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

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...

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Bibliographic Details
Published in:Cancer genetics 2013, Vol.206 (1), p.26-31
Main Authors: Fiala, Ondrej, Pesek, Milos, Finek, Jindrich, Benesova, Lucie, Belsanova, Barbora, Minarik, Marek
Format: Article
Language:English
Subjects:
Adult
Aged
Amino Acid Substitution - physiology
Antineoplastic Agents - therapeutic use
Biomarkers, Pharmacological - metabolism
Biomarkers, Tumor - genetics
Biomarkers, Tumor - physiology
Carcinoma, Non-Small-Cell Lung - diagnosis
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Case-Control Studies
Cohort Studies
Cysteine - genetics
Drug Resistance, Neoplasm - genetics
EGFR tyrosine kinase inhibitors
Female
Glycine - genetics
Hematology, Oncology and Palliative Medicine
Humans
KRAS mutation
Lung Neoplasms - diagnosis
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Male
Medical Education
Middle Aged
Mutation, Missense - physiology
non–small cell lung cancer
predictive factor
Prognosis
Protein Kinase Inhibitors - therapeutic use
Protein-Tyrosine Kinases - antagonists & inhibitors
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins - physiology
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
ras Proteins - metabolism
ras Proteins - physiology
Receptor, Epidermal Growth Factor - antagonists & inhibitors
targeted treatment of NSCLC
Treatment Outcome
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Summary: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.
ISSN:2210-7762
2210-7770
DOI:10.1016/j.cancergen.2012.12.003