title: HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients.
abstract: In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.
authors.affiliation: Department of Medicine/Medical Oncology and Pathology, University of Colorado Cancer Center, Campus Box 8117; PO Box 6511, Aurora, CO 80045, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: L
authors.initials: L
authors.lastname: Toschi
authors.forename: I
authors.initials: I
authors.lastname: Domenichini
authors.forename: S
authors.initials: S
authors.lastname: Bartolini
authors.forename: G L
authors.initials: GL
authors.lastname: Ceresoli
authors.forename: E
authors.initials: E
authors.lastname: Rossi
authors.forename: V
authors.initials: V
authors.lastname: Ludovini
authors.forename: A
authors.initials: A
authors.lastname: Cancellieri
authors.forename: E
authors.initials: E
authors.lastname: Magrini
authors.forename: L
authors.initials: L
authors.lastname: Bemis
authors.forename: W A
authors.initials: WA
authors.lastname: Franklin
authors.forename: L
authors.initials: L
authors.lastname: Crino
authors.forename: P A
authors.initials: PA
authors.lastname: Bunn
authors.forename: F R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: M
authors.initials: M
authors.lastname: Varella-Garcia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D020893:Receptor, ErbB-3 / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012737:Sex Factors; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011799:Quinazolines; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000077156:Gefitinib