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Published on: April 11, 2016
24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using
Florent Baty1, Markus Joerger2, Martin Früh2
1Department of Pulmonary Medicine, Cantonal Hospital St. Gallen, Roschacherstrasse 95, 9007, St. Gallen, Switzerland. florent.baty@kssg.ch.
Background:
The SAKK 19/05 trial investigated the safety and efficacy of the combined targeted therapy bevacizumab and erlotinib (BE) in unselected patients with advanced non-squamous non-small cell lung cancer (NSCLC). Although activating EGFR mutations were the strongest predictors of the response to BE, some patients not harboring driver mutations could benefit from the combined therapy. The identification of predictive biomarkers before or short after initiation of therapy is therefore paramount for proper patient selection, especially among EGFR wild-types. The first aim of this study was to investigate the early change in blood gene expression in unselected patients with advanced non-squamous NSCLC treated by BE. The second aim was to assess the predictive value of blood gene expression levels at baseline and 24h after BE therapy.
Methods:
Blood samples from 43 advanced non-squamous NSCLC patients taken at baseline and 24h after initiation of therapy were profiled using Affymetrix' exon arrays. The 24h gene dysregulation was investigated in the light of gene functional annotations using gene set enrichment analysis. The predictive value of blood gene expression levels was assessed and validated using an independent dataset.
Results:
Significant gene dysregulations associated with the 24h-effect of BE were detected from blood-based whole-genome profiling. BE had a direct effect on "Pathways in cancer", by significantly down-regulating genes involved in cytokine-cytokine receptor interaction, MAPK signaling pathway and mTOR signaling pathway. These pathways contribute to phenomena of evasion of apoptosis, proliferation and sustained angiogenesis. Other signaling pathways specifically reflecting the mechanisms of action of erlotinib and the anti-angiogenesis effect of bevacizumab were activated. The magnitude of change of the most dysregulated genes at 24h did not have a predictive value regarding the patients' response to BE. However, predictive markers were identified from the gene expression levels at 24h regarding time to progression under BE.
Conclusions:
The 24h-effect of the combined targeted therapy BE could be accurately monitored in advanced non-squamous NSCLC blood samples using whole-genome exon arrays. Putative predictive markers at 24h could reflect patients' response to BE after adjusting for their mutational status. Trial registration ClinicalTrials.gov: NCT00354549.
Insights
Early changes in blood gene expression after bevacizumab and erlotinib (BE) therapy can predict treatment outcomes in advanced non-small cell lung cancer (NSCLC). These blood gene expression markers may help select patients for targeted lung cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- The SAKK 19/05 trial evaluated bevacizumab and erlotinib (BE) combination therapy for advanced non-squamous non-small cell lung cancer (NSCLC).
- While EGFR mutations predict response to BE, some EGFR wild-type patients benefit, necessitating predictive biomarkers.
- Early identification of predictive biomarkers is crucial for optimizing patient selection in NSCLC treatment.
Purpose of the Study:
- To investigate early changes in blood gene expression following BE therapy in advanced non-squamous NSCLC patients.
- To assess the predictive value of blood gene expression at baseline and 24 hours post-BE initiation for treatment response.
Main Methods:
- Blood samples from 43 NSCLC patients were analyzed using Affymetrix exon arrays at baseline and 24 hours post-BE therapy.
- Gene set enrichment analysis was used to investigate 24-hour gene dysregulation.
- Predictive value of gene expression was assessed and validated on an independent dataset.
Main Results:
- Whole-genome profiling revealed significant gene dysregulation in blood 24 hours after BE therapy.
- BE impacted cancer pathways, down-regulating genes in cytokine-cytokine receptor interaction, MAPK, and mTOR signaling.
- While 24-hour gene expression changes did not predict overall response, they identified markers for time to progression under BE.
Conclusions:
- Early (24h) blood gene expression changes after BE therapy in advanced NSCLC can be monitored using whole-genome exon arrays.
- Putative predictive markers identified at 24 hours may reflect patient response to BE, even after accounting for mutational status.
- This approach aids in refining patient selection for targeted lung cancer therapies.
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