Annotated selected abstracts

15329413

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
William Pao, Vincent Miller, Maureen Zakowski, Jennifer Doherty, Katerina Politi, Inderpal Sarkaria, Bhuvanesh Singh, Robert Heelan, Valerie Rusch, Lucinda Fulton, Elaine Mardis, Doris Kupfer, Richard ...
(Program in Cancer Biology and Genetics and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. paow@mskcc.org)
Proc. Natl. Acad. Sci. U.S.A.

somatic_mutations in the tyrosine_kinase tk_domain of the epidermal_growth factor_receptor egfr gene are reportedly associated with sensitivity of lung cancers to gefitinib_iressa kinase_inhibitor in-frame_deletions occur in exon whereas point_mutations occur_frequently in codon exon we found from sequencing the egfr_tk domain that of gefitinib-sensitive tumors had similar types of alterations no mutations were found in eight gefitinib-refractory tumors five of seven tumors sensitive to erlotinib_tarceva related kinase_inhibitor for which the clinically_relevant target is undocumented had analogous somatic_mutations as_opposed to none of erlotinib-refractory tumors because most mutation-positive tumors were adenocarcinomas from patients who_smoked cigarettes in lifetime_never smokers we screened egfr_exons 2-28 in adenocarcinomas resected from untreated never_smokers seven tumors had tk_domain mutations in contrast to of non-small_cell lung cancers resected from untreated former or current_smokers immunoblotting of lysates from cells transiently_transfected with various egfr constructs demonstrated that compared to wild-type protein an exon_deletion mutant induced diminished levels of phosphotyrosine whereas the phosphorylation at tyrosine of an exon point mutant was inhibited at 10-fold_lower concentrations of drug collectively_these data show_that adenocarcinomas from never_smokers comprise distinct_subset of lung cancers frequently containing mutations within the tk_domain of egfr that are associated with gefitinib and erlotinib sensitivity

16014882

Erlotinib in previously treated non-small-cell lung cancer.
Frances A Shepherd, José Rodrigues Pereira, Tudor Ciuleanu, Eng Huat Tan, Vera Hirsh, Sumitra Thongprasert, Daniel Campos, Savitree Maoleekoonpiroj, Michael Smylie, Renato Martins, Maximiliano van Koo ...
(Department of Medical Oncology, University Health Network, Princess Margaret Hospital Site, University of Toronto, Canada.)
N. Engl. J. Med.

we_conducted randomized_placebo-controlled double-blind_trial to determine_whether the epidermal_growth factor_receptor inhibitor erlotinib prolongs_survival in non-small-cell_lung cancer after the failure of first-line or second-line_chemotherapy patients with stage_iiib or iv non-small-cell_lung cancer with performance_status from to were eligible_if they had received one or two prior chemotherapy_regimens the patients were stratified_according to center performance_status response to prior chemotherapy number of prior regimens and prior_platinum-based therapy and were randomly_assigned in ratio to receive oral erlotinib at dose of mg_daily or placebo the median_age of the patients who_underwent randomization was years percent had received two prior chemotherapy_regimens and percent had received platinum-based_chemotherapy the response_rate was percent in the erlotinib group and less_than percent in the placebo_group the median_duration of the response was months and months respectively progression-free_survival was months and months respectively hazard_ratio adjusted for stratification categories overall_survival was months and months respectively hazard_ratio in favor of erlotinib five percent of patients discontinued erlotinib because of toxic_effects erlotinib can_prolong survival in patients with non-small-cell_lung cancer after first-line or second-line_chemotherapy

15728811

EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.
Susumu Kobayashi, Titus J Boggon, Tajhal Dayaram, Pasi A Jänne, Olivier Kocher, Matthew Meyerson, Bruce E Johnson, Michael J Eck, Daniel G Tenen, Balázs Halmos
(Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.)
N. Engl. J. Med.

mutations of the epidermal_growth factor_receptor egfr gene have_been identified in specimens from patients with non-small-cell_lung cancer who have response to anilinoquinazoline egfr inhibitors despite the dramatic_responses to such inhibitors most patients ultimately have relapse the mechanism of the drug_resistance is unknown here_we report the case of patient with egfr-mutant gefitinib-responsive advanced_non-small-cell lung cancer who_had relapse after two years of complete_remission during treatment with gefitinib the dna sequence of the egfr gene in his tumor biopsy_specimen at relapse revealed the presence of second point_mutation resulting in threonine-to-methionine amino_acid change at position of egfr structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance