Six-gene signature predicts survival after targeted therapy for NSCLC

The presence of a six-gene profile in the microRNA of patients with advanced non-squamous non-small-cell lung cancer (NSCLC) predicts reduced survival likelihood after first-line treatment with targeted therapy followed by chemotherapy for disease progression, indicate research results.

While the findings “should be further validated”, the researchers believe their analysis “supports the hypothesis that circulating [microRNA's] may further be developed as predictive markers for EGFR-targeted treatment” in an NSCLC population whose response to epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors is unknown.

Using 49 participants from the phase II SAKK (Swiss Group for Clinical Cancer Research) 19/05 trial, the Swiss research team analysed pretreatment blood samples, and those taken 24 hours after initiation of bevacizumab or erlotinib to identify prognostic microRNA's for overall survival.

The patients received bevacizumab 15 mg/kg on the first day of each 3-week cycle and concurrent erlotinib 150 mg/day until disease progression or intolerable toxicity, and survived for a median of 16.1 months.

Expression profiling of the 424 microRNA's identified in the peripheral blood of the patients revealed 10 that were significantly associated with overall survival. The strongest prognostic marker was hsa-miR-29a, with a hazard ratio of 6.44, note Markus Joerger, from Cantonal Hospital in St Gallen, and colleagues in Lung Cancer. Indeed, significantly fewer patients with high expression levels of this microRNA were alive after 10 months compared with their counterparts who had low expression, at 54% versus 83%.

Six microRNA's – hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424 – had the most robust association with survival after precision resampling analysis, giving a 44% reduced chance of survival for patients possessing this genetic signature. Cumulative survival rates for those with high- versus low-risk signatures were approximately 29 months versus more than 45 months.

Further analysis indicated 12 microRNA's that were significantly associated with the percentage of tumour shrinkage after treatment. In particular, has-miR-665, which at high expression levels significantly increased patients' chances of experiencing tumour shrinkage.

“Molecular subclassification of NSCLC is essential to improve clinical outcome, but there are several drawbacks including small quantities or poor quality of diagnostic tumour tissue, genetic tumour heterogeneity in space and time, and the risk and reluctance to do repeated biopsies in patients with incurable tumours,” write Joerger et al.

“Therefore, circulating biomarkers are an attractive alternative to tumour-derived biomarkers”, they conclude.

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