title: Circulating microRNA profiling in patients with advanced non-squamous NSCLC receiving bevacizumab/erlotinib followed by platinum-based chemotherapy at progression (SAKK 19/05).
abstract: OBJECTIVE
  Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression.
  
  
  METHODS
  Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNA's. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearman's rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints).
  
  
  RESULTS
  Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNA's were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNA's (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNA's, resulting in a HR of 0.66 (95%-CI 0.53-0.82).
  
  
  CONCLUSIONS
  Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.
authors.affiliation: Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland. Electronic address: markus.joerger@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Joerger
authors.affiliation: Department of Pneumology, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Baty
authors.affiliation: Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Früh
authors.affiliation: Department of Medical Oncology, University Hospital Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Droege
authors.affiliation: Department of Medical Oncology, University Hospital Zurich, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Stahel
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Fribourg, Switzerland.
authors.forename: D C
authors.initials: DC
authors.lastname: Betticher
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Chur, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: von Moos
authors.affiliation: Department of Medical Oncology, University Hospital, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Ochsenbein
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Winterthur, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Pless
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Luzern, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Gautschi
authors.affiliation: Department of Medical Oncology, Cantonal Hospital, Luzern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Rothschild
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Brauchli
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Klingbiel
authors.affiliation: Oncology Department, Clinica Luganese, Lugano, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Zappa
authors.affiliation: Department of Pneumology, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Brutsche
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D003131:Combined Modality Therapy; D018450:Disease Progression; D000069347:Erlotinib Hydrochloride; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D035683:MicroRNAs; D011799:Quinazolines; D000068258:Bevacizumab; D010984:Platinum; D000069347:Erlotinib Hydrochloride
keywords: Bevacizumab; Biomarkers; Chemotherapy; Erlotinib; Lung cancer; MicroRNA's