61PD - 24h-blood profile gene expression biomarkers of the response to targeted therapy in advanced non-squamous non-small cell lung cancer (NSCLC)

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Biomarkers
Topics Anticancer agents
Translational Research
Non-Small Cell Lung Cancer
Basic Principles in the Management and Treatment (of cancer)
Therapy
Biological Therapy
Presenter Florent Baty
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors F. Baty1, M. Jörger2, M. Frueh2, M.H. Brutsche1
  • 1Pneumologie, Kantonsspital St. Gallen, 9007 - St. Gallen/CH
  • 2Klinik Für Onkologie/hämatologie, Kantonsspital St. Gallen, 9007 St. Gallen - St. Gallen/CH

Abstract

Background

Combined targeted therapies represent novel therapeutic approaches simultaneously acting on several specific molecular pathways in cancer. Patients not harboring driver mutations may benefit from such therapies, but identifying predictive biomarkers is paramount for proper patient selection.

Methods

The phase II clinical trial SAKK 19/05 studied the safety and efficacy of combined first-line treatment with bevacizumab and erlotinib in unselected patients with NSCLC. Blood samples were taken in 43 non-squamous NSCLC patients at baseline and 24 h after the beginning of initiation of the combined bevacizumab/erlotinib targeted therapy. Messenger RNA was extracted and hybridized on Affymetrix GeneChip Human Exon 1.0 ST arrays. The early change in gene expression was investigated using dually constrained correspondence analysis. Validation of the prognostic value of our biomarkers was done using the online survival analysis software in NSCLC (KM-Plotter). The predictive value of the identified biomarkers was done on a targeted gene approach.

Results

Blood gene expression variations measured 24 h after initiation of targeted therapy indicate a direct effect on genes that belong to the KEGG pathway “Pathways in cancer”. More specifically, a significant down-regulation was found in genes that are part of the cytokine-cytokine receptor interaction (IGF1R, IGF2R), MPAK signaling pathway (DAPK2, PLD1, MMP9), and mTOR signaling pathway (BIRC3). Although the magnitude of change over 24 h was not predicting patient's outcome, the level of gene expression at baseline and 24 h of ILR1, FLT3, PLD1, BIRC3, and IGF1R was predictive of the tumor shrinkage at week 12, and time-to-progression under targeted therapy, independent of EGFR mutational status. These findings were independently validated using the KM-Plotter webtool.

Conclusions

Blood gene expression levels at baseline and 24 h after the initiation of bevacizumab/erlotinib provide potential novel biomarkers of the response to combined targeted therapy in advanced NSCLC.

Clinical trial identification

NCT00354549

Legal entity responsible for the study

Swiss Group for Clinical Cancer Research (SAKK)

Funding

Swiss Group for Clinical Cancer Research (SAKK)

Disclosure

All authors have declared no conflicts of interest.