Wampfler, Jason A.

54 Background: After diagnosis and treatment, lung cancer survivors do not return to a health-related quality of life (QOL) and function comparable to pre-diagnosis levels as observed in other adult cancer survivors. We hypothesize that inadequate attention has been paid to addressing and improving QOL and function among lung cancer survivors. Our primary goal is to evaluate existing symptoms and QOL deficits among lung cancer survivors. Methods: We are evaluating patterns of QOL deficits (scored 5 or less on the scale from 0 [worst] to 10 [best]) in relation to time of lung cancer diagnosis, treatments, progression and/or recurrence, and health-related conditions. We are collecting and analyzing relevant health care utilization for selected QOL deficits, and identifying availability, accessibility, and effectiveness of evidence-based interventions. The expected outcomes will be new knowledge on patterns of QOL deficits, quality-adjusted life years in relation to the availability, accessibility, and adequacy of needed care and the effectiveness of interventions targeting improvement in QOL and symptoms. Results: In our initial analysis, among 3,707 lung cancer survivors who were diagnosed in 1999 to 2010, post-cancer treatment, and followed through 2011, 39% (1,442) reported deficits in overall QOL, 71% fatigue, 60% dyspnea, 41% being sedentary, 17% low spiritual well-being (SWB), and 10% currently smoking cigarettes. Among the 1,442 lung cancer survivors with a deficit in overall QOL, 97.5% reported severe fatigue or dyspnea, being sedentary or smoking, or having low SWB. In the remaining 36 of the 1,442, 24 had pain, cough, poor appetite, or other symptoms; only 12 (<1%) did not report deficit in any of the measured QOL domains. Analyses are ongoing. Conclusions: Based on evidence gained to date, we are developing and testing interventions targeting symptoms and QOL deficits. We expect to gain strong evidence for recommendations in redefining and delivering care and support that are necessary for improving the health and QOL of lung cancer survivors.

Abstract The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case–control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14–1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00–2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 24(12); 1902–6. ©2015 AACR.

AbstractThis analysis was performed to create a scoring system to estimate the survival of patients with non‐small cell lung cancer (NSCLC). Data from 1274NSCLCpatients were analyzed to create and validate a scoring system. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor. Prognostic factors that were significant on bothUVandMVanalyses were used to develop the score. These included quality of life, age, performance status, primary tumor diameter, nodal status, distant metastases, and smoking cessation. The score for each factor was determined by dividing the 5‐year survival rate (%) by 10 and summing these scores to form a total score.MVmodels and the score were validated using bootstrapping with 1000 iterations from the original samples. The score for each prognostic factor ranged from 1 to 7 points with higher scores reflective of better survival. Total scores (sum of the scores from each independent prognostic factor) of 32–37 correlated with a 5‐year survival of 8.3% (95%CI = 0–17.1%), 38–43 correlated with a 5‐year survival of 20% (95%CI = 13–27%), 44–47 correlated with a 5‐year survival of 48.3% (95%CI = 41.5–55.2%), 48–49 correlated to a 5‐year survival of 72.1% (95%CI = 65.6–78.6%), and 50–52 correlated to a 5‐year survival of 84.7% (95%CI = 79.6–89.8%). The bootstrap method confirmed the reliability of the score. Prognostic factors significantly associated with survival on bothUVandMVanalyses were used to construct a valid scoring system that can be used to predict survival ofNSCLCpatients. Optimally, this score could be used when counseling patients, and designing future trials.

Purpose Recent evidence has suggested a relationship between the baseline quality of life (QOL) self-reported by patients with cancer and genetic disposition. We report an analysis exploring relationships among baseline QOL assessments and candidate genetic variations in a large cohort of patients with lung cancer. Patients and Methods QOL data were provided by 1,299 patients with non–small-cell lung cancer observed at the Mayo Clinic between 1997 and 2007. Overall QOL and subdomains were assessed by either Lung Cancer Symptom Scale or Linear Analog Self Assessment measures; scores were transformed to a scale of 0 to 10, with higher scores representing better status. Baseline QOL scores assessed within 1 year of diagnosis were dichotomized as clinically deficient (CD) or not. A total of 470 single nucleotide polymorphisms (SNPs) in 56 genes of three biologic pathways were assessed for association with QOL measures. Logistic regression with training/validation samples was used to test the association of SNPs with CD QOL. Results Six SNPs on four genes were replicated using our split schemes. Three SNPs in the MGMT gene (adjusted analysis, rs3858300; unadjusted analysis, rs10741191 and rs3852507) from DNA repair pathway were associated with overall QOL. Two SNPs (rs2287396 [GSTZ1] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with fatigue in unadjusted analysis. In adjusted analysis, two SNPs (rs2756109 [ABCC2] and rs9524885 [ABCC4]) from glutathione metabolic pathway were associated with pain. Conclusion We identified three SNPs in three glutathione metabolic pathway genes and three SNPs in two DNA repair pathway genes associated with QOL measures in patients with non–small-cell lung cancer.

Purpose Evidence has suggested a clinically meaningful relationship between self-reported quality of life (QOL) of a patient with cancer at the time of receiving a cancer diagnosis and overall survival (OS). This study evaluated the prognostic value of QOL assessments with regard to OS in a large cohort of patients with lung cancer. Patients and Methods A total of 2,442 patients with non–small-cell lung cancer were observed between 1997 and 2007 and completed a single-item measure of overall QOL within the first 6 months of receiving a lung cancer diagnosis; these were dichotomized using an a priori definition of a clinically deficient score (CDS; ≤ 50 v > 50). Kaplan-Meier estimates and Cox models were used to evaluate the prognostic importance of QOL on OS alone and in the presence of covariates. Logistic regression modeling was used to identify which clinical and patient characteristics were related to a clinically meaningful deficit in QOL. Results QOL deficits at time of lung cancer diagnosis were significantly associated with OS (hazard ratio [HR], 1.55; P < .001), as were performance status, older age, smoking history, male sex, treatment factors, and stage of disease. The median survival for patients with CDS QOL was 1.6 years versus 5.6 years for patients with non-CDS QOL. After controlling for all these covariates, the indication of a clinically deficient baseline QOL still contributed significantly to the prediction of patient survival (HR, 0.67; P < .001). Conclusion Overall QOL measured by a simple single item at the time of lung cancer diagnosis is a significant and independent prognostic factor for survival in patients with lung cancer.

Abstract Chronic obstructive pulmonary disease (COPD) is a strong risk factor for lung cancer. Published studies about variations of genes encoding glutathione metabolism, DNA repair, and inflammatory response pathways in susceptibility to COPD were inconclusive. We evaluated 470 single-nucleotide polymorphisms (SNP) from 56 genes of these three pathways in 620 cases and 893 controls to identify susceptibility markers for COPD risk, using existing resources. We assessed SNP- and gene-level effects adjusting for sex, age, and smoking status. Differential genetic effects on disease risk with and without lung cancer were also assessed; cumulative risk models were established. Twenty-one SNPs were found to be significantly associated with risk of COPD (P &lt; 0.01); gene-based analyses confirmed two genes (GCLC and GSS) and identified three additional genes (GSTO2, ERCC1, and RRM1). Carrying 12 high-risk alleles may increase risk by 2.7-fold; eight SNPs altered COPD risk without lung cancer by 3.1-fold and 4 SNPs altered the risk with lung cancer by 2.3-fold. Our findings indicate that multiple genetic variations in the three selected pathways contribute to COPD risk through GCLC, GSS, GSTO2, ERCC1, and RRM1 genes. Functional studies are needed to elucidate the mechanisms of these genes in the development of COPD, lung cancer, or both. Cancer Prev Res; 5(3); 365–73. ©2011 AACR.

Abstract Purpose: Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non–small cell lung cancer (NSCLC) treated with chemotherapy. Experimental Design: A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups. Results: A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20–1.77 and HR = 1.25; 95% CI = 1.05–1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11–1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50–0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38–0.77; HR = 0.67; 95% CI = 0.52–0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30–2.80; HR = 1.83; 95% CI = 1.27–2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis. Conclusion: Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations. Clin Cancer Res; 17(11); 3830–40. ©2011 AACR.

Abstract We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non–small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.