title: Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma.
abstract: Activating mutation in exons 19 or 21 of epidermal growth factor receptor (EGFR) in non-small-cell lung cancers (NSCLC) are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib. Cancer patients harboring activating EGFR mutations benefit from first-line TKI therapy. Yet 10% of patients present a primary TKI resistance, while 50% of the others develop a secondary resistance within 9-12 months after starting TKI. The RECIST's definition of progression appears flawed when applied to EGFR-mutated NSCLC patients. Most often, tumor volume shrinking widely exceeds 30% during TKI response and kinetics of growth is low during relapse. At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial-mesenchymal transition or transdifferentiation to small-cell cancer. The best strategy for secondary resistance is not well-defined: maintaining TKI therapy, switching to chemotherapy, combining both treatments, or using new therapies targeting other signaling pathways.
authors.affiliation: Service de Pneumologie, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, France; Equipe de Recherche 2 et GRC-UPMC 04 Theranoscan, Université Pierre et Marie Curie, Paris VI, France. Electronic address: jacques.cadranel@tnn.aphp.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ruppert
authors.forename: Michèle
authors.initials: M
authors.lastname: Beau-Faller
authors.forename: Marie
authors.initials: M
authors.lastname: Wislez
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: Afatinib; Dacomitinib; EGFR mutations; Erlotinib; Gefitinib; Non-small-cell lung cancer; Secondary resistance; Tyrosine kinase inhibitors