Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing.

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR.

Treatment outcome comparisons between exons 19 and 21 EGFR mutations for non-small-cell lung cancer patients with malignant pleural effusion after first-line and second-line tyrosine kinase inhibitors.

Recent studies demonstrated a significantly increased frequency of epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). The purpose of this study is to investigate the effect of first-line and second-line EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC with MPEs harboring exon 19 deletion and L858R mutation. From 2010 to 2015, 203 NSCLC patients with MPEs harboring EGFR mutation treated with EGFR-TKIs were reviewed. The efficacy were evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. The objective response rate (ORR) and disease control rate (DCR) for patients treated with first-line and second-line EGFR-TKIs were 21.9%, 91.4% and 14.7%, 85.3%, respectively. The overall median PFS and OS of enrolled NSCLC patients with MPE were 9.3 months (95% CI, 8.4-10.2 months), 20.9 months (95% CI, 18.9-22.9 months) after first-line TKIs, and 7.6 months (95% CI, 6.6-8.6 months), 15.3 months (95% CI, 13.6-15.9 months) after second-line TKIs. The exon 19 deletion arm had a longer median PFS (9.4 vs 7.1 months, p=0.003) and OS (16.8 vs 13.8 months, p=0.003) compared with the L858R mutation arm after second-line TKIs. In a conclusion, EGFR genotype was an independent predictor of PFS and OS. No significant side effects differences between the two mutation groups was observed for first or second-line EGFR-TKIs. This study demonstrated that EGFR mutations are significant predictors for advanced NSCLC patients with MPE receiving second-line EGFR-TKIs treatment.

Efficacy of Second-line Tyrosine Kinase Inhibitors in the Treatment of Metastatic Advanced Non-small-cell Lung Cancer Harboring Exon 19 and 21 EGFR Mutations.

Background: Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity, the sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of second-line EGFR-TKIs in the treatment of NSCLC patients according to different EGFR genotypes. Methods: The treatment outcomes of 166 NSCLC patients with different EGFR mutations treated by second-line TKIs were retrospectively reviewed. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. Results: The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the exon 19 L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p<0.001), OS: (13.7 vs. 7.9 months, p=0.006)]. No significant difference on PFS and OS was observed between exon 19 deletion and L858R mutation group for patients with bone metastasis. EGFR genotype and ECOG PS were independent predictors of PFS. Never smoking, exon 19 deletion, EGOC PS (0-1) and no brain metastasis were correlated with longer OS. No significant difference on side effect between exon 19 and 21 mutation group was observed. Conclusions: NSCLC patients harboring exon 19 deletion achieved better PFS and OS than those with L858R mutation, indicating that EGFR mutation is a significant prognostic factor for advanced NSCLC patients with and without brain metastasis receiving second-line EGFR-TKIs treatment.

The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases.

BACKGROUND: Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM. METHODS: A total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire. RESULTS: The average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable. CONCLUSIONS: Adding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.

The Efficacy of Taxanes- and Oxaliplatin-Based Chemotherapy in the Treatment of Gastric Cancer After D2 Gastrectomy for Different Lauren Types.

To investigate the efficacy of Taxanes- and Oxaliplatin-based chemotherapies (TC and OC) in the treatment of gastric cancer patients after D2 gastrectomy with different Lauren types. In this study, 299 patients of gastric adenocarcinoma with D2 lymph node dissection were reviewed between 2007 and 2014. Chemotherapies were classified as Oxaliplatin-based and Taxanes-based regimen. Treatment outcomes were analyzed according to different Lauren types, such as the intestinal type, diffuse type, and mixed type groups, respectively. The disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used for univariate analysis, and Cox regression was used for multivariate analysis. In diffuse type gastric cancer, the Oxaliplatin-based arm had a longer median DFS and OS compared with Taxanes-based arm (DFS: 47.0 vs 28.6 months, P = 0.04; OS: 51.9 vs 34.5 months, P = 0.048). The chemotherapy regimen was an independent prognostic factor for DFS and OS of diffuse type gastric cancer patients by multivariate analysis (P = 0.01). In the intestinal type, although the DFS and OS of intestinal type patients in TC group were higher than those in OC group (DFS: 53.4 vs 42.4 months; OS: 69.7 vs 57.8 months), there was no statistical significance observed (both P > 0.05). For the mixed type, the 2 different chemotherapy regimens achieved similar median DFS and OS. In a conclusion, the patients of diffuse type were more sensitive to OC, and the intestinal type patients may be benefit from TC. Therefore, it will be of benefit for gastric patients by introducing Lauren classification clinically and to help the choice of chemotherapy regimen for gastric patients after D2 gastrectomy.