Brain metastases in patients with non-small cell lung cancer: the role of mutated-EGFRs with an exon 19 deletion or L858R point mutation in cancer cell dissemination
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Shih-Hsin Hsiao1,2, Yu-Ting Chou3, Sey-En Lin4, Ru-Chun Hsu2, Chi-Li Chung2,5, Yu-Rung Kao6, H. Eugene Liu7,8 and Cheng-Wen Wu1,3,6,9
1Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan
2Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Tapei 110, Taiwan
3Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan
4Department of Pathology, Wang Fang Hospital, Taipei Medical University, Tapei 11696, Taiwan
5Division of Thoracic Medicine, Department of Internal Medicine, School of Medicine and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
6Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
7Division of Hematology and Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Tapei 11696, Taiwan
8Graduate Institute of Clinical Medicine, Collage of Medicine, Taipei Medical University, Tapei 110, Taiwan
9Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan
Cheng-Wen Wu, email: [email protected]
Keywords: EGFR mutation, EGFR exon 19 deletion or L858R point mutation, non-small cell lung cancer, brain metastases
Received: February 18, 2017 Accepted: May 21, 2017 Published: June 16, 2017
Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up.
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