receiving cisplatin-vinorelbine therapy.
authors.affiliation: Department of Oncology, National University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark. zarah.zimling@rh.regionh.dk
authors.forename: Zarah Glad
authors.initials: ZG
authors.lastname: Zimling
authors.forename: Jens Benn
authors.initials: JB
authors.lastname: Sørensen
authors.forename: Thomas Alexander
authors.initials: TA
authors.lastname: Gerds
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bech
authors.forename: Claus Bøgelund
authors.initials: CB
authors.lastname: Andersen
authors.forename: Eric
authors.initials: E
authors.lastname: Santoni-Rugiu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome; D014404:Tubulin / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C498585:TUBB3 protein, human; D014404:Tubulin; D014747:Vinblastine; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D000077235:Vinorelbine