title: Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study.
abstract: Targeting the epidermal growth factor receptor has played a central role in advanced non-small cell lung cancer research, treatment, and patient outcomes over the last several years; however, a number of questions about this approach remain to be addressed. Through the Istituto Toscano Tumori and the Italian Association of Women Against Lung Cancer Project, we collected 411 lung adenocarcinomas from several clinical centers in Tuscany. Mutations were assessed by sequencing exons 18-21 of the epidermal growth factor receptor gene, and by restriction fragment length polymorphism analysis of codons 12 and 13 of the K-RAS gene. Epidermal growth factor receptor mutations (12.6%) were more frequently observed in females (p<0.0001), in non-smokers (p=0.005), and in the presence of bronchioloalveolar features (p=0.0004). K-RAS mutations (17.9%) were more frequent in males (p=0.0007) and were associated with smoking habits (p=0.005). Epidermal growth factor receptor and K-RAS mutations were mutually exclusive (p=0.001). We focused on 21 female patients with advanced/metastatic lung adenocarcinoma who received gefitinib 250 mg/day (expanded access) or erlotinib 150 mg/die as second/third-line therapy; partial response was associated with classic epidermal growth factor receptor mutations (p=0.006) and with a non-smoking history (p=0.02). None of the female patients with partial response and/or stable disease showed K-RAS alterations. Although the data obtained in our study have yet to be analyzed and confirmed with a larger number of patients treated with tyrosine kinase inhibitors, they should provide useful information for targeted therapy, in particular for non-smoking female lung cancer patients.
authors.affiliation: Department of Surgery, University of Pisa, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Boldrini
authors.forename: Greta
authors.initials: G
authors.lastname: Alì
authors.forename: Silvia
authors.initials: S
authors.lastname: Gisfredi
authors.forename: Silvia
authors.initials: S
authors.lastname: Ursino
authors.forename: Editta
authors.initials: E
authors.lastname: Baldini
authors.forename: Franca
authors.initials: F
authors.lastname: Melfi
authors.forename: Marco
authors.initials: M
authors.lastname: Lucchi
authors.forename: Camilla E
authors.initials: CE
authors.lastname: Comin
authors.forename: Cristina
authors.initials: C
authors.lastname: Maddau
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Camacci
authors.forename: Adele
authors.initials: A
authors.lastname: Servadio
authors.forename: Alfredo
authors.initials: A
authors.lastname: Mussi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D012737:Sex Factors; D012907:Smoking / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib