M Joerger1, F Baty2, M Früh3, C Droege4, R A Stahel5, D C Betticher6, R von Moos7, A Ochsenbein8, M Pless9, O Gautschi10, S Rothschild10, P Brauchli11, D Klingbiel11, F Zappa12, M Brutsche2. 1. Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland. Electronic address: markus.joerger@gmail.com. 2. Department of Pneumology, Cantonal Hospital, St. Gallen, Switzerland. 3. Department of Medical Oncology & Hematology, Cantonal Hospital, St. Gallen, Switzerland. 4. Department of Medical Oncology, University Hospital Basel, Switzerland. 5. Department of Medical Oncology, University Hospital Zurich, Switzerland. 6. Department of Medical Oncology, Cantonal Hospital, Fribourg, Switzerland. 7. Department of Medical Oncology, Cantonal Hospital, Chur, Switzerland. 8. Department of Medical Oncology, University Hospital, Bern, Switzerland. 9. Department of Medical Oncology, Cantonal Hospital, Winterthur, Switzerland. 10. Department of Medical Oncology, Cantonal Hospital, Luzern, Switzerland. 11. SAKK Coordinating Center, Bern, Switzerland. 12. Oncology Department, Clinica Luganese, Lugano, Switzerland.
Abstract
OBJECTIVES: 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. MATERIALS AND 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). CONCLUSION: 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.
OBJECTIVES: 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. MATERIALS AND 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). CONCLUSION: 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: Eva C Schwarz; Christina Backes; Arne Knörck; Nicole Ludwig; Petra Leidinger; Cora Hoxha; Gertrud Schwär; Thomas Grossmann; Sabine C Müller; Martin Hart; Jan Haas; Valentina Galata; Isabelle Müller; Tobias Fehlmann; Hermann Eichler; Andre Franke; Benjamin Meder; Eckart Meese; Markus Hoth; Andreas Keller Journal: Cell Mol Life Sci Date: 2016-02-13 Impact factor: 9.261
Authors: Vasily N Aushev; Eunjee Lee; Jun Zhu; Kalpana Gopalakrishnan; Qian Li; Susan L Teitelbaum; James Wetmur; Davide Degli Esposti; Hector Hernandez-Vargas; Zdenko Herceg; Humberto Parada; Regina M Santella; Marilie D Gammon; Jia Chen Journal: Clin Cancer Res Date: 2017-11-14 Impact factor: 12.531
Authors: Petra Leidinger; Thomas Brefort; Christina Backes; Medea Krapp; Valentina Galata; Markus Beier; Jochen Kohlhaas; Hanno Huwer; Eckart Meese; Andreas Keller Journal: Oncotarget Date: 2016-01-26