title: Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry.
abstract: The purpose of this study was to investigate whether detectable protein biomarker overexpression is a prerequisite for the presence of increased gene copy number or activating mutations and responsiveness to the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib in patients with lung adenocarcinomas. EGFR status was prospectively analyzed in tumor biopsy samples by three methods: protein expression (n = 117) by standardized immunohistochemistry (IHC), gene copy number (n = 97) by fluorescent in situ hybridization (FISH), and mutation analysis by sequencing (n = 126). Fifty-nine percent of the samples were positive by IHC, 40% were positive by FISH, and 13.5% contained activating kinase domain mutations. Thirty-four percent of the FISH-positive and 27% of the mutant samples were also IHC-negative. All EGFR mutant patients had major clinical responses (five complete response and five partial response) to gefitinib or erlotinib treatment, although three of these tumors were IHC-negative and four were FISH-negative. In a retrospective analysis of samples from nine patients with excellent therapeutic responses (three complete response, five partial response, one stable disease) to erlotinib or gefitinib, mutations were identified in eight cases, but IHC was negative in four of these tumors. These results indicate that molecular diagnostic methods appear to be most important for the identification of lung adenocarcinoma patients who may benefit from EGFR inhibitor treatments.
authors.affiliation: KPS Medical Biotechnology and Healthcare Services, Budapest, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Pinter
authors.forename: Judit
authors.initials: J
authors.lastname: Papay
authors.forename: Andrea
authors.initials: A
authors.lastname: Almasi
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Sapi
authors.forename: Edit
authors.initials: E
authors.lastname: Szabo
authors.forename: Melinda
authors.initials: M
authors.lastname: Kanya
authors.forename: Anna
authors.initials: A
authors.lastname: Tamasi
authors.forename: Balazs
authors.initials: B
authors.lastname: Jori
authors.forename: Edit
authors.initials: E
authors.lastname: Varkondi
authors.forename: Judit
authors.initials: J
authors.lastname: Moldvay
authors.forename: Klara
authors.initials: K
authors.lastname: Szondy
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Keri
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.forename: Sandor
authors.initials: S
authors.lastname: Eckhardt
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kopper
authors.forename: Richard
authors.initials: R
authors.lastname: Schwab
authors.forename: Istvan
authors.initials: I
authors.lastname: Petak
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib