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Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma

 Hye Ryun Kim  ;  Byoung Chul Cho  ;  Hyo Sup Shim  ;  Sun Min Lim  ;  Se Kyu Kim  ;  Joon Chang  ;  Dae Joon Kim  ;  Joo Hang Kim 
 LUNG CANCER, Vol.83(3) : 374-382, 2014 
Journal Title
Issue Date
Adenocarcinoma/diagnosis* ; Adenocarcinoma/drug therapy ; Adenocarcinoma/mortality ; Adult ; Aged ; Class I Phosphatidylinositol 3-Kinases ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; Lung/diagnostic imaging ; Lung/drug effects* ; Lung/pathology ; Lung Neoplasms/diagnosis* ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/mortality ; Male ; Middle Aged ; Mutation/genetics ; Oncogene Protein v-akt/genetics ; PTEN Phosphohydrolase/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Prognosis ; Protein Kinase Inhibitors/therapeutic use* ; Protein-Serine-Threonine Kinases/genetics ; Radiography ; Receptor, Epidermal Growth Factor/antagonists & inhibitors ; Receptor, Epidermal Growth Factor/genetics ; Smoking ; Survival Analysis ; Treatment Outcome ; Tumor Burden/drug effects
AKT1, 2 ; EGFR ; Lung adenocarcinoma ; PI3KCA ; PTEN ; Response to EGFR TKIs ; STK11 mutations
OBJECTIVES: Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ∼ 20-30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR-downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. MATERIALS AND METHODS: Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA, PTEN, AKT and STK11, which are all EGFR-downstream genes. Mutations in PIK3CA, PTEN, AKT, and STK11 were analyzed by polymerase chain reaction-based sequencing. RESULTS: PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR. The proportion of patients who had mutations in EGFR-downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR-downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs.14.5% in patients with mutation in EGFR-downstream gene, P<0.0001), shorter median progression-free survival (12.0 vs. 3.0 months, P=0.060), and shorter median overall survival (18.9 vs. 25.0 months, P=0.048). CONCLUSION: Mutations in the EGFR-downstream genes may confer resistance to EGFR-TKIs and result in poor treatment outcomes in never-smoker adenocarcinoma patients with activating EGFR mutations.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dae Joon(김대준)
Kim, Se Kyu(김세규)
Kim, Joo Hang(김주항)
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Lim, Sun Min(임선민)
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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