Hye Ryun Kim1, Byoung Chul Cho1, Hyo Sup Shim2, Sun Min Lim1, Se Kyu Kim3, Joon Chang3, Dae Joon Kim4, Joo Hang Kim5. 1. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. 2. Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea. 3. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. 4. Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea. 5. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: kjhang@yuhs.ac.
Abstract
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.
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 adenocarcinomapatients 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 adenocarcinomapatients with activating EGFR mutations.
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