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

被引:15
作者
Hsiao, Shih-Hsin [1 ,2 ,3 ]
Chou, Yu-Ting [4 ]
Lin, Sey-En [5 ]
Hsu, Ru-Chun [3 ]
Chung, Chi-Li [3 ,6 ,7 ]
Kao, Yu-Rung [8 ]
Liu, H. Eugene [9 ,10 ]
Wu, Cheng-Wen [1 ,2 ,4 ,8 ,11 ]
机构
[1] Natl Yang Ming Univ, Sch Life Sci, Program Mol Med, Taipei 112, Taiwan
[2] Acad Sinica, Taipei 112, Taiwan
[3] Taipei Med Univ Hosp, Div Pulm Med, Dept Internal Med, Taipei 110, Taiwan
[4] Natl Tsing Hua Univ, Inst Biotechnol, Coll Life Sci, Hsinchu 30013, Taiwan
[5] Taipei Med Univ, Dept Pathol, Wang Fang Hosp, Taipei 11696, Taiwan
[6] Taipei Med Univ, Sch Med, Dept Internal Med, Div Thorac Med, Taipei 110, Taiwan
[7] Taipei Med Univ, Sch Resp Therapy, Coll Med, Taipei 110, Taiwan
[8] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan
[9] Taipei Med Univ, Wan Fang Hosp, Dept Internal Med, Div Hematol & Oncol, Taipei 11696, Taiwan
[10] Taipei Med Univ, Collage Med, Grad Inst Clin Med, Taipei 110, Taiwan
[11] Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei 112, Taiwan
关键词
EGFR mutation; EGFR exon 19 deletion or L858R point mutation; non-small cell lung cancer; brain metastases; TYROSINE KINASE INHIBITORS; REAL-TIME; CHEMOTHERAPY; GEFITINIB; RISK; ADENOCARCINOMA; ASSOCIATION; CARCINOMA; SURVIVAL; DISEASE;
D O I
10.18632/oncotarget.18509
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:53405 / 53418
页数:14
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