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1.  Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597 
Journal of Clinical Oncology  2013;31(33):4179-4187.
Selenium has been reported to have chemopreventive benefits in lung cancer. We conducted a double-blind, placebo-controlled trial to evaluate the incidence of second primary tumors (SPTs) in patients with resected non–small-cell lung cancer (NSCLC) receiving selenium supplementation.
Patients and Methods
Patients with completely resected stage I NSCLC were randomly assigned to take selenized yeast 200 μg versus placebo daily for 48 months. Participation was 6 to 36 months postoperatively and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, negative chest x-ray, and no other evidence of recurrence.
The first interim analysis in October 2009, with 46% of the projected end points accumulated, showed a trend in favor of the placebo group with a low likelihood that the trial would become positive; thus, the study was stopped. One thousand seven hundred seventy-two participants were enrolled, with 1,561 patients randomly assigned. Analysis was updated in June 2011 with the maturation of 54% of the planned end points. Two hundred fifty-two SPTs (from 224 patients) developed, of which 98 (from 97 patients) were lung cancer (38.9%). Lung and overall SPT incidence were 1.62 and 3.54 per 100 person-years, respectively, for selenium versus 1.30 and 3.39 per 100 person-years, respectively, for placebo (P = .294). Five-year disease-free survival was 74.4% for selenium recipients versus 79.6% for placebo recipients. Grade 1 to 2 toxicity occurred in 31% of selenium recipients and 26% of placebo recipients, and grade ≥ 3 toxicity occurred in less than 2% of selenium recipients versus 3% of placebo recipients. Compliance was excellent. No increase in diabetes mellitus or skin cancer was detected.
Selenium was safe but conferred no benefit over placebo in the prevention of SPT in patients with resected NSCLC.
PMCID: PMC3821010  PMID: 24002495
2.  Immunohistochemical analysis of C/EBPα in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: a correlative study of E3590 
We sought to determine the association of C/EBPα expression status with clinical, pathologic and molecular characteristics, as well as outcomes, in non-small-cell lung cancer (NSCLC). This is the first comprehensive study of this transcription factor in patients with NSCLC.
Patients and Methods
Our cohort originated from ECOG 3590 (randomized trial of postoperative adjuvant therapy with thoracic radiation or cisplatin and etoposide plus thoracic radiation in patients with completely resected stages II and IIIA NSCLC; and its laboratory correlate, ECOG 4592). 164 tumor samples contained sufficient material for immunohistochemical (IHC) analysis. C/EBPα tumor staining was compared to that of basal bronchial cells (3+). 0 or 1+ (weak) suggested lack of, while 2 or 3+ (strong) suggested C/EBPα expression.
90 tumors (55%) had 0 or 1+ C/EBPα staining, and the remaining 74 (45%) 2 or 3+. Patients with squamous cell carcinomas had a higher percentage of weak C/EBPα IHC staining compared to other histologies (p=0.048) and there was a trend for loss of C/EBPα in poorly differentiated compared to well differentiated tumors (p=0.07). There was no association between C/EBPα IHC and mutations in p53 or K-ras. The median disease-free survival for patients with weak and strong C/EBPα IHC expression was 29.6 and 30.6 months, respectively (p=0.94). The median overall survival between the weak and strong groups was 43.5 and 38.5 months, respectively (p=0.83).
Loss of expression of C/EBPα is seen in over half of stage II and IIIA NSCLC, specifically in squamous cell carcinomas and poorly differentiated tumors. Since down-regulation of C/EBPα is a common event in NSCLC, further elucidation of the involvement of C/EBPα in the pathogenesis and progression of lung cancer may identify novel therapeutic targets.
PMCID: PMC3380244  PMID: 17239984
lung cancer; C/EBPα; transcription factor; immunohistochemistry; non-small cell lung cancer; squamous cell carcinoma, and survival
3.  The NQO1*2/*2 polymorphism is associated with poor overall survival in patients following resection of stages II and IIIa non-small cell lung cancer 
Oncology reports  2011;25(6):1765-1772.
NAD(P)H:quinone oxidoreductase 1 (NQO1), is a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones into hydroquinones. A polymorphism (NQO1*2) alters enzymatic activity of NQO1 resulting in diminished NQO1 activity. Malignancies with NQO1*2 may be resistant to radiation and chemotherapy with resulting poorer survival. NQO1 allele was evaluated in subjects enrolled in ECOG 3590, a randomized comparison of radiation (RT) vs radiation and chemotherapy with cisplatin/etoposide (RCT) in patients with completely resected stages II and IIIa NSCLC. Overall survival was estimated using the Kaplan-Meier method and compared via the log-rank test. Cox models were used to assess the impact of covariates on outcomes. Among 152 patients with assessable samples, 24 (16%) had NQO1*2. Median follow-up was 139 months. The presence of NQO1*2/*2 was associated with decreased overall survival (OS) (median in the heterozygote/wild-type group 42.3 vs. 33.5 months in the variant group, p=0.04). In a multivariable Cox model, variant NQO1 (HR=1.58, p=0.05), age <60 (HR=0.67, p=0.04), PS 1 (HR=1.47, p=0.05), cardiovascular disease (HR=1.93, p=0.003) and alkaline phosphatase <100 mg/ml (HR=0.59, p=0.005) were all significant predictors of OS. NQO1*2/*2 may be an independent predictor of poor overall survival in individuals with resected stages II and IIIa NSCLC. Although the basis for the NQO1 association with decreased survival requires additional evaluation, NQO1 may represent a biomarker for guiding individualized therapy.
PMCID: PMC3211091  PMID: 21479364
lung cancer; NAD(P)H:quinone oxidoreductase 1; polymorphism; p53
4.  Gene promoter methylation assayed in exhaled breath, with differences in smokers and lung cancer patients 
Respiratory Research  2009;10(1):86.
There is a need for new, noninvasive risk assessment tools for use in lung cancer population screening and prevention programs.
To investigate the technical feasibility of determining DNA methylation in exhaled breath condensate, we applied our previously-developed method for tag-adapted bisulfite genomic DNA sequencing (tBGS) for mapping of DNA methylation, and adapted it to exhaled breath condensate (EBC) from lung cancer cases and non-cancer controls. Promoter methylation patterns were analyzed in DAPK, RASSF1A and PAX5β promoters in EBC samples from 54 individuals, comprised of 37 controls [current- (n = 19), former- (n = 10), and never-smokers (n = 8)] and 17 lung cancer cases [current- (n = 5), former- (n = 11), and never-smokers (n = 1)].
We found: (1) Wide inter-individual variability in methylation density and spatial distribution for DAPK, PAX5β and RASSF1A. (2) Methylation patterns from paired exhaled breath condensate and mouth rinse specimens were completely divergent. (3) For smoking status, the methylation density of RASSF1A was statistically different (p = 0.0285); pair-wise comparisons showed that the former smokers had higher methylation density versus never smokers and current smokers (p = 0.019 and p = 0.031). For DAPK and PAX5β, there was no such significant smoking-related difference. Underlying lung disease did not impact on methylation density for this geneset. (4) In case-control comparisons, CpG at -63 of DAPK promoter and +52 of PAX5β promoter were significantly associated with lung cancer status (p = 0.0042 and 0.0093, respectively). After adjusting for multiple testing, both loci were of borderline significance (padj = 0.054 and 0.031). (5) The DAPK gene had a regional methylation pattern with two blocks (1)~-215~-113 and (2) -84 ~+26); while similar in block 1, there was a significant case-control difference in methylation density in block 2 (p = 0.045); (6)Tumor stage and histology did not impact on the methylation density among the cases. (7) The results of qMSP applied to EBC correlated with the corresponding tBGS sequencing map loci.
Our results show that DNA methylation in exhaled breath condensate is detectable and is likely of lung origin. Suggestive correlations with smoking and lung cancer case-control status depend on individual gene and CpG site examined.
PMCID: PMC2759916  PMID: 19781081

Results 1-4 (4)