Circulating micro-RNA profiling in patients with advanced non-squamous non small-cell lung cancer receiving bevacizumab/erlotinib first-line treatment followed by platinum-based chemotherapy at disease progression (SAKK 19/05)
Markus Joerger, Florent Baty, Martin Früh, Rolph Stahel, Daniel Betticher, Roger Von Moos, Lukas Bubendorf, Adrian Ochsenbein, Miklos Pless, Oliver Gautschi, Francesco Zappa & Martin Brutsche
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abstract
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Background: This study was initiated by the Swiss Group for Clinical
Cancer Research (SAKK) 19/05 study to assess the predictive and
prognostic value of circulating miRNA profiles from peripheral
blood of patients with non-squamous non small-cell lung cancer
(NSCLC) receiving 1st-line bevacizumab/erlotinib followed by
platinum-based chemotherapy at the time of progression . Patients
and Methods: We included 50 patients with available baseline and 24
hours blood samples. The primary objective of the study was to
identify prognostic miRNAs for overall survival (OS). Following
confirmation of RNA content and quality, patient samples were
analyzed with Agilent human miRNA 8x60K microarrays (release 16.0).
One glass slide formatted with eight high-definition 60K arrays.
Based on miRBase release 16.0. Each array containing 40 probes
targetting each of the 1’347 miRNAs. Data preprocessing
included quantile normalization and range migration algorithm
filtering. Predictive and prognostic miRNA expression profiles were
identified by using the unpaired two-tailed parametric T-test (for
quantiative endpoints such as tumor shrinkage) or log-rank testing
(for survival endpoints). Results: Data preprocessing kept 49
patients and 424 miRNA’s for further analysis. Ten
miRNA’s significantly predicted OS, including miR-29a
(HR=6.44, 95%-CI 2.39-17.33, p-value 0.0002). Six miRNA candidates
(hsa-miR-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a,
hsa-miR-500a, hsa-miR-424) were found to be insensitive to
perturbations according to internal crossvalidation (jackknife) on
their HR for OS. The respective principal component analysis defined
a multi-miRNA signature including these 6 miRNA candidates that
significantly predicted OS in the study population. MicroRNA-665
significantly correlated with percentage tumor shrinkage following
1st-line bevacizumab/erlotinib (rho=0.62, p-value=0.0002).
Conclusions: Profiling of easily accessible circulating miRNAs
successfully identified a prognostic 6-microRNA signature in
patients with advanced non-squamous NSCLC, as well as predictive
miRNAs for molecularly-targeted treatment and conventional
chemotherapy. This technique should be further evaluated for
potential treatment monitoring in patients with advanced NSCLC.
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type of project
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fundamental research
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status
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completed
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start of project
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2012
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end of project
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2013
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project manager
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Markus Joerger
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