title: The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.
abstract: The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.
authors: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University Prague, Czech Republic. fiala.o@centrum.cz
authors: Ondrej
authors: O
authors: Fiala
authors: Milos
authors: M
authors: Pesek
authors: Jindrich
authors: J
authors: Finek
authors: Lucie
authors: L
authors: Benesova
authors: Barbora
authors: B
authors: Belsanova
authors: Marek
authors: M
authors: Minarik
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000502:physiology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D003545:Cysteine / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D003545:Cysteine; D005998:Glycine