Effects of concurrent TP53 mutations on the efficacy and prognosis of targeted therapy for advanced EGFR mutant lung adenocarcinoma.

BACKGROUND: How concurrent TP53 mutations affect targeted therapy of advanced Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinoma remains controversial, particularly the deep classification of TP53 mutations. METHODS: This study retrospectively analyzed the clinical data of advanced EGFR mutant lung adenocarcinoma patients treated with EGFR-tyrosine kinase inhibitors (TKIs) in the First Affiliated Hospital of Soochow University. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models. RESULTS: Total 156 advanced lung adenocarcinoma patients treated with EGFR-TKIs were included in this study. Multivariate analysis showed that male [hazard rate (HR): 1.537, 95% confidence interval (CI): 1.055-2.240, P = 0.025], brain metastasis (HR: 1.707, 95%CI: 1.086-2.682, P = 0.020) and concurrent TP53 mutations (HR: 1.569, 95%CI: 1.051-2.341, P = 0.028) were independent negative predictors of progression-free survival (PFS). EGFR L858R mutations (HR: 2.475, 95%CI: 1.443-4.248, p = 0.001), smoking history (HR: 2.530, 95%CI: 1.352-4.733, P = 0.004) and concurrent TP53 mutations (HR: 2.326, 95%CI: 1.283-4.218, P = 0.005) were associated with worse survival. Further analysis revealed that mutations in TP53 exons 4, 5 and 8 (P<0.05), missense mutations (P = 0.006) and nondisruptive mutations (P<0.001) were associated with shorter PFS, whereas mutations in TP53 exons 5 and 7 (P<0.05), missense mutations and non-missense mutations (P = 0.006; P = 0.007), disruptive mutations and nondisruptive mutations (P = 0.013; P = 0.013) were all associated with poorer survival times. In addition, the PFS and overall survival (OS) of nondisruptive mutations in exon 7 were worse than those in other exons (P = 0.041; P<0.001). CONCLUSIONS: Concurrent TP53 mutations conferred worse EGFR-TKIs efficacy and prognosis in advanced EGFR mutant lung adenocarcinoma and the effects of different TP53 mutation types were heterogeneous.

Forkhead box L2 is a target of miR-133b and plays an important role in the pathogenesis of non-small cell lung cancer.

BACKGROUND: Forkhead box L2 (FOXL2) has been recognized as a transcription factor in the progression of many malignancies, but its role in non-small cell lung cancer (NSCLC) remains unclear. This research clarified on the role of FOXL2 and the specific molecular mechanism in NSCLC. METHODS: RNA and protein levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting assays. Cell proliferation was examined by cell counting kit-8 (CCK-8) and clonogenic assays. Transwell and wound healing assays were used to detect cell invasion and migration. Cell cycle alterations were assessed by flow cytometry. The relationship between FOXL2 and miR-133b was verified by dual-luciferase reporter assays. In vivo metastasis was monitored in the tail vein-injected mice. RESULTS: FOXL2 was upregulated in NSCLC cells and tissues. Downregulation of FOXL2 restrained cell proliferation, migration, and invasion and arrested the cell cycle of NSCLC cells. Moreover, FOXL2 promoted the epithelial-mesenchymal transition (EMT) process of NSCLC cells by inducing the transforming growth factor-ß (TGF-ß)/Smad signaling pathway. miR-133b directly targeted the 3'-UTR of FOXL2 and negatively regulated FOXL2 expression. Knockdown of FOXL2 blocked metastasis in vivo. CONCLUSIONS: miR-133b downregulates FOXL2 by targeting the 3'-UTR of FOXL2, thereby inhibiting cell proliferation, EMT and metastasis induced by the TGF-ß/Smad signaling pathway in NSCLC. FOXL2 may be a potential molecular target for treating NSCLC.

Survival and prognostic factors for patients with malignant central airway obstruction following airway metallic stent placement.

BACKGROUND: There have been many studies on the effectiveness and complications of airway stent, but few had focused on factors that affect survival after stent placement. This study intended to assess the factors associated with the survival in patients with malignant central airway obstruction (MCAO) after airway metallic stent placement. METHODS: The clinical data of adult MCAO patients who underwent stent placement form February 2003 to June 2017 in the First Affiliated Hospital of Soochow University in China were retrospectively analyzed. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models. RESULTS: Total 102 MCAO patients were included in this study. The median survival time of these patients after airway metallic stent placement was 4.1 months. Multivariate analysis showed that MCAO patients receiving radiotherapy [hazard ratio (HR) 0.554; 95% confidence interval (CI): 0.308-0.999] or chemoradiotherapy (HR 0.251; 95% CI: 0.126-0.499) after stenting had better prognosis. However, ECOG PS ≥3 score prior to the stenting (HR 2.193; 95% CI: 1.364-3.526) and stents placed in both trachea and main bronchus (HR 2.458; 95% CI: 1.384-4.366) were associated with worse survival. CONCLUSIONS: In our results, survival of MCAO patients after airway metallic stenting was related to ECOG PS score prior to the stenting, the site of stent placement and we have hereby proposed for the first time that having opportunity to receive radiotherapy or chemoradiotherapy after stenting contribute to better prognosis.