Efficacy and long-term survival of advanced lung adenocarcinoma patients with uncommon EGFR mutations treated with 1st generation EGFR-TKIs compared with chemotherapy as first-line therapy.

PURPOSE: This study aims to understand the effects and long-term survival of 1st generation epithelial growth factor receptor tyrosine kinase inhibitors(EGFR-TKI)or platinum-based chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations. PATIENTS AND METHODS: Specimens from 4276 advanced (IIIB/IV) patients were diagnosed with lung adenocarcinoma and underwent EGFR gene detection at the Affiliated Cancer Hospital of Zhengzhou University. The clinic characteristics, survival outcomes data, treatment outcomes and data of subsequent therapies after first-line treatment were collected of patients with uncommon EGFR mutations. The results were compared with common EGFR mutations. RESULTS: For patients with uncommon EGFR mutations, EGFR-TKIs or platinum-based chemotherapy as first-line therapy, showed no difference in objective response rate (ORR 33% vs 27.1% P = 0.499) and disease control rate (DCR 76.5% vs 87.5%, P = 0.194). EGFR-TKIs showed a superior progression-free survival than chemotherapy (median PFS, 7.2 vs 4.9 mt, HR = 0.604; P = 0.0088). Interestingly, compared with chemotherapy, we found that overall survival (median OS, 14.3 vs 20.7 mts, HR = 1.759; P = 0.0336) was significantly worse in patients with EGFR-TKIs. Multivariate analysis showed that extra metastases (HR = 2.240, P = 0.001) and smoking history (HR = 2.048, P = 0.013) were independent prognostic factors for OS in lung adenocarcinoma patients with EGFR uncommon mutations. CONCLUSIONS: Compared with chemotherapy, use of the 1st generation of EGFR-TKIs as first-line therapy can improve the short-term efficacy of patients with EGFR uncommon mutations advanced lung adenocarcinoma, but platinum-based chemotherapy showed a longer overall survival.

Glycerol kinase 5 confers gefitinib resistance through SREBP1/SCD1 signaling pathway.

BACKGROUND: Drug resistance is common in cancer chemotherapy. This study investigates the role of Glycerol kinase 5 (GK5) in mediating gefitinib resistance in NSCLC. METHODS: The exosomal mRNA of GK5 was detected using a tethered cationic lipoplex nanoparticle (TCLN) biochip. Real-time PCR and Western blot were used to examine the expression of GK5 mRNA and protein in gefitinib-sensitive and -resistant human lung adenocarcinoma cells. The cell counting kit-8, EdU assay, flow cytometry, and JC-1 dye were used to measure cell proliferation, cell cycle, and the mitochondrial membrane potential. RESULTS: We found that the exosomal mRNA of GK5 in the plasma of patients with gefitinib-resistant adenocarcinoma was significantly higher compared with that of gefitinib-sensitive patients. The mRNA and protein levels of GK5 were significantly upregulated in gefitinib-resistant human lung adenocarcinoma PC9R and H1975 cells compared with gefitinib-sensitive PC9 cells. Silencing GK5 in PC9R cells induced mitochondrial damage, caspase activation, cell cycle arrest, and apoptosis via SREBP1/SCD1 signaling pathway. CONCLUSIONS: We demonstrated that GK5 confers gefitinib resistance in lung cancer by inhibiting apoptosis and cell cycle arrest. GK5 could be a novel therapeutic target for treatment of NSCLC with resistance to EGFR tyrosine kinase inhibitors.

Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: Higher serum 25-hydroxyvitamin D (25(OH)D) levels are reportedly associated with better survival in early-stage non-small cell lung cancer (NSCLC). Therefore, whether vitamin D supplementation can improve the prognosis of patients with NSCLC was examined (UMIN000001869).Patients and Methods: A randomized, double-blind trial comparing vitamin D supplements (1,200 IU/day) with placebo for 1 year after operation was conducted. The primary and secondary outcomes were relapse-free survival (RFS) and overall survival (OS), respectively. Prespecified subgroup analyses were performed with stratification by stage (early vs. advanced), pathology (adenocarcinoma vs. others), and 25(OH)D levels (low, <20 ng/mL vs. high, ≥20 ng/mL). Polymorphisms of vitamin D receptor (VDR) and vitamin D-binding protein (DBP) and survival were also examined.Results: Patients with NSCLC (n = 155) were randomly assigned to receive vitamin D (n = 77) or placebo (n = 78) and followed for a median of 3.3 years. Relapse and death occurred in 40 (28%) and 24 (17%) patients, respectively. In the total study population, no significant difference in either RFS or OS was seen with vitamin D compared with the placebo group. However, by restricting the analysis to the subgroup with early-stage adenocarcinoma with low 25(OH)D, the vitamin D group showed significantly better 5-year RFS (86% vs. 50%, P = 0.04) and OS (91% vs. 48%, P = 0.02) than the placebo group. Among the examined polymorphisms, DBP1 (rs7041) TT and CDX2 (rs11568820) AA/AG genotypes were markers of better prognosis, even with multivariate adjustment.Conclusions: In patients with NSCLC, vitamin D supplementation may improve survival of patients with early-stage lung adenocarcinoma with lower 25(OH)D levels. Clin Cancer Res; 24(17); 4089-97. ©2018 AACR.