Trends in oral and vaginally administered estrogen use among US women 50 years of age or older with commercial health insurance.

OBJECTIVE: We aimed to provide information through 2015 about use in the United States of estrogen products, including orally and vaginally administered products, in postmenopausal women. METHODS: We used prescription claims for US commercial health insurance to calculate, in women 50 years of age or older (n = 12,007,364), the age-standardized and age-specific annual prevalence of estrogen use, by formulation and route of administration, for the period 2006 through 2015. RESULTS: The age-standardized annual prevalence of a prescription claim for oral estrogens declined over time, from 83 per 1,000 women in 2007 to 42 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for vaginal estrogens peaked in 2011, at 42 per 1,000 women, before declining to 35 per 1,000 women in 2015. The age-standardized annual prevalence of a prescription claim for transdermal estrogen fluctuated between 15 and 17 per 1,000 women. In age groups under 65 years of age, annual prevalence rates for vaginal rings and inserts declined over the latter half of the study period. CONCLUSIONS: Analyses of US prescription claims data between 2006 and 2015 for women 50 years of age or older showed declining use of oral estrogen generally and vaginally administered estrogen products specifically in age groups less than 65 years of age.

Pesticide exposure and liver cancer: a review.

PURPOSE: To review the epidemiologic literature examining pesticide exposure and liver cancer incidence. METHODS: A search of the MEDLINE and Embase databases was conducted in October 2015. Eligibility criteria included examining hepatocellular carcinoma (HCC) or primary liver cancer, pesticides as an exposure of interest, and individual-level incidence. The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Forty-eight papers were assessed for eligibility and 15 studies were included in the review. The majority of studies were conducted in China and Egypt (n = 8), used a case-control design (n = 14), and examined HCC (n = 14). Most studies showed no association between self-reported and/or occupational exposure to pesticides and liver cancer risk. Six studies demonstrated statistically significant positive associations, including three biomarker-based studies (two using pre-diagnostic sera) that reported higher serum levels of dichlorodiphenyltrichloroethane (DDT) were associated with increased HCC risk. Studies indirectly measuring pesticide exposure using self-reported exposure, occupation, job-exposure matrices, or geographic residence demonstrated inconsistent results. These studies were limited by exposure assessment methods, lack of confounder information, minimal case confirmation, selection bias, and/or over-adjustment. CONCLUSIONS: There is mixed evidence suggesting a possible association between specific pesticides and HCC risk, with the strongest evidence observed in biomarker-based studies. In particular, organochlorine pesticides, including DDT, may increase HCC risk. Future research should focus on improved pesticide exposure assessment methods, potentially incorporating multiple approaches including biomonitoring while considering the chemicals of interest, historical exposure to address latency periods, and examining specific chemicals and exposure pathways.

A prospective and retrospective analysis of smoking behavior changes in ever smokers with high risk for lung cancer from New Mexico and Pennsylvania.

Cigarette smoking is the leading preventable cause of death worldwide. The aim of this study is to conduct a prospective and retrospective analysis of smoking behavior changes in the Lovelace Smokers Cohort (LSC) and the Pittsburgh Lung Screening Study cohort (PLuSS). Area under the curve (AUC) for risk models predicting relapse based on demographic, smoking, and relevant clinical variables was 0.93 and 0.79 in LSC and PLuSS, respectively. The models for making a quit attempt had limited prediction ability in both cohorts (AUC≤0.62). We identified an ethnic disparity in adverse smoking behavior change that Hispanic smokers were less likely to make a quit attempt and were more likely to relapse after a quit attempt compared to non-Hispanic Whites. SNPs at 15q25 and 11p14 loci were associated with risk for smoking relapse in the LSC. Rs6495308 at 15q25 has a large difference in minor allele frequency between non-Hispanic Whites and Hispanics (0.46 versus 0.23, P<0.0001) and was associated with risk for ever relapse at same magnitude between the two ethnic groups (OR=1.36, 95% CI=1.10 to 1.67 versus 1.59, 95% CI=1.00 to 2.53, P=0.81). In summary, the risk prediction model established in LSC and PLuSS provided an excellent to outstanding distinguishing for abstainers who will or will not relapse. The ethnic disparity in adverse smoking behavior between Hispanics and non-Hispanic Whites may be at least partially explained by the sequence variants at 15q25 locus that contains multiple nicotine acetylcholine receptors.

COPD phenotypes in a lung cancer screening population.

BACKGROUND AND AIMS: COPD (chronic obstructive pulmonary disease) is a very heterogeneous disease, and phenotypic categorization of a high-risk population has many potential benefits. The present study uses a symptom questionnaire, low-dose computed tomography (LDCT) and pulmonary function tests (PFT) to phenotypically subgroup a high-risk population. METHODS: Study group consisted of current or former smokers who underwent lung cancer screening with LDCT as a subgroup of Pittsburgh Lung Screening Study. In addition to LDCT, PFT and a symptom query questionnaire were obtained from each patient. RESULTS: The study group consisted of 3183 subjects (age 50-79) subdivided into eight groups according to presence of symptoms, obstruction on PFT and presence of emphysema on LDCT. A total of 501 (15.7%) subjects were asymptomatic, with no airflow obstruction or evidence of emphysema. There were 866 (27.2%) subjects with both obstruction on PFT and emphysema on LDCT, but only 660 (20.7%) had symptoms. Five hundred thirty (16.6%) of the subjects had no emphysema on LDCT but had obstruction on PFT, although only 370 (11.6%) had symptoms. Four hundred seventy-four (14.9%) of subjects had emphysema on LDCT, but no airflow obstruction, with 312 (9.8%) symptomatic. Finally, 812 (25.5%) of subjects had no evidence of airflow obstruction on PFT or emphysema on LDCT, but had symptoms. CONCLUSION: Combining LDCT with PFT and a comprehensive questionnaire allows subgroup classification of COPD phenotypes in a high-risk population and may lead to earlier intervention and an improved framework for future studies.

Expression of PAM50 Genes in Lung Cancer: Evidence that Interactions between Hormone Receptors and HER2/HER3 Contribute to Poor Outcome.

Non-small cell lung cancers (NSCLCs) frequently express estrogen receptor (ER) ß, and estrogen signaling is active in many lung tumors. We investigated the ability of genes contained in the prediction analysis of microarray 50 (PAM50) breast cancer risk predictor gene signature to provide prognostic information in NSCLC. Supervised principal component analysis of mRNA expression data was used to evaluate the ability of the PAM50 panel to provide prognostic information in a stage I NSCLC cohort, in an all-stage NSCLC cohort, and in The Cancer Genome Atlas data. Immunohistochemistry was used to determine status of ERß and other proteins in lung tumor tissue. Associations with prognosis were observed in the stage I cohort. Cross-validation identified seven genes that, when analyzed together, consistently showed survival associations. In pathway analysis, the seven-gene panel described one network containing the ER and progesterone receptor, as well as human epidermal growth factor receptor (HER)2/HER3 and neuregulin-1. NSCLC cases also showed a significant association between ERß and HER2 protein expression. Cases positive for HER2 expression were more likely to express HER3, and ERß-positive cases were less likely to be both HER2 and HER3 negative. Prognostic ability of genes in the PAM50 panel was verified in an ERß-positive cohort representing all NSCLC stages. In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma. Genes in the PAM50 panel, including those linking ER and HER2, identify lung cancer patients at risk for poor outcome, especially among ERß-positive cases and squamous cell carcinoma.

Pesticide exposure and hepatocellular carcinoma risk: A case-control study using a geographic information system (GIS) to link SEER-Medicare and California pesticide data.

BACKGROUND: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is associated with low survival. U.S. studies examining self-reported pesticide exposure in relation to HCC have demonstrated inconclusive results. We aimed to clarify the association between pesticide exposure and HCC by implementing a novel data linkage between Surveillance, Epidemiology, and End Results (SEER)-Medicare and California Pesticide Use Report (PUR) data using a geographic information system (GIS). METHODS: Controls were frequency-matched to HCC cases diagnosed between 2000 and 2009 in California by year, age, race, sex, and duration of residence in California. Potential confounders were extracted from Medicare claims. From 1974 to 2008, pounds (1 pound represents 0.45 kg) of applied organophosphate, organochlorine, and carbamate pesticides provided in PURs were aggregated to the ZIP Code level using area weighting in a GIS. ZIP Code exposure estimates were linked to subjects using Medicare-provided ZIP Codes to calculate pesticide exposure. Agricultural residents were defined as living in ZIP Codes with a majority area intersecting agricultural land cover according to the 1992, 2001, and 2006 National Land Cover Database (NLCD) rasters. Multivariable conditional logistic regression was used to estimate the association between pesticide exposure and HCC. RESULTS: Among California residents of agriculturally intensive areas, previous annual ZIP Code-level exposure to over 14.53 kg/km(2) of organochlorine pesticides (75(th) percentile among controls) was associated with an increased risk of HCC after adjusting for liver disease and diabetes (adjusted odds ratio [OR] 1.87, 95% confidence interval [CI] 1.17, 2.99; p=0.0085). ZIP Code-level organochlorines were significantly associated with an increased risk of HCC among males (adjusted OR 2.76, 95% CI 1.58, 4.82; p=0.0004), but not associated with HCC among females (adjusted OR 0.83, 95% CI 0.35, 1.93; p=0.6600) (interaction p=0.0075). CONCLUSIONS: This is the first epidemiologic study to use GIS-based exposure estimates to study pesticide exposure and HCC. Our results suggest that organochlorine pesticides are associated with an increase in HCC risk among males but not females.

Lung Cancer Risk Prediction Using Common SNPs Located in GWAS-Identified Susceptibility Regions.

INTRODUCTION: Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We evaluated the lung cancer-predictive performance of single-nucleotide polymorphisms (SNPs) in these regions. METHODS: Lung cancer cases (N = 778) and controls (N = 1166) were genotyped for 77 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used stepwise logistic regression and decision-tree analyses. In a subset nested in the Pittsburgh Lung Screening Study, change in area under the receiver operator characteristic curve and net reclassification improvement were used to compare predictions made by risk factor models with and without genetic variables. RESULTS: Variable selection and model development kept two SNPs in each of three GWAS regions, rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1. The ratio of cases to controls was three times higher among subjects with a high-risk genotype in every one as opposed to none of the three GWAS regions (odds ratio, 3.14; 95% confidence interval, 2.02-4.88; adjusted for sex, age, and pack-years). Adding a three-level classified count of GWAS regions with high-risk genotypes to an age and smoking risk factor-only model improved lung cancer prediction by a small amount: area under the receiver operator characteristic curve, 0.725 versus 0.717 (p = 0.056); overall net reclassification improvement was 0.052 across low-, intermediate-, and high- 6-year lung cancer risk categories (<3.0%, 3.0%-4.9%, ≥ 5.0%). CONCLUSION: Specifying genotypes for SNPs in three GWAS-identified susceptibility regions improved lung cancer prediction, but probably by an extent too small to affect disease control practice.

Epigenetic Repression of CCDC37 and MAP1B Links Chronic Obstructive Pulmonary Disease to Lung Cancer.

INTRODUCTION: Lung cancer and chronic obstructive pulmonary disease (COPD) share environmental risk factors. COPD also increases the risk of lung cancer; however, the molecular mechanisms are unclear. METHODS: An epigenome-wide association study of lung tumors and cancer-free lung tissue (CFLT) pairs from non-small-cell lung cancer cases with (n = 18) or without (n = 17) COPD was conducted using the HumanMethylation450 beadchip (HM450K). COPD-associated methylation of top-ranked genes was confirmed in a larger sample set, independently validated, and their potential as sputum-based biomarkers was investigated. RESULTS: Methylation of CCDC37 and MAP1B was more prevalent in lung tumors from COPD than non-COPD cases [54 of 71 (76%) versus 20 of 46 (43%), p = 0.0013] and [48 of 71 (68%) versus 17 of 46 (37%), p = 0.0035], respectively, after adjustment for age, sex, smoking status, and tumor histology. HM450K probes across CCDC37 and MAP1B promoters showed higher methylation in tumors than CFLT with the highest methylation seen in tumors from COPD cases (p < 0.05). These results were independently validated using The Cancer Genome Atlas data. CCDC37 methylation was more prevalent in sputum from COPD than non-COPD smokers (p < 0.005) from two cohorts. CCDC37 and MAP1B expression was dramatically repressed in tumors and CFLT from COPD than non-COPD cases, p less than 0.02. CONCLUSIONS: The reduced expression of CCDC37 and MAP1B associated with COPD likely predisposes these genes to methylation that in turn, may contribute to lung cancer.

Indolent, Potentially Inconsequential Lung Cancers in the Pittsburgh Lung Screening Study.

RATIONALE: The finding of indolent, potentially inconsequential cancers (overdiagnosis) is inherent to cancer screening in general, and there is a growing body of literature about this concept in lung cancer screening. OBJECTIVES: We report on indolent, potentially inconsequential lung cancers in the Pittsburgh Lung Screening Study (PLuSS) population screened for lung cancer with annual low-dose computed tomography. METHODS: We identified 93 subjects with screen-detected prevalence cancers in PLuSS. We defined indolent, potentially inconsequential cancers as stage I prevalence lung cancer cases that had volumetric doubling time >400 days (when available) and maximal standardized uptake value max on positron emission tomography (PET) scan ≤1 (when available). MEASUREMENTS AND MAIN RESULTS: Approximately 18.5% (n = 17) of all 93 screen-detected prevalence lung cancers in PLuSS were indolent, potentially inconsequential cancers. All such cancers except for one were adenocarcinomas by histology. Median tumor size of such cancers at the time of final diagnosis was 10 mm (range, 7-22 mm). Median doubling time was significantly longer in this group when compared with the rest of the prevalence stage 1 cancers (752 vs. 284.5 d). CONCLUSIONS: Although the precise definitions may vary, the existence of indolent, potentially inconsequential cancers in low-dose computed tomography lung cancer screening is real. Clinicians involved in managing patients with low-dose computed tomography-detected slow-growing nodules, especially with a standardized uptake value ≤1 on PET scan, should consider the possibility of indolent, potentially inconsequential cancer in the longitudinal management of these nodules.

Differential expression of circulating microRNAs according to severity of colorectal neoplasia.

There is a need to develop a colorectal cancer (CRC) screening test that is noninvasive, cost effective, and sensitive enough to detect preneoplastic lesions. This case-control study examined the feasibility of using circulating extracellular microRNAs (miRNAs) to differentiate a spectrum of colorectal neoplasia of various severity and hence for early detection of colorectal neoplasia. Archived serum samples of 10 normal controls and 31 cases, including 10 with nonadvanced adenoma, 10 with advanced adenoma, and 11 with CRC, were profiled for circulating miRNAs using next-generation sequencing. Multiple linear regression, adjusting for age, gender, and smoking status, compared controls and the 3 case groups for levels of 175 miRNAs that met stringent criteria for miRNA sequencing analysis. Of the 175 miRNAs, 106 miRNAs were downregulated according to severity of neoplasia and showed a relative decrease in the expression from controls to nonadvanced adenoma to advanced adenoma to CRC (Ptrend < 0.05). Pairwise group comparisons showed that 39 and 80 miRNAs were differentially expressed in the advanced adenoma and CRC groups compared with the controls, respectively. Differences in miRNA levels between the nonadvanced adenoma group and controls were modest. Our study found that expression of many miRNAs in serum was inversely correlated with the severity of colorectal neoplasia, and differential miRNA profiles were apparent in preneoplastic cases with advanced lesions, suggesting circulating miRNAs could serve as potential biomarkers for CRC screening.

Improving selection criteria for lung cancer screening. The potential role of emphysema.

RATIONALE: Lung cancer (LC) screening using low-dose chest computed tomography is now recommended in several guidelines using the National Lung Screening Trial (NLST) entry criteria (age, 55-74; ≥30 pack-years; tobacco cessation within the previous 15 yr for former smokers). Concerns exist about their lack of sensitivity. OBJECTIVES: To evaluate the performance of NLST criteria in two different LC screening studies from Europe and the United States, and to explore the effect of using emphysema as a complementary criterion. METHODS: Participants from the Pamplona International Early Lung Action Detection Program (P-IELCAP; n = 3,061) and the Pittsburgh Lung Screening Study (PLuSS; n = 3,638) were considered. LC cumulative frequencies, incidence densities, and annual detection rates were calculated in three hypothetical cohorts, including subjects who met NLST criteria alone, those with computed tomography-detected emphysema, and those who met NLST criteria and/or had emphysema. MEASUREMENTS AND MAIN RESULTS: Thirty-six percent and 59% of P-IELCAP and PLuSS participants, respectively, met NLST criteria. Among these, higher LC incidence densities and detection rates were observed. However, applying NLST criteria to our original cohorts would miss as many as 39% of all LC. Annual screening of subjects meeting either NLST criteria or having emphysema detected most cancers (88% and 95% of incident LC of P-IELCAP and PLuSS, respectively) despite reducing the number of screened participants by as much as 52%. CONCLUSIONS: LC screening based solely on NLST criteria could miss a significant number of LC cases. Combining NLST criteria and emphysema to select screening candidates results in higher LC detection rates and a lower number of cancers missed.

15q12 variants, sputum gene promoter hypermethylation, and lung cancer risk: a GWAS in smokers.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Detection of promoter hypermethylation of tumor suppressor genes in exfoliated cells from the lung provides an assessment of field cancerization that in turn predicts lung cancer. The identification of genetic determinants for this validated cancer biomarker should provide novel insights into mechanisms underlying epigenetic reprogramming during lung carcinogenesis. METHODS: A genome-wide association study using generalized estimating equations and logistic regression models was conducted in two geographically independent smoker cohorts to identify loci affecting the propensity for cancer-related gene methylation that was assessed by a 12-gene panel interrogated in sputum. All statistical tests were two-sided. RESULTS: Two single nucleotide polymorphisms (SNPs) at 15q12 (rs73371737 and rs7179575) that drove gene methylation were discovered and replicated with rs73371737 reaching genome-wide significance (P = 3.3×10(-8)). A haplotype carrying risk alleles from the two 15q12 SNPs conferred 57% increased risk for gene methylation (P = 2.5×10(-9)). Rs73371737 reduced GABRB3 expression in lung cells and increased risk for smoking-induced chronic mucous hypersecretion. Furthermore, subjects with variant homozygote of rs73371737 had a two-fold increase in risk for lung cancer (P = .0043). Pathway analysis identified DNA double-strand break repair by homologous recombination (DSBR-HR) as a major pathway affecting susceptibility for gene methylation that was validated by measuring chromatid breaks in lymphocytes challenged by bleomycin. CONCLUSIONS: A functional 15q12 variant was identified as a risk factor for gene methylation and lung cancer. The associations could be mediated by GABAergic signaling that drives the smoking-induced mucous cell metaplasia. Our findings also substantiate DSBR-HR as a critical pathway driving epigenetic gene silencing.

Human herpesvirus 8 seroconversion in a population-based cohort of men in Tobago.

Human herpesvirus 8 (HHV-8) is the causal agent of Kaposi's sarcoma (KS). In Tobago, KS is not common; however, HHV-8 seropositivity has been reported to be 39.9% in men with prostate cancer compared to <22.9% in healthier women and men. To understand HHV-8 transmission, we examined HHV-8 seroconversion and seroreversion, and risk factors for these changes in Tobago men. Serum specimens from a sub-cohort of Tobago Prostate Survey men, aged 40-81 years (n = 381/442), were collected at baseline and a subsequent visit between 3 and 9 years and tested for HHV-8 seropositivity using an immunofluorescence assay for antibodies against HHV-8 lytic antigens. Poisson distribution was used to calculate HHV-8 seroconversion and seroreversion rates and their 95% confidence intervals. Differences in baseline characteristics between HHV-seroconverters versus persistent HHV-8 seronegative men and HHV-8 seroreverters versus HHV-8 seropositive men were examined. HHV-8 seropositivity was 12.3% (N = 381) at baseline, with HHV-8 seropositivity significantly higher in increasing age groups, 40-49 (4.0%) to 70-81 (37.5%) years (P-value trend <0.0001). HHV-8 seroconversion and seroreversion rates were 0.23 per 100 person-years (95% C.I., 0.06-0.58) and 2.42 per 100 person-years (95% C.I., 0.89-5.26), respectively. There were significantly more HHV-8 seroconverters who reported "ever smoked cigarettes of >6 months" at baseline compared to HHV-8 persistent seronegative men (P-value = 0.03). Baseline characteristics of HHV-8 seroreverters did not differ from persistent seropositive men. Low HHV-8 seroconversion and seroreversion rates were found. Data suggest that HHV-8 transmission occurred at earlier ages, <40 years, in Tobago men.

Incidence of head and neck squamous cell carcinoma among subjects at high risk of lung cancer: results from the Pittsburgh Lung Screening Study.

BACKGROUND: Earlier detection and diagnosis of head and neck squamous cell carcinoma (HNSCC) should lead to improved outcomes. However, to the authors' knowledge, no effective screening strategy has been identified to date. In the current study, the authors evaluated whether it would be useful to screen subjects targeted for lung cancer screening for HNSCC as well. METHODS: Medical records, death certificates, and cancer registry and questionnaire data were used to determine the number of observed incident HNSCC cases in the Pittsburgh Lung Screening Study (PLuSS), a cohort of current and former smokers aged ≥50 years with a ≥12.5 pack-year smoking history. The expected number of cases was estimated using stratum-specific incidence rates obtained from Surveillance, Epidemiology, and End Results data for 2000 through 2011. The standardized incidence ratio was calculated to examine the difference between the observed and expected number of cases. RESULTS: Of the 3587 at-risk participants in the PLuSS, 23 (0.64%) developed HNSCC over a total of 32,201 person-years of follow-up. This finding was significantly higher than expected based on incidence rates obtained from the Surveillance, Epidemiology, and End Results program (13.70 cases expected; standardized incidence ratio, 1.68 [95% confidence interval, 1.06-2.52]). The excess burden of HNSCC in the PLuSS was 28.9 cases per 100,000 person-years. Observed incident cases were significantly more often male, had started smoking at a younger age, smoked more per day, and had more pack-years of smoking than the rest of the PLuSS at-risk participants. CONCLUSIONS: The results of the current study provide a rationale for offering head and neck cancer screening along with computed tomography screening for lung cancer. Randomized controlled trials that assess the effectiveness of adding examination of the head and neck area to lung cancer screening programs are warranted.

Linking pesticides and human health: a geographic information system (GIS) and Landsat remote sensing method to estimate agricultural pesticide exposure.

Accurate pesticide exposure estimation is integral to epidemiologic studies elucidating the role of pesticides in human health. Humans can be exposed to pesticides via residential proximity to agricultural pesticide applications (drift). We present an improved geographic information system (GIS) and remote sensing method, the Landsat method, to estimate agricultural pesticide exposure through matching pesticide applications to crops classified from temporally concurrent Landsat satellite remote sensing images in California. The image classification method utilizes Normalized Difference Vegetation Index (NDVI) values in a combined maximum likelihood classification and per-field (using segments) approach. Pesticide exposure is estimated according to pesticide-treated crop fields intersecting 500 m buffers around geocoded locations (e.g., residences) in a GIS. Study results demonstrate that the Landsat method can improve GIS-based pesticide exposure estimation by matching more pesticide applications to crops (especially temporary crops) classified using temporally concurrent Landsat images compared to the standard method that relies on infrequently updated land use survey (LUS) crop data. The Landsat method can be used in epidemiologic studies to reconstruct past individual-level exposure to specific pesticides according to where individuals are located.

Identification of epidermal growth factor receptor (EGFR) genetic variants that modify risk for head and neck squamous cell carcinoma.

EGFR polymorphisms have not been thoroughly evaluated for association with head and neck squamous cell carcinoma (HNSCC) risk. We genotyped 578 HNSCC patients and 588 cancer-free controls for 60 EGFR single nucleotide polymorphisms (SNPs) and tested associations with HNSCC risk. EGFR intronic SNPs rs12535536, rs2075110, rs1253871, rs845561 and rs6970262 and synonymous SNP rs2072454 were associated with HNSCC risk among all subjects (p < 0.05). SNPs rs12538371, rs845561, and rs6970262 were significantly associated with HNSCC risk (p < 0.05) among never tobacco users. We identified EGFR variants that likely modify risk for HNSCC including three variants that contribute to tobacco-independent risk.

Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score.

RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs. OBJECTIVES: To develop a predictive score for LC risk for patients with COPD. METHODS: The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP. MEASUREMENTS AND MAIN RESULTS: By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category. CONCLUSIONS: The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

Prognosis and conditional disease-free survival among patients with ovarian cancer.

PURPOSE: Traditional disease-free survival (DFS) does not reflect changes in prognosis over time. Conditional DFS accounts for elapsed time since achieving remission and may provide more relevant prognostic information for patients and clinicians. This study aimed to estimate conditional DFS among patients with ovarian cancer and to evaluate the impact of patient characteristics. PATIENTS AND METHODS: Patients were recruited as part of the Hormones and Ovarian Cancer Prediction case-control study and were included in the current study if they had achieved remission after a diagnosis of cancer of the ovary, fallopian tube, or peritoneum (N = 404). Demographic and lifestyle information was collected at enrollment; disease, treatment, and outcome information was abstracted from medical records. DFS was calculated using the Kaplan-Meier method. Conditional DFS estimates were computed using cumulative DFS estimates. RESULTS: Median DFS was 2.54 years (range, 0.03-9.96 years) and 3-year DFS was 48.2%. The probability of surviving an additional 3 years without recurrence, conditioned on having already survived 1, 2, 3, 4, and 5 years after remission, was 63.8%, 80.5%, 90.4%, 97.0%, and 97.7%, respectively. Initial differences in 3-year DFS at time of remission between age, stage, histology, and grade groups decreased over time. CONCLUSION: DFS estimates for patients with ovarian cancer improved dramatically over time, in particular among those with poorer initial prognoses. Conditional DFS is a more relevant measure of prognosis for patients with ovarian cancer who have already achieved a period of remission, and time elapsed since remission should be taken into account when making follow-up care decisions.

Validation of a blood protein signature for non-small cell lung cancer.

BACKGROUND: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. RESULTS: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. CONCLUSIONS: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.

Inherited variation in the ATP-binding cassette transporter ABCB1 and survival after chemotherapy for stage III-IV lung cancer.

BACKGROUND: The ATP-binding cassette transporter gene ABCB1 and the glutathione S-transferase gene GSTP1 code for a multidrug resistance protein and for a detoxifying phase II metabolic enzyme, respectively, with substrate specificities that include chemotherapy drugs often used to treat lung cancer. METHODS: We genotyped 11 ABCB1 and eight GSTP1 single nucleotide polymorphisms (SNPs) in 698 white lung cancer patients (all current or former cigarette smokers) and used log-rank test statistics and proportional hazards regression to evaluate associations between SNP genotype and survival. RESULTS: Using data from all 698 cases, one SNP in ABCB1 (rs2235013) was statistically significantly associated with overall survival (p = 0.038, log-rank test). Chemotherapy and stage jointly (p = 0.025) significantly modified the association between rs2235013 and survival, with statistically significant (p = 0.013, log-rank test) association observed in the subgroup of stage III to IV lung cancer patients who received chemotherapy as part of their first course of treatment (n = 160; 93.1% nonsmall cell). Patients who inherited the minor T allele at ABCB1 rs2235013 experienced better overall survival and recurrence-free survival (hazard ratio, per minor T allele, [95% confidence interval]: 0.66 [0.49-0.90] and 0.55 [0.31-0.95], respectively; adjusted for year of diagnosis, sex, age at diagnosis, cigarette pack years, and stage). In addition, in the advanced stage chemotherapy-treated subgroup, four ABCB1 SNPs (rs6949448, rs2235046, rs1128503, and rs10276036) in mutual high linkage disequilibrium with rs2235013 and an independent ABCB1 SNP (rs1045642) showed statistically significant association (p < 0.05) with survival. CONCLUSIONS: Inherited variation in ABCB1 may affect survival specifically in advanced stage lung cancer patients who receive chemotherapy.