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


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).


CONCLUSIONS
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.
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.
Hye Ryun
HR
Kim
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.
Byoung Chul
BC
Cho
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hyo Sup
HS
Shim
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.
Sun Min
SM
Lim
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Se Kyu
SK
Kim
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Joon
J
Chang
Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
Dae Joon
DJ
Kim
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.
Joo Hang
JH
Kim
D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011859:Radiography; D012907:Smoking; D016019:Survival Analysis; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
D000091162:AMP-Activated Protein Kinase Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C109790:STK11 protein, human
AKT1, 2; EGFR; Lung adenocarcinoma; PI3KCA; PTEN; Response to EGFR TKIs; STK11 mutations