Lung Cancer In High-risk Population Research Articles

Genome-wide association study based risk prediction model in predicting lung cancer risk in Chinese

To evaluate the predictive power of risk model by combining traditional epidemiological factors and genetic factors. Our previous GWAS data of lung cancer in Chinese were used in training set (Nanjing and Shanghai: 1473 cases vs. 1962 control) and testing set (Beijing and Wuhan: 858 cases vs. 1 115 control). All the single nucleotide polymorphisms (SNPs) associated with lung cancer risk were systematically selected and stepwise logistic regression analysis was used to select independent factors in the training set. The wGRS (weighted genetic score) was further used to calculate genetic risk score. To evaluate the contribution of the genetic factors, 3 risk models were established by using the training set, i.e. smoking model (based on smoking status) , genetic risk model (based on genetic risk score) and combined model (based on smoke and genetic risk score). The predictability of the models were evaluated by the areas under the receiver operating characteristic (ROC) curves, area under curve (AUC), net reclassification improvement (NRI) and integrated discrimination index (IDI). Besides, the results were further verified in the testing set. In the training set, it was found that the AUC of the smoking, genetic risk and combined models were 0.65 (0.63-0.66), 0.60 (0.59-0.62) and 0.69 (0.67-0.71), respectively. Compared with combined model, the predictive power of other two models significantly declined, the difference was statistically significant (P<0.001). Furthermore, compared with the smoking model, the NRI of the combined model increased by 4.57% (2.23%-6.91%) and IDI increased by 3.11% (2.52%-3.69%) in the training set, the difference was statistically significant (P<0.001). Similarly, in the testing set NRI increased by 2.77%, the difference was not statistically significant (P=0.069) , and IDI increased by 3.16%, the difference was statistically significant (P<0.001). This study showed that combining 14 genetic variants with traditional epidemiological factors could improve the predictive power of risk model for lung cancer. The model could be used in the screening of high-risk population of lung cancer in Chinese and provide evidence for the early diagnosis and treatment of lung cancer.

Gene Signatures Stratify Computed Tomography Screening Detected Lung Cancer in High-Risk Populations

BackgroundAlthough screening programmes of smokers have detected resectable early lung cancers more frequently than expected, their efficacy in reducing mortality remains debatable. To elucidate the biological features of computed tomography (CT) screening detected lung cancer, we examined the mRNA signatures on tumours according to the year of detection, stage and survival. MethodsGene expression profiles were analysed on 28 patients (INT–IEO training cohort) and 24 patients of Multicentre Italian Lung Detection (MILD validation cohort). The gene signatures generated from the training set were validated on the MILD set and a public deposited DNA microarray data set (GSE11969). Expression of selected genes and proteins was validated by real-time RT-PCR and immunohistochemistry. Enriched core pathway and pathway networks were explored by GeneSpring GX10. FindingsA 239-gene signature was identified according to the year of tumour detection in the training INT–IEO set and correlated with the patients' outcomes. These signatures divided the MILD patients into two distinct survival groups independently of tumour stage, size, histopathological type and screening year. The signatures can also predict survival in the clinically detected cancers (GSE11969). Pathway analyses revealed tumours detected in later years enrichment of the PI3K/PTEN/AKT pathway, with up-regulation of PDPK1, ITGB1 and down-regulation of FOXO1A. Analysis of normal lung tissue from INT–IEO cohort produced signatures distinguishing patients with early from late detected tumours. InterpretationThe distinct pattern of “indolent” and “aggressive” tumour exists in CT-screening detected lung cancer according to the gene expression profiles. The early development of an aggressive phenotype may account for the lack of mortality reduction by screening observed in some cohorts.

Screening High-Risk Populations for Lung Cancer: Guideline Recommendations

The aim of this practice guideline was to develop evidence-based recommendations for screening high-risk populations for lung cancer. The guideline was developed using the methods of Cancer Care Ontario's Program in Evidence-Based Care. The core methodology of the Program in Evidence-Based Care's guideline development process is systematic review. A systematic review had recently been completed by a collaboration of the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network. The evidence from that systematic review formed the basis of the recommendations, which were reviewed, and amended where necessary, by clinical experts in the fields of medical and radiation oncology, radiology, lung disease, and population health. The systematic review included eight randomized controlled trials and 13 single-arm studies evaluating screening with low-dose computed tomography (LDCT) in patients at risk for lung cancer. One large randomized trial reported a statistically significant reduction in lung cancer mortality with LDCT at 6 years compared with chest radiography. The practice guideline recommendations generally align with the parameters of the National Lung Screening Study. Deviations were described and justified by the guideline working group. The recommendations support screening persons at high-risk for lung cancer with advice for determining a positive result on LDCT, appropriate follow-up, and optimal screening interval. The benefits of screening high-risk populations for lung cancer with LDCT outweigh the harms if screening is implemented in a strictly controlled manner.

CT Scans Recommended for Lung Cancer Screening

Abstract The U.S. Preventive Services Task Force has released draft recommendations calling for annual low-dose computed tomography scans to screen for lung cancer in high-risk populations.

The value of positron emission tomography in early detection of lung cancer in high‐risk population: a systematic review

Early detection trials with chest radiography and sputum cytology were ineffective in decreasing lung cancer mortality. The advent of low-dose spiral chest computed tomography (LDCT) provided clinicians with a new tool that could be with early diagnosis; however, this also raised significant concerns regarding the systematic use of LDCT with its high false-positive rate for benign nodules. At this time, there is limited information about the true role of PET (positron emission tomography) for early detection of lung cancer. We used systematic methods, including Preferred Reporting Items for Systematic reviews and Meta-Analyses statement, to identify relevant studies, assess study eligibility, evaluate study methodological quality, and summarize findings regarding diagnostic accuracy and outcome. In total, only seven eligible studies were selected from 82 potentially relevant studies. The sensitivity of 18F-FDG-PET for the detection of T1 lung cancers ranged between 68% and 95%. The rate of detection tended to be lower for carcinoid tumors, adenocarcinoma and bronchoalveolar cell carcinomas. FDG-PET using SUV (standardized uptake value) level can predict the outcome of the screening detected lung cancer. A combination of FDG-PET and LDCT may improve screening for lung cancer in high-risk patients. PET or PET/CT may be used as a useful tool for early detection of lung cancer in high-risk population based on the existing information. However, there is still limited information with regards to evidence of survival benefits from PET screening in high-risk patients.

EarlyCDT®-Lung test: improved clinical utility through additional autoantibody assays

Tumor-associated autoantibodies (AAbs) have been described in patients with lung cancer, and the EarlyCDT®-Lung test that measures such AAbs is available as an aid for the early detection of lung cancer in high-risk populations. Improvements in specificity would improve its cost-effectiveness, as well as reduce anxiety associated with false positive tests. Samples from 235 patients with newly diagnosed lung cancer and matched controls were measured for the presence of AAbs to a panel of six (p53, NY-ESO-1, CAGE, GBU4-5, Annexin I, and SOX2) or seven (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, and MAGE A4) antigens. Data were assessed in relation to cancer type and stage. The sensitivity and specificity of these two panels were also compared in two prospective consecutive series of 776 and 836 individuals at an increased risk of developing lung cancer. The six-AAb panel gave a sensitivity of 39 % with a specificity of 89 %, while the seven-AAb panel gave a sensitivity of 41 % with a specificity of 91 % which, once adjusted for occult cancers in the population, resulted in a specificity of 93 %. Analysis of these AAb assays in the at-risk population confirmed that the seven-AAb panel resulted in a significant increase in the specificity of the test from 82 to 90 %, with no significant change in sensitivity. The change from a six- to a seven-AAb assay can improve the specificity of the test and would result in a PPV of 1 in 8 and an overall accuracy of 92 %.

Early detection of lung cancers – Comparison of computed tomography, cytology and fuzzy-based tumor markers panels

Lung cancer is still a primary cause of cancer death in the western world. Thus, a comprehensive primary diagnostic program which comprises the measurement of biomarkers released by lung cancers is of great importance in the clinical management of lung cancer patients. This review present data for the early lung cancer detection comparing computed tomography (CT), sputum cytology and a tumor marker panel of CYFRA 21-1, CEA, NSE, ProGRP, and SCC which was included into fuzzy classification.Sensitivities in the CT studies were mainly reported with 100% and in sputum analyses with a maximum of 87.5%. The corresponding specificity in sputum cytology analysis was 92.7%. By use of CT, all peripheral squamous or adenocarcinomas of the lung were detected, but there was a lack in detection of SCLC or central localised tumors. In addition, CT detected many non-calcified nodules, of which only a fraction is actual lung cancer leading to a considerable amount of false positive results. At 95{\%}-specificity the sensitivity of a tumor marker panel included into fuzzy modelling for the detection of NSCLC was 50% at stage I. Also SCLC patients could be detected in more than 70% in limited disease stage. Detection rates of advanced tumor stages were even higher. The positive predictive value of biological markers was 80% while the negative predictive value reached around 90%. Modern biological marker approaches in combination with CT and sputum cytology analyses may improve the differential diagnosis especially for the early detection of lung cancer in high-risk populations.

Long-term outcomes of a pilot CT screening for lung cancer.

Background:Low-dose computed tomography (CT) screening can detect early stage lung cancer in high-risk populations. However, no data on repeated annual screening over more than 5 years are available, and the impact of screening on lung cancer mortality is controversial.Methods:We analysed outcomes in high-risk asymptomatic volunteers (smokers and former smokers, >50 years) enrolled in a pilot study over 1 year from June 2000, who received annual low-dose CT for 7 years. Cumulative lung cancer incidence and survival were represented by Kaplan–Meier curves. Standardized incidence and mortality ratios were used to estimate risks relative to the general Italian and US population.Results:Compliance was 86% at the end of the seventh year in 1035 recruited volunteers (71% men, mean age 58 years). Lung cancer was diagnosed in 54 (5.3%); radical surgery was possible in 48/54 (87%); 39/54 (72%) had stage I disease. Five-year survival was 63% overall, 89% for stage I cases. During 6308 person-years of observation, 47 participants had died versus 75 expected in the Italian general population standardised for age and sex. Fourteen lung cancer deaths were registered versus 27 expected in a standardised US smoker population.Conclusions:Seventy percent of screening-diagnosed patients had stage I disease, and the survival of screen-detected cancer patients was high. Lung cancer mortality was favourable compared to age- and sex-matched population of US smokers, suggesting that mortality can be lowered by screening, although larger trials with longer follow-up are necessary to confirm these findings.

Evolution of lung nodules ≤5 mm detected with low-dose CT in asymptomatic smokers

Low-dose CT is widely employed for the early diagnosis of lung cancer in high-risk populations even if screening programmes have not been clinically validated yet; however, the optimum follow-up schedule for small lung nodules of uncertain status has not been defined. The aim of this study was to assess outcomes for small pulmonary nodules (diameter < or =5 mm) detected by CT in asymptomatic smokers In 2000-2001, 1035 high-risk people were enrolled in an observational study for the early detection of lung cancer by yearly CT. The prevalence, incidence and evolution of small lung solid nodules are described 238 solid lung nodules < or = 5 mm were identified at initial low-dose CT in 165 people (prevalence 15.9%). 26% of them were not detected in the following 4 years, 43.3% did not change and 10.1% grew to >5 mm; three were removed and found to be malignant (all T1N0); the remaining 21 were followed yearly In the following year, 79 new small nodules were detected (incidence 7.9%). 11.4% were not detected in the subsequent 3 years, 79.7% did not change, 2.5% grew to > 5 mm and were followed yearly In conclusion, prevalent and incident nodules < or =5 mm detected by low-dose CT screening for lung cancer can be safely checked at 1 year intervals.

Author’s Reply

I am grateful to David Yankelevitz, MD, for pointing out what he believes to be errors in my February editorial in JACR [ 1 Hillman B.J. CT screening for lung cancer: appearances can be deceiving. J Am Coll Radiol. 2007; 4: 83-85 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar ]. However, his “Who? Us?” response to my concern over the International Early Lung Cancer Action Program (I-ELCAP) [ 2 Henschke C.I. Yankelevitz D.F. Libby D.M. Pasmantier M.W. Smith J.P. Miettinen O.S. International Early Lung Cancer Action Program InvestigatorsSurvival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006; 355: 1763-1771 Crossref PubMed Scopus (1397) Google Scholar ] exhortation to promote generalized computed tomographic screening for lung cancer in high-risk populations on the basis of their findings seems to me naive. I leave it to the readers of JACR to reread the last paragraph of the discussion in the 2006 I-ELCAP report and review interviews [ 3 Goldberg P. Henschke says her observational study should change medical practice. Cancer Lett. 2006; 32: 1-8 Google Scholar ] given by I-ELCAP authors at the time of the publication to determine which of us more closely characterizes the situation. CT Screening for Lung Cancer: Editorials Can Be DeceivingJournal of the American College of RadiologyVol. 4Issue 6PreviewIn his editorial titled “CT Screening for Lung Cancer: Appearances Can Be Deceiving,” Bruce Hillman, MD, [1] addressed the most recent publication of the International Early Lung Cancer Action Program (I-ELCAP) [2]. The editorial’s title refers to Hillman’s point that the I-ELCAP investigators’ “simple message,” namely, that computed tomographic (CT) screening “works, and everyone at risk ought to undergo it,” has deceived an “unexpected” number of radiologists who “ought to better understand the flaws in drawing definitive conclusions from the I-ELCAP report.” Full-Text PDF

Occupational exposure to asbestos and man-made vitreous fibres and risk of lung cancer: a multicentre case-control study in Europe

Objectives: To investigate the contribution of occupational exposure to asbestos and man-made vitreous fibres (MMVF) to lung cancer in high-risk populations in Europe. Methods: A multicentre case-control study was conducted...

Evaluation of chromosomal aneusomy in bronchial epithelium of smokers as a marker for lung cancer risk

7184 Background: The clinical outcome of lung cancer will be significantly improved if the disease is diagnosed in an early stage, which makes development of new diagnostic strategies necessary. In the search for biomarkers, which can be used for prediction and early diagnosis of lung cancer in high-risk population, we tested a fluorescence in situ hybridization (FISH) assay for aneusomy in bronchial epithelium. Methods: The FISH probe (LAVysion, Vysis/Abbott) consists of 4 distinctly labeled DNA targets: one centromeric (CEP6) and 3 locus-specific (5p15.2, EGFR, cMYC). Four groups of individuals were examined: NN= 17 non-smokers without tumor; NT= 10 non-smokers with non-small cell lung carcinoma (NSCLC); SN= 35 smokers without tumor; and ST= 17 smokers with NSCLC. Non-malignant bronchial epithelium was obtained from individuals accrued in clinical trials (NN and SN) or undergoing tumor resection (NT and ST). Cutoff for the percentage of abnormal cells was defined based on 100% specificity in the NN individuals. Results: The frequency of individuals with FISH aneusomy, defined as gain for at least two DNA targets, was 40% in NT, 37% in SN, and 55% in ST. In smokers (former or current), the presence of FISH aneusomy in non-malignant bronchial epithelium made an increased odds ratio (OR) of 2.4 for having lung cancer compared to the smokers without this abnormality (p=0.14). However, a combination of two specific targets, c-MYC and CEP6 provided a stronger and significant association with cancer in smokers (OR = 7.08; p=0.02). Conclusions: FISH aneusomy in non-malignant bronchial epithelium from smokers might discriminate between individuals with and without cancer. The value of this assay as a marker for risk or early detection or as a surrogate endpoint for response evaluation in chemoprevention trials are being tested in ongoing studies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca NIH-NCI SPORE in Lung Cancer

Sex-related differences in bronchial epithelial changes associated with tobacco smoking.

Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day x number of years of smoking). Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.

CARET, the beta-carotene and retinal efficacy trial to prevent lung cancer in high-risk populations : Omenn GS. Fred Hutchinson Cancer Research Ct., Seattle, WA 98195. Public Health Rev 1991;1992;19:205–8

CARET, the beta-carotene and retinal efficacy trial to prevent lung cancer in high-risk populations : Omenn GS. Fred Hutchinson Cancer Research Ct., Seattle, WA 98195. Public Health Rev 1991;1992;19:205–8

CARET, the β-carotene and retinol efficacy trial to prevent lung cancer in asbestos-exposed workers and in smokers

CARET is a two-armed, double-blind, randomized chemo-prevention trial to test the hypothesis that oral administration of beta-carotene 30 mg/day plus retinyl palmitate 25,000 IU/day will decrease the incidence of lung cancer in high-risk populations: heavy smokers and asbestos-exposed workers who have smoked. The agents combine anti-oxidant and nuclear tumor suppressor mechanisms. Fastidious monitoring for possible side effects is facilitated by inclusion of a Vanguard population. As of 31 December 1990, 6,105 participants of the 18,000 needed have been randomized in the trial. Efficacy results are expected in 1999.