title: EGFR exon-level biomarkers of the response to bevacizumab/erlotinib in non-small cell lung cancer.
abstract: Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.
authors.affiliation: Division of Pulmonary Medicine, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: Florent
authors.initials: F
authors.lastname: Baty
authors.forename: Sacha
authors.initials: S
authors.lastname: Rothschild
authors.forename: Martin
authors.initials: M
authors.lastname: Früh
authors.forename: Daniel
authors.initials: D
authors.lastname: Betticher
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dröge
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauch
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Susanne
authors.initials: S
authors.lastname: Crowe
authors.forename: Francesco
authors.initials: F
authors.lastname: Zappa
authors.forename: Miklos
authors.initials: M
authors.lastname: Pless
authors.forename: Martin
authors.initials: M
authors.lastname: Brutsche
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005091:Exons; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D012372:ROC Curve; D016896:Treatment Outcome; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors
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