Multiple resistant factors in lung cancer with primary resistance to EGFR-TK inhibitors confer poor survival.
OBJECTIVE
EGFR activating mutations have been recognized as the most important predictor of response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, 20-30% of patients harboring EGFR activating mutations show a poor response requiring investigation for underlying mechanisms.


METHODS
Characteristics of 541 patients with lung cancer harboring EGFR activating mutations were analyzed to determine contributing factors that could differentiate responders and non-responders. In addition, previously suggested moleculo-pathologic factors of resistance such as IκB, IGF1R, PTEN, MET, AXL and BIM were evaluated in patients exhibiting primary resistance who had sufficient biopsied tissues available for analyses.


RESULTS
Responders to EGFR-TKIs had a higher incidence of deletion mutations and more frequent presence of EGFR amplifications than non-responders. The median OS was 21 months (95% CI 26.1-30.4) in responders compared to 8 months (95% CI 8.7-15.8) in non-responders (p<0.001). In analyses of patients with primary resistance, we found that 27.3% (6/22) of them exhibited decreased expression of IκB, and 9.1% (2/22) of patients showed increased expression of IGF1R. Loss of PTEN was noted in 54.5%, and BIM polymorphism was found in 19% of patients. No patients had MET amplification, while expression of AXL was detected in 5 patients. Two patients had simultaneous T790M EGFR or PIK3CA mutation alongside EGFR activating mutation. Most of patients exhibited multiple abnormalities of these factors. The overall survival was worse in the group with multiple resistant factors.


CONCLUSIONS
Our study suggests that mechanisms of primary resistance may be more complex than those underlying acquired resistance, with several factors concomitantly contributing to primary resistance.
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Go Woon
GW
Kim
Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Joon Seon
JS
Song
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea; Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Chang-Min
CM
Choi
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Jin Kyung
JK
Rho
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Sun Ye
SY
Kim
Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Se Jin
SJ
Jang
Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Young Soo
YS
Park
Department of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Sung-Min
SM
Chun
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Woo Sung
WS
Kim
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Jung-Shin
JS
Lee
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Sang-We
SW
Kim
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea.
Dae Ho
DH
Lee
Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Republic of Korea. Electronic address: jclee@amc.seoul.kr.
Jae Cheol
JC
Lee
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics; D012189:Retrospective Studies
D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C000597236:IGF1R protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human; C494929:PTEN protein, human
BIM polymorphism; EGFR tyrosine kinase inhibitor; Epidermal growth factor receptor mutation; Non-small cell lung carcinoma; Overall survival; Primary resistance