Background: Lung cancer in young patients (less or equal to 45 years) is uncommon and has clinical characteristics different from that in older patients. We investigated the outcomes and prognostic factors of young patients with advanced non-small cell lung cancer (NSCLC). Methods: From January 2000 to December 2009, we enrolled patients aged ≤45 years and diagnosed with stage IIIB or IV NSCLC. Their clinical data, including age, gender, performance status, histologic types, disease stages, laboratory data at diagnosis, treatment modalities, and survival were reviewed and analyzed. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI). Results: A total of 144 patients with advanced NSCLC were included. Female patients were more prevalent (n = 74, 51.4%). Adenocarcinoma was the most common histologic type (n = 119, 82.6%) in both genders (male, n = 54, 77.1%; female, n = 65, 87.8%). Epidermal growth factor receptor (EGFR) sequences were determined using tumor specimens from 58 patients, and 29 showed an EGFR mutation. No significant difference in median survival was found between patient groups with and without the EGFR mutation (798 vs. 708 days, p = 0.65). In multivariate analysis, male gender (HR, 1.70; 95% CI: 1.08-2.68), body mass index (BMI) less than 25 kg/m² (HR, 2.72; 95% CI: 1.39-5.30), stage IV disease (HR, 2.62; 95% CI: 1.50-4.57), and anemia (HR, 2.08; 95% CI: 1.15-3.77) were associated with a short survival time. Conclusions: Low BMI, stage IV disease, anemia at diagnosis, and male gender were the negative prognostic factors for young patients with advanced NSCLC.

Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti‐CSC agent may lead to improved disease control. We used CSC‐associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top‐ranked candidate. In non–small‐cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis‐associated Src tyrosine kinase signalling, cell migration and epithelial‐to‐mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR‐98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.

Rationale: Patients of NSCLC with mutated EGFR are relatively sensitive to EGFR-TKI treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI, compared with platinum-based chemotherapy. However, many advanced NSCLC patients with mutated EGFR do not response to first-line EGFR-TKI treatment and still have shorter PFS. Objectives: The aim of this study was to identify genetic variants associated PFS among lung adenocarcinoma (ADC) patients treated with first-line EGFR-TKIs. Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and treated with first-line EGFR-TKIs (n=128). Significant single nucleotide polymorphisms (SNPs) were selected for follow-up-association analysis (n=198) and for replication assay in another independent cohort (n=153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P<10^-8) and with an estimated hazard ratio greater than 4. This association was also replicated in a larger but similar cohort as well as in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs are associated with the expression of EGFR, which encodes the TKI target, and with a nearby gene NMU, which encodes a GPCR ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers in the treatment of late-stage lung cancer patients, we found that these SNPs were not associated with EGFR mutation status, or with BIM polymorphism. Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.