Research Papers:

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

Shih-Hsin Hsiao, Yu-Ting Chou, Sey-En Lin, Ru-Chun Hsu, Chi-Li Chung, Yu-Rung Kao, H. Eugene Liu and Cheng-Wen Wu _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:53405-53418. https://doi.org/10.18632/oncotarget.18509

Metrics: PDF 1227 views  |   HTML 2989 views  |   ?  


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

Correspondence to:

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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 18509