24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling.

Baty, Florent; Joerger, Markus; Früh, Martin; Klingbiel, Dirk; Zappa, Francesco; Brutsche, Martin (2017). 24h-gene variation effect of combined bevacizumab/erlotinib in advanced non-squamous non-small cell lung cancer using exon array blood profiling. Journal of translational medicine, 15(1), p. 66. BioMed Central 10.1186/s12967-017-1174-z

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Früh, Martin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1479-5876

Publisher:

BioMed Central

Language:

English

Submitter:

Nicole Corminboeuf

Date Deposited:

08 Mar 2018 14:51

Last Modified:

05 Dec 2022 15:10

Publisher DOI:

10.1186/s12967-017-1174-z

PubMed ID:

28359318

Uncontrolled Keywords:

Blood predictive markers Combined targeted therapies Exon arrays Non-small cell lung cancer

BORIS DOI:

10.7892/boris.111333

URI:

https://boris.unibe.ch/id/eprint/111333

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