Low-dose Computed Tomography Arm Research Articles

Modeling the impact of novel systemic treatments on lung cancer screening benefits.

Since low-dose computed tomography (LDCT) screening was shown to be effective in the National Lung Screening Trial (NLST), novel targeted therapies and immunotherapies for advanced lung cancer have become available. This study investigated the impact of these treatment advances on the expected benefits of LDCT screening. A microsimulation model of LDCT screening for high-risk individuals under standard systemic treatments (chemotherapy and radiation therapy) and novel treatments (immunotherapy and targeted therapy) was used. The model assumed a reduction in advanced-stage disease consistent with the NLST, and given the stage at diagnosis, it projected survival. The disease-specific relative mortality reduction (MR) due to LDCT screening was projected in the trial setting and in a population eligible for LDCT screening under the current US Preventive Services Task Force (USPSTF) recommendations. The availability of novel treatments reduced the MR in the LDCT arm of the NLST from 15% to 13.5% and the number of lung cancer deaths prevented from 310 to 224 per 100,000 persons screened. Over 10years, population LDCT screening based on USPSTF recommendations prevented 374 lung cancer deaths per 100,000 under standard treatments (13.3% MR) and 236 per 100,000 under fully adopted novel treatments (10.6% MR). The number needed to screen to avert one death over 10 years was 270 under standard treatments and 440 under novel treatments. The transition from standard systemic treatments to novel treatments is expected to reduce the relative and absolute mortality benefits of LDCT screening. Benefit-harm tradeoffs of LDCT screening are likely to change as novel treatments become widespread.

Do competing causes of mortality contribute to overdiagnosis in lung cancer screening?

Overdiagnosed cancers are those that are screen-detected but never would have been symptomatic during patients’ lifetimes. Indolent cancers are overdiagnosed cancers. Non-indolent cancers can be overdiagnosed when patients die of causes other than the screen-detected cancer and would have, in the absence of screening, been asymptomatic and undiagnosed at the time of death. This is termed competing cause of mortality (CCM) overdiagnosis. Deaths soon after screen detection may represent CCM overdiagnosis. We examined time from screen-detection to death among the 35 participants in the National Lung Screening Trial (NLST) low-dose computed tomography arm with screen-detected lung cancer and died of non-lung-cancer causes. Seven participants died within 6 months, and 20 died more than 24 months after diagnosis. Deaths due to non-lung cancer causes soon after screen detection were uncommon, arguing against widespread CCM overdiagnosis in the NLST. However, CCM overdiagnosis is likely more frequent in community-based screening given the higher prevalence of comorbidities.

Outcomes of a lung cancer screening program in a Hispanic urban population: The University of Miami experience.

e19011 Background: The National Lung Screening Trial (NLST) revealed a 20% reduction in lung cancer (LC) mortality when low-dose computed tomography (LDCT) was utilized for LC screening vs chest radiography. NLST participants were predominantly Non-Hispanic Whites, with only 1.8% Hispanics. The goal of our study was to investigate the attributes of a LC screening program in a largely Hispanic urban population and compare with NLST. Methods: We performed a retrospective analysis of 421 consecutive cases who underwent LDCT screening from 2016-2019 at University of Miami (UM), with similar inclusion criteria as the NLST. Demographic characteristics, smoking status, lung RADS, LC detection and compliance were examined & compared with NLST cohort using summary statistics and χ2 tests for categorical variables. Results: Demographic and smoking characteristics of the UM cohort didn’t resemble those of NLST LDCT cohort. UM cohort had a different racial and ethnic profile, with a higher percentage of Hispanics (47.3% vs 1.8%) and African Americans (15% vs 4.5%) in the UM cohort vs NLST cohort respectively (p < 0.001). UM cohort generally had lesser smoking intensity, and significantly fewer active smokers when compared to the NSLT cohort; 38.5% vs 48.1% respectively. The proportion of positive LDCT screens (Lung-RADS Class 3 or 4) in the UM cohort (14.1%) was almost similar to the NLST cohort (13.7%) (p = 0.81). The UM cohort had a higher LC detection rate (3.3%) than the NLST cohort (1.1%) (p < 0.001). In keeping with goals of screening, both cohorts had 50% or more LC cases detected at an early curable stage. Overall patient adherence to screening guidelines was more than 90% in NLST cohort; whereas almost a quarter of referred patients in UM cohort didn’t show for their initial decision-making visit and only 45% completed two or more scans. Conclusions: Our LDCT screening program was based in a Hispanic urban location (UM) with 47.3% Hispanics. Compared to NLST LDCT arm, the UM cohort had fewer active smokers, lighter smoking history, a more diverse population, somewhat higher LC detection rate, weaker adherence to screening related visits. More data is needed to understand obstacles to compliance with screening in minority populations.

Ten-year results of the Multicentric Italian Lung Detection trial demonstrate the safety and efficacy of biennial lung cancer screening

BackgroundThe Multicentric Italian Lung Detection (MILD) trial demonstrated that prolonged low-dose computed tomography (LDCT) screening could achieve a 39% reduction in lung cancer (LC) mortality. We have here evaluated the long-term results of annual vs. biennial LDCT and the impact of screening intensity on overall and LC-specific mortality at 10 years. Patients and methodsBetween 2005 and 2018, the MILD trial prospectively randomised the 2376 screening arm participants to annual (n = 1190) or biennial (n = 1186) LDCT, for a median screening period of 6.2 years and 23,083 person-years of follow-up. The primary outcomes were 10-year overall and LC-specific mortality, and the secondary end-points were the frequency of advanced-stage and interval LCs. ResultsThe biennial LDCT arm showed a similar overall mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.57–1.12) and LC-specific mortality at 10 years (HR 1.10, 95% CI 0.59–2.05), as compared with the annual LDCT arm. Biennial screening saved 44% of follow-up LDCTs in subjects with negative baseline LDCT, and 38% of LDCTs in all participants, with no increase in the occurrence of stage II-IV or interval LCs. ConclusionsThe MILD trial provides original evidence that prolonged screening beyond five years with biennial LDCT can achieve an LC mortality reduction comparable to annual LDCT, in subjects with a negative baseline examination.

Lung Cancer Incidence and Mortality with Extended Follow-up in the National Lung Screening Trial

IntroductionThe National Lung Screening Trial (NLST) randomized high-risk current and former smokers to three annual screens with either low-dose computed tomography (LDCT) or chest radiography (CXR) and demonstrated a significant reduction in lung cancer mortality in the LDCT arm after a median of 6.5 years' follow-up. We report on extended follow-up of NLST subjects. MethodsSubjects were followed by linkage to state cancer registries and the National Death Index. The number needed to screen (NNS) to prevent one lung cancer death was computed as the reciprocal of the difference in the proportion of patients dying of lung cancer across arms. Lung cancer mortality rate ratios (RRs) were computed overall and adjusted for dilution effect, with the latter including only deaths with a corresponding diagnosis close enough to the end of protocol screening. ResultsThe median follow-up times were 11.3 years for incidence and 12.3 years for mortality. In all, 1701 and 1681 lung cancers were diagnosed in the LDCT and CXR arms, respectively (RR = 1.01, 95% confidence interval [CI]: 0.95–1.09). The observed numbers of lung cancer deaths were 1147 (with LDCT) versus 1236 (with CXR) (RR = 0.92, 95% CI: 0.85–1.00). The difference in the number of patients dying of lung cancer (per 1000) across arms was 3.3, translating into an NNS of 303, which is similar to the original NNS estimate of around 320. The dilution-adjusted lung cancer mortality RR was 0.89 (95% CI: 0.80–0.997). With regard to overall mortality, there were 5253 (with LDCT) and 5366 (with CXR) deaths, for a difference across arms (per 1000) of 4.2 (95% CI: –2.6 to 10.9). ConclusionExtended follow-up of the NLST showed an NNS similar to that of the original analysis. There was no overall increase in lung cancer incidence in the LDCT arm versus in the CXR arm.

Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new confirmation of lung cancer screening efficacy.

BackgroundThe National Lung Screening Trial showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduces LC mortality. We evaluated the benefit of prolonged LDCT screening beyond 5 years, and its impact on overall and LC specific mortality at 10 years.DesignThe Multicentric Italian Lung Detection (MILD) trial prospectively randomized 4099 participants, to a screening arm (n = 2376), with further randomization to annual (n = 1190) or biennial (n = 1186) LDCT for a median period of 6 years, or control arm (n = 1723) without intervention. Between 2005 and 2018, 39 293 person-years of follow-up were accumulated. The primary outcomes were 10-year overall and LC specific mortality. Landmark analysis was used to test the long-term effect of LC screening, beyond 5 years by exclusion of LCs and deaths that occurred in the first 5 years.ResultsThe LDCT arm showed a 39% reduced risk of LC mortality at 10 years [hazard ratio (HR) 0.61; 95% confidence interval (CI) 0.39–0.95], compared with control arm, and a 20% reduction of overall mortality (HR 0.80; 95% CI 0.62–1.03). LDCT benefit improved beyond the 5th year of screening, with a 58% reduced risk of LC mortality (HR 0.42; 95% CI 0.22–0.79), and 32% reduction of overall mortality (HR 0.68; 95% CI 0.49–0.94).ConclusionsThe MILD trial provides additional evidence that prolonged screening beyond 5 years can enhance the benefit of early detection and achieve a greater overall and LC mortality reduction compared with NLST trial.ClinicalTrials.gov identifierNCT02837809.

Medical Care Costs Were Similar Across the Low-dose Computed Tomography and Chest X-Ray Arms of the National Lung Screening Trial Despite Different Rates of Significant Incidental Findings.

The National Lung Screening Trial (NLST) reported lung cancer and all-cause mortality reductions for low-dose computed tomography (LDCT) versus chest x-ray (CXR) screening. Although LDCT lung screening has received a grade B from the United States Preventive Services Task Force and is a covered service under most health plans, concerns remain on the costs engendered by screening, and the impact of the high rate of significant incidental finding (SIF) detection on those costs. We linked American College of Radiology Imaging Network NLST and Medicare fee-for-service claims data for participants from 23 sites for 2002-2009. We performed participant-level analyses using generalized linear regression models to estimate the adjusted annual mean of the 3-year total medical costs per person in each study arm and within screen outcome categories (ever positive with abnormalities suspicious for lung cancer, always negative for abnormalities suspicious for lung cancer, but with SIFs, and always negative without SIFs). The adjusted annual mean total per person costs were not significantly different between screening arms [LDCT, $11,029 (95% confidence interval, $10,107-$11,951); CXR, $10,905 (95% confidence interval, $10,059-$11,751)], despite higher proportions of individuals with SIFs in the LDCT versus the CXR arm (18% vs. 4%; P<0.0001). We found little difference in total annual per person costs between LDCT-screened and CXR-screened Medicare participants, despite the higher number of SIFs in the LDCT arm of the study.

Abstract 5298: Lung cancer risk and scarring on imaging and histology in the National Lung Screening Trial

Abstract Background: The contribution of pulmonary scars to lung cancer development and the degree to which lung cancers cause a scarring response are unclear. Also unknown is how lung scarring impacts lung cancer screening. Methods: We evaluated associations between scarring and lung cancer in the National Lung Screening Trial (NLST), a lung cancer screening trial among current or former, heavy smokers, 55-74 years-old. Baseline scarring (presence vs. absence) on screening low dose computed tomography (LDCT) scan was assessed at baseline (T0). Associations of T0 scarring with screen-detected lung cancers and with interval-detected lung cancers missed on screening within 3 years of T0 screen were analyzed using multinomial logistic regression. Cox proportional hazards models were used to analyze the relationship between T0 scarring and incident lung cancers diagnosed &amp;gt;3 years after T0. Regression models included age, sex, race, smoking history, chronic obstructive pulmonary disease, history of pneumonia, and family history of lung cancer. A thoracic pathologist (first author) evaluated lung cancer pathology slides from the Lung Screening Study (LSS) subset of NLST for scar grade (none, sparse, dense) and maturity (none, immature, intermediate, mature). Associations between T0 scarring on LDCT and histological scarring were examined by logistic regression. Results: NLST’s LDCT arm enrolled 26,722 participants (65% from the LSS). T0 scars were present in 132 (22%) screen-detected, 12 (29%) interval-detected, and 94 (26%) incident lung cancer cases. T0 scarring did not increase or decrease screen-detection of cancers [odds ratio (OR) 95% CI: 1.03 (0.84-1.26)]. However, scarring might increase the chance of an interval-detected cancer [OR (95% CI): 1.54 (0.76-3.12)]. After screening stopped, T0 scarring was associated with increased incident lung cancer risk [hazard ratio (HR) (95% CI): 1.27 (1.00-1.62); P=0.048]. Pathology slides were available for 258 (38%) lung cancers in LSS. Lung scarring was found in 172 (67%) of these cancers with 58 (22%) being characterized as mature scars. On microscopic review, scars were found in 80 (66%) ADC, 46 (82%) squamous cell carcinomas, and 20 (51%) bronchioloalveolar carcinomas. Microscopic scarring tended to be more frequent among cases with T0 scarring than those without T0 scarring (75% vs. 64%; P=0.10) [OR (95% CI): 1.89 (0.98-3.86)]. Conclusion: The association between T0 scarring and incident lung cancer over a period of more than 3 years is consistent with an etiologic contribution of scarring to development of lung cancer. The relationship between T0 scarring and scarring on microscopic evaluation suggests that scarring preceded the cancer, further supporting an etiologic relationship. Finally, the borderline association of T0 scarring and interval cancers suggests that scarring may decrease the sensitivity of screening. Citation Format: Alison L. Van Dyke, Christine D. Berg, Neil E. Caporaso, Hormuzd A. Katki, Anil K. Chaturvedi, Eric A. Engels. Lung cancer risk and scarring on imaging and histology in the National Lung Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5298. doi:10.1158/1538-7445.AM2017-5298

Prediction of lung cancer incidence on the low-dose computed tomography arm of the National Lung Screening Trial: A dynamic Bayesian network.

Identifying high-risk lung cancer individuals at an early disease stage is the most effective way of improving survival. The landmark National Lung Screening Trial (NLST) demonstrated the utility of low-dose computed tomography (LDCT) imaging to reduce mortality (relative to X-ray screening). As a result of the NLST and other studies, imaging-based lung cancer screening programs are now being implemented. However, LDCT interpretation results in a high number of false positives. A set of dynamic Bayesian networks (DBN) were designed and evaluated to provide insight into how longitudinal data can be used to help inform lung cancer screening decisions. The LDCT arm of the NLST dataset was used to build and explore five DBNs for high-risk individuals. Three of these DBNs were built using a backward construction process, and two using structure learning methods. All models employ demographics, smoking status, cancer history, family lung cancer history, exposure risk factors, comorbidities related to lung cancer, and LDCT screening outcome information. Given the uncertainty arising from lung cancer screening, a cancer state-space model based on lung cancer staging was utilized to characterize the cancer status of an individual over time. The models were evaluated on balanced training and test sets of cancer and non-cancer cases to deal with data imbalance and overfitting. Results were comparable to expert decisions. The average area under the curve (AUC) of the receiver operating characteristic (ROC) for the three intervention points of the NLST trial was higher than 0.75 for all models. Evaluation of the models on the complete LDCT arm of the NLST dataset (N=25,486) demonstrated satisfactory generalization. Consensus of predictions over similar cases is reported in concordance statistics between the models' and the physicians' predictions. The models' predictive ability with respect to missing data was also evaluated with the sample of cases that missed the second screening exam of the trial (N=417). The DBNs outperformed comparison models such as logistic regression and naïve Bayes. The lung cancer screening DBNs demonstrated high discrimination and predictive power with the majority of cancer and non-cancer cases.

Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials.

The benefits and harms of lung cancer (LC) screening with low-dose computed tomography (LDCT) are debatable. Positive results from the US National Lung Screening Trial were not evident in the European trials, possibly due to their smaller sample sizes. To address this issue, we conducted a patient-level pooled analysis of two Italian randomized controlled trials. Data from DANTE and MILD trials were combined for a total of 3640 individuals in the LDCT arm and 2909 in the control arm. LC and overall mortality were analyzed using multivariate hazard ratios (HRs) and log-rank tests stratified by study. The median follow-up was 8.2 years, with a total of 30 480 person-years in the LDCT arm and 22 157 in the control arm. A total of 192 patients developed LC in the LDCT arm and 105 in the control arm. Half of the LC cases in the LDCT arm had stage IA or IB cancer, as compared with 21% in the control arm. Overall mortality rates/100 000 person-years were 925 in the LDCT arm and 1074 in the control arm, and LC mortality rates were 299 and 357, respectively. The multivariate pooled overall mortality HR was 0.89 (95% confidence interval: 0.74-1.06) and the LC mortality HR was 0.83 (95% confidence interval: 0.61-1.12) for the LDCT arm as compared with the control arm. The present pooled analysis shows a nonsignificant 11% reduction in overall mortality in individuals undergoing LDCT screening as compared with the control arm. A pooled analysis of all European trials would be a useful contribution to assess the real benefit of LDCT screening.

Screening with Low-Dose Computed Tomography Does Not Improve Survival of Small Cell Lung Cancer

IntroductionSmall cell lung cancer (SCLC) constitutes a distinct component of symptomatic or advanced-stage lung cancers in clinical practice and in lung cancer screening trials. The purpose of this study was to describe the outcome of SCLC in lung cancer screening trials and compare the frequency of SCLC in our cohort with that in the major lung cancer screening trials. MethodsSubjects with a diagnosis of SCLC were selected from two lung cancer screening trials by low-dose computed tomography (LDCT), and their demographic characteristics, clinical parameters, tumor stage at diagnosis, therapy, and survival times were recorded. Survival curves were estimated using the Kaplan-Meier method. ResultsTen cases of SCLC were reported in 45,141 person-years (22 in 100,000 person-years), representing the 6% of all lung cancer cases. Cumulative tobacco consumption was 82 pack-years compared with 39 and 46 pack-years for the overall study population and subjects with non-SCLC, respectively. Most of the neoplasms were in an advanced stage (seven in stage IV and one each in stages IIIb, IIIa, and Ia). Two subjects were treated with lobectomy for curative purposes and died of diffuse metastasis within 2 years of diagnosis. The median overall survival time in the LDCT arms was 20.6 months, with no survivors remaining at 3 years. ConclusionsSubjects in whom SCLC develops are a subgroup of smokers with extremely high cumulative tobacco consumption. Consequently, the frequency of SCLC in our population was lower than in other screening populations, with higher cumulative tobacco consumption. Screening for lung cancer by LDCT does not improve survival of SCLC, with no survivors remaining at 3 years after diagnosis.

Noninvasive Computed Tomography-based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial.

Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas.

Lung Cancer Early Detection: The Role of Circulating MicroRNAs

Lung cancer screening with low-dose Computed Tomography (LDCT) was recently shown to be effective in reducing lung cancer mortality (Aberle et al., 2011). An ~ 20% of reduction of mortality was observed at 3 years in the LDCT arm of a randomized multicenter study, the National Lung Cancer Screening Trial (NLST), which enrolled ~ 53.000 high-risk individuals (> 55 years, > 30 packs-year) planned to receive annual LDCT or chest X-ray (Aberle et al., 2011). This groundbreaking result occurred after several years of debate about the benefits of LDCT screening in terms of improved early diagnosis and survival, and whether an annual LDCT scan in asymptomatic high-risk individuals should be recommended or not (Field and Duffy, 2008). However, both the high number of individuals who need to be screened to detect one lung cancer patient (~ 1 patient out of 100 individuals) and the sizeable false-positive rate of LDCT observed in these screening trials (most of the lung nodules detected are benign, ~ 96%) are limiting the widespread applicability of LDCT screening programs (Aberle et al., 2011). Therefore, there is an urgent need to identify novel biomarkers for the early diagnosis of lung cancer to better identify the high-risk population, thus reducing the number of unnecessary LDCTs for individuals without lung cancer and the rate of false-positive findings. In this issue of EBioMedicine, Wang et al. (2015) describes a new set of biomarkers diagnostic for lung cancer. The authors found that the increased serum levels of 5 microRNAs (miR-483-5p, miR-193a-3p, miR-25, miR-214 and miR-7) in a Chinese cohort of lung cancer patients and healthy individuals were diagnostic for lung cancer. MicroRNAs (miRNAs) are short non-coding RNA molecules involved in the regulation of many cellular processes by acting as endogenous triggers of the mRNA interference pathway (Krol et al., 2010). Importantly, fluctuations of circulating miRNAs were shown to be associated with many malignant and non-malignant diseases, including lung cancer (Chen et al., 2008). Of note, circulating miRNAs are remarkably stable in the blood despite harsh conditions due to the presence of high levels of RNases (Mitchell et al., 2008). Therefore, circulating miRNAs appear to be excellent candidates for blood-borne tumor markers for the diagnosis of cancer. An important aspect in the present study by Wang et al. is the extensive validation of these miRNA biomarkers in independent cohorts of patients. Indeed, the authors used four independent cohorts of patients and healthy individuals (for a total of 221 NSCLC, 56 with benign nodules, and 161 healthy individuals) to train and validate the 5-miRNA signature. The cohorts were recruited from different health centers (multicentric study) and individuals were of different ethnicity (Chinese and American individuals) to appreciate eventual differences in the basal blood miRNA level, which could negatively affect the diagnostic test performance. These are all very important aspects that should be taken in consideration when designing a screening study for cancer biomarker identification. Indeed, the failure of many proposed cancer biomarkers once validated in clinical trials is mainly ascribable to a poor study design adopted during the discovery phase, which, in most of the cases, did not include cohorts of patients sufficiently large and independent (Poste, 2011). Other research groups have recently described circulating miRNA signatures in serum and plasma for the early diagnosis of lung cancer, with comparable results in terms of sensitivity and specificity for detecting lung cancer (Sozzi et al., 2014, Montani et al., 2015, Wozniak et al., 2015). Some of these signatures have been already validated in existing lung cancer screening studies (Sozzi et al., 2014, Montani et al., 2015), which is mandatory to assess the accuracy of these diagnostic biomarkers in detecting asymptomatic early-stage lung cancer. It would be interesting to perform a meta-analysis of all of these signatures by using both serum and plasma samples from the same cohort of individuals. This would allow the direct comparison of their diagnostic performance and, eventually, identify a core of biomarkers to increase the overall accuracy of a miRNA-based test for lung cancer early detection.

Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT.

Chemoprevention is an important potential tool in reducing lung cancer incidence. Noncalcified nodules (NCN) observed on low-dose computed tomography (LDCT) have been proposed as intermediate endpoints in chemoprevention trials, but whether NCNs represent cancer precursors is unclear. We analyzed data from subjects in the LDCT arm of the National Lung Screening Trial (NLST) to examine short- and long-term lung cancer risks associated with NCNs and to elucidate whether some NCNs may be cancer precursors. NLST subjects received a baseline and two additional LDCT screens and were followed for a median of 6.5 years. We examined lung cancer incidence over three distinct periods from baseline-0-23 months (short-term), 24-59 months (medium-term), and 60-84 months (long-term)-in relation to baseline NCN characteristics. Spatially, lung cancer incidence was analyzed at the person, lung, and lobe levels relative to NCN location. A total of 26,272 subjects received the baseline LDCT screen, with 468, 413, and 190 lung cancers observed in the three periods. The presence of an NCN gave significantly elevated long-term lung cancer risk ratios (RR) of 1.8, 2.4, and 3.5 at the person, lung, and lobe levels; corresponding short-term RRs were 10.3, 16.8, and 38.0. Ground-glass attenuation was positively associated with long-term lung cancer risk but inversely associated with short-term risk; NCN size was positively associated with short-term risk but not significantly associated with long-term risk. That NCNs convey significantly elevated excess long-term of lung cancer lends evidence to the hypothesis that some NCNs may be cancer precursors.

Abstract 871: Clinical utility of a plasma microRNA biomarker within lung cancer screening

Abstract Recent screening trials indicate that low-dose computed tomography (LDCT) reduces lung-cancer mortality in high risk subjects. However, high false positive rates, costs and potential harms highlight the need for complementary biomarkers. MicroRNAs (miRNAs) are tissue and disease specific molecules, actively released by cells in the circulatory system, which are associated with protein complexes and/or packaged in exosomes and microvesicles. Circulating miRNAs are rather stable and easily detectable in body fluids suggesting the possibility of using miRNAs as a new promising class of biomarkers. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) of a non-invasive plasma miRNA signature classifier (MSC) to identify lung cancer occurrence and mortality was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicentre Italian Lung Detection (MILD) trial. Plasma samples from 939 subjects including 69 lung cancer patients and 870 disease-free individuals were analyzed using a Real-Time quantitative PCR (qRT-PCR) based assay for MSC. Combined sensitivity and specificity of plasma MSC and LDCT were assessed in a blinded validation study. MSC correctly identified patients with lung cancer at 87% sensitivity, 81% specificity, and 99% NPV, and 18 of 19 lung cancer deaths at 95% sensitivity 81% specificity, and 99.86% NPV. MSC identified 43 of 49 (88%) LDCT-detected cancers, 8 of 9 (89%) interval cancers in the LDCT arm, and 9 of 11 (82%) cancers in the observational arm. Diagnostic performance of MSC was confirmed by time dependency analysis. MSC fell to negative after lung cancer resection in 16 of 22 evaluable subjects. In lung cancer patients, there was a trend in mortality across levels of MSC (p=0.0336) and survival rate significantly differed according to MSC in all subjects (X21=49.53, p&amp;lt;0.0001). Combination of MSC and LDCT resulted in a 5-fold reduction of LDCT false positive rate. This large validation study highlights the clinical diagnostic and prognostic value of plasma MSC for lung cancer screening in high-risk populations. The combined use of LDCT and MSC could reduce the false positive rate of LDCT improving the efficacy of lung cancer screening. Citation Format: Mattia Boeri, Carla Verri, Gabriella Sozzi, Luca Roz, Davide Conte, Paola Suatoni, Alfonso Marchiano, Carlo La Vecchia, Marta Rossi, Francesca Bravi, Eva Negri, Nicola Sverzellati, Ugo Pastorino. Clinical utility of a plasma microRNA biomarker within lung cancer screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 871. doi:10.1158/1538-7445.AM2014-871

Clinical Utility of a Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study

Recent screening trial results indicate that low-dose computed tomography (LDCT) reduces lung cancer mortality in high-risk patients. However, high false-positive rates, costs, and potential harms highlight the need for complementary biomarkers. The diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicenter Italian Lung Detection (MILD) trial. Plasma samples from 939 participants, including 69 patients with lung cancer and 870 disease-free individuals (n = 652, LDCT arm; n = 287, observation arm) were analyzed by using a quantitative reverse transcriptase polymerase chain reaction-based assay for MSC. Diagnostic performance of MSC was evaluated in a blinded validation study that used prespecified risk groups. The diagnostic performance of MSC for lung cancer detection was 87% for sensitivity and 81% for specificity across both arms, and 88% and 80%, respectively, in the LDCT arm. For all patients, MSC had a negative predictive value of 99% and 99.86% for detection and death as a result of disease, respectively. LDCT had sensitivity of 79% and specificity of 81% with a false-positive rate of 19.4%. Diagnostic performance of MSC was confirmed by time dependency analysis. Combination of both MSC and LDCT resulted in a five-fold reduction of LDCT false-positive rate to 3.7%. MSC risk groups were significantly associated with survival (χ1(2) = 49.53; P < .001). This large validation study indicates that MSC has predictive, diagnostic, and prognostic value and could reduce the false-positive rate of LDCT, thus improving the efficacy of lung cancer screening.

The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology.

The National Lung Screening Trial (NLST), which compared lung cancer screening with low-dose computed tomography (LDCT) versus chest radiography (CXR), demonstrated a statistically significant mortality benefit of LDCT screening. In the current study, the authors performed a post hoc analysis to examine whether the benefit was affected by various baseline factors, including age, sex, and smoking status, and whether it differed by tumor histology. Lung cancer death rates were computed as events over person-years of observation; the mortality risk ratio (RR) was defined as the lung cancer death rate in the LDCT versus CXR trial arms. Poisson regression was used to test for interactions of sex, age (< 65 years vs ≥ 65 years), and smoking status (current vs former) with trial arm. Mortality RRs were also computed for specific lung cancer histologies. The overall mortality RR was 0.92 in men and 0.73 in women, with a P value for interaction of .08. RRs were similar for individuals aged < 65 years versus those aged ≥ 65 years (0.82 vs 0.87), and for current versus former smokers (0.81 vs 0.91). By tumor histology, mortality RRs were 0.75 for adenocarcinoma, 0.71 for all non-small cell lung cancers except squamous, 1.23 for squamous cell carcinoma, and 0.90 for small cell carcinoma. RRs were similar for men and women for nonsquamous non-small cell lung cancers (0.71 and 0.70, respectively); women were found to have lower RRs for small cell and squamous cell carcinoma. A benefit of LDCT did not appear to vary substantially by age or smoking status; there was weak evidence of a differential benefit by sex. A differential benefit across lung cancer histologies may exist.

Baseline results of the Depiscan study: A French randomized pilot trial of lung cancer screening comparing low dose CT scan (LDCT) and chest X-ray (CXR)

Lung cancer has the highest mortality-rate per cancer, with an overall 5-year survival <15%. Several non-randomized studies pointed out the high sensitivity of low dose computed tomography (LDCT) to detect early stage lung cancer. In France, Depiscan, a pilot RCT of LDCT versus chest X-ray (CXR), started on October 2002 to determine the feasibility of enrollment by general practitioners (GPs), investigations and diagnostic procedures by university hospital radiologists and multidisciplinary teams, data management by centralized clinical research assistants, and anticipate the future management of a large national trial. GPs and occupational physicians (OPs) selected and enrolled 1000 subjects in 1 year. Eligible subjects were asymptomatic males or females aged 50-75 years with a current or former cigarette smoking history of >/=15 cigarettes per day for at least 20 years (former smokers having quit <15 years prior to enrollment). Based to randomization, annual LDCT or CXR screenings were planned at baseline and annually for 2 years. Between October 2002 and December 2004, 765 subjects were enrolled by 89 out of the 232 participating GPs and OPs. Complete clinical and imaging baseline data were available for 621 individuals out of the 765 enrolled, due to 144 noncompliant subjects who withdrew their consent. At least one nodule was detected in 152 out of 336 subjects (45.2%) in the LDCT screening, versus 21 out of 285 subjects (7.4%) in the CXR screening arm. Eight lung cancers were detected in the LDCT arm and one in the CXR arm. This pilot trial allows estimating that non-calcified nodules are 10 [6.36-17.07] times more often detected from LDCT than from CXR. However enrollment by GPs was more difficult than expected with 41% active investigators and a high rate (19%) of noncompliant patients. This experience speaks to the need for a high level of GPs formation and a large, coordinated clinical research team in such a trial. 02526.