Targeted sequencing identifies genetic alterations that confer primary resistance to EGFR tyrosine kinase inhibitor (Korean Lung Cancer Consortium).
BACKGROUND
Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients.


METHODS
One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies).


RESULTS
All 132 patients with EGFR mutation were treated with gefitinib for their treatment of advanced NSCLC. Twenty patients showed primary resistance to EGFR TKI, and were classified as non-responders. A total of 543 somatic single-nucleotide variants (498 missense, 13 nonsense) and 32 frameshift insertions/deletions, with a median of 3 mutations per sample. TP53 was most commonly mutated (47%) and mutations in SMAD4 was also common (19%), as well as DDR2 (16%), PIK3CA (15%), STK11 (14%), and BRAF (7%). Genomic mutations in the PI3K/Akt/mTOR pathway were commonly found in non-responders (45%) compared to responders (27%), and they had significantly shorter progression-free survival and overall survival compared to patients without mutations (2.1 vs. 12.8 months, P=0.04, 15.7 vs. not reached, P<0.001). FGFR 1-3 alterations, KRAS mutations and TP53 mutations were more commonly detected in non-responders compared to responders.


CONCLUSIONS
Genomic mutations in the PI3K/Akt/mTOR pathway were commonly identified in non-responders and may confer resistance to EGFR TKI. Screening lung adenocarcinoma patients with clinical cancer gene test may aid in selecting out those who show primary resistance to EGFR TKI (NCT01697163).
Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Sun Min
SM
Lim
Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Hye Ryun
HR
Kim
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.
Eun Kyung
EK
Cho
Department of Oncology, Asan Medical Center, University of Ulsan college of Medicine, Seoul, Korea.
Young Joo
YJ
Min
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jin Seok
JS
Ahn
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Myung-Ju
MJ
Ahn
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Keunchil
K
Park
Department of Internal Medicine, Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Byoung Chul
BC
Cho
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Ji-Hyun
JH
Lee
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Hye Cheol
HC
Jeong
Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Eun Kyung
EK
Kim
Department of Internal Medicine, Division of Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Joo-Hang
JH
Kim
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology; D017422:Sequence Analysis, DNA / Q000379:methods; D016896:Treatment Outcome
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
epidermal growth factor; next-generation sequencing; primary resistance; tyrosine kinase inhibitor