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.     

Lung Cancer Screening With Low Dose Computed Tomography in Patients With and Without Prior History of Cancer in the National Lung Screening Trial

IntroductionPatients with a prior history of cancer (PHC) are at increased risk of second primary malignancy, of which lung cancer is the most common. We compared the performance metrics of positive screening rates and cancer detection rates (CDRs) among those with versus without PHC.MethodsWe conducted a secondary analysis of 26,366 National Lung Screening Trial participants screened with low dose computed tomography between August 2002 and September 2007. We evaluated absolute rates and age-adjusted relative risks (RRs) of positive screening rates on the basis of retrospective Lung CT Screening Reporting & Data System (Lung-RADS) application, invasive diagnostic procedure rate, complication rate, and CDR in those with versus without PHC using a binary logistic regression model using Firth’s penalized likelihood. We also compared cancer type, stage, and treatment in those with versus without PHC.ResultsA total of 4.1% (n = 1071) of patients had PHC. Age-adjusted rates of positive findings were similar in those with versus without PHC (Baseline: PHC = 13.7% versus no PHC = 13.3%, RR [95% confidence interval (CI)]: 1.04 [0.88–1.24]; Subsequent: PHC = 5.6% versus no PHC = 5.5%, RR [95% CI]: 1.02 [0.84–1.23]). Age-adjusted CDRs were higher in those with versus without PHC on baseline (PHC=1.9% versus no PHC = 0.8%, RR [95% CI]: 2.51 [1.67–3.81]) but not on subsequent screenings (PHC = 0.6% versus no PHC = 0.4%, RR [95% CI]: 1.37 [0.99–1.93]). There were no differences in cancer stage, type, or treatment by PHC status.ConclusionsPatients with PHC may benefit from lung cancer screening, and with their providers, should be made aware of the possibility of higher cancer detection, invasive procedures, and complication rates on baseline lung cancer screening, but not on subsequent low dose computed tomography screening examinations.     

Role of Low-Dose Computerized Tomography in Lung Cancer Screening among Never-Smokers

Introduction

The incidence of lung cancer among never-smokers has been increasing rapidly. The U. S. National Lung Screening Trial and the NELSON trial showed that screening using low-dose computerized tomography (LDCT) effectively reduced lung cancer mortality among heavy smokers. However, its effectiveness in never-smokers has not been well investigated. This study investigated the role of LDCT in lung cancer screening among never-smokers.

Lung cancer mortality reduction by LDCT screening—Results from the randomized German LUSI trial

In 2011, the U.S. National Lung Cancer Screening Trial (NLST) reported a 20% reduction of lung cancer mortality after regular screening by low-dose computed tomography (LDCT), as compared to X-ray screening. The introduction of lung cancer screening programs in Europe awaits confirmation of these first findings from European trials that started in parallel with the NLST. The German Lung cancer Screening Intervention (LUSI) is a randomized trial among 4,052 long-term smokers, 50–69 years of age, recruited from the general population, comparing five annual rounds of LDCT screening (screening arm; n = 2,029 participants) with a control arm (n = 2,023) followed by annual postal questionnaire inquiries. Data on lung cancer incidence and mortality and vital status were collected from hospitals or office-based physicians, cancer registries, population registers and health offices. Over an average observation time of 8.8 years after randomization, the hazard ratio for lung cancer mortality was 0.74 (95% CI: 0.46–1.19; p = 0.21) among men and women combined. Modeling by sex, however showed a statistically significant reduction in lung cancer mortality among women (HR = 0.31 [95% CI: 0.10–0.96], p = 0.04), but not among men (HR = 0.94 [95% CI: 0.54–1.61], p = 0.81) screened by LDCT (p_{heterogeneity} = 0.09). Findings from LUSI are in line with those from other trials, including NLST, that suggest a stronger reduction of lung cancer mortality after LDCT screening among women as compared to men. This heterogeneity could be the result of different relative counts of lung tumor subtypes occurring in men and women.     

Characteristics and Outcomes of Lung Cancer Screening Among Individuals With or Without Cancer History

BackgroundLung cancer screening with low-dose computed tomography (LDCT) can reduce mortality from lung cancer. Individuals with previous malignancy are at an increased risk of lung cancer but are often underrepresented in clinical trials. This study compares the outcomes of LDCT screening among individuals with and without cancer history.Materials and MethodsThe study cohort included consecutive participants undergoing LDCT screening at a tertiary care cancer institution. Abnormal screening result was defined as having Lung-RADS 3 or 4 at baseline (T0). Participant information was prospectively collected and predicted risk of lung cancer was calculated per the PLCOm2012 model.ResultsA total of 454 participants underwent LDCT screening. Abnormal screening result occurred in 57 (13.2%) participants at T0, and lung cancer was diagnosed in 11 (2.4%) participants. Among 153 individuals with cancer history, abnormal result occurred in 9.8%, compared with 15.4% among those without cancer history (P = .11). Lung cancer was diagnosed in 1.3%, compared with 3.5% (P = .22). The predicted risk of lung cancer at 6 years was higher among individuals with cancer history than those without: 4.8% versus 2.2% (P < .001). In a multivariable analysis, cancer history significantly reduced the likelihood of abnormal screening (odds ratio, 0.49; 95% confidence interval, 0.26-0.94; P = .03). We observed a higher proportion of participants who had a previous CT scan available for comparison at T0 among individuals with cancer history than those without: 43.1% versus 9.1% (P < .001).ConclusionsIn this single-institutional study, individuals with cancer history were significantly less likely to have abnormal screening results than those without cancer history.     

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

IntroductionInherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.MethodsWe conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.ResultsWe detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722–0.820; p value 5.31 × 10^-16), rs380286 (OR: 0.770, 95% CI: 0.723–0.820; p value 4.32 × 10^-16), and rs4975616 (OR: 0.778, 95% CI: 0.730–0.829; p value 1.04 × 10^-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.ConclusionsWe found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.     

Risk Prediction Model Versus United States Preventive Services Task Force Lung Cancer Screening Eligibility Criteria: Reducing Race Disparities

IntroductionDisparities exist in lung cancer outcomes between African American and white people. The current United States Preventive Services Task Force (USPSTF) lung cancer screening eligibility criteria, which is based solely on age and smoking history, may exacerbate racial disparities. We evaluated whether the PLCOm2012 risk prediction model more effectively selects African American ever-smokers for screening.MethodsLung cancer cases diagnosed between 2010 and 2019 at an urban medical center serving a racially and ethnically diverse population were retrospectively reviewed for lung cancer screening eligibility based on the USPSTF criteria versus the PLCOm2012 model.ResultsThis cohort of 883 ever-smokers comprised the following racial and ethnic makeup: 258 white (29.2%), 497 African American (56.3%), 69 Hispanic (7.8%), 24 Asian (2.7%), and 35 other (4.0%). Compared with the USPSTF criteria, the PLCOm2012 model increased the sensitivity for the African American cohort at lung cancer risk thresholds of 1.51%, 1.70%, and 2.00% per 6 years (p < 0.0001). For example, at the 1.70% risk threshold, the PLCOm2012 model identified 71.3% African American cases, whereas the USPSTF criteria only identified 50.3% (p < 0.0001). In contrast, in case of whites there was no difference (66.0% versus 62.4%, respectively [p = 0.203]). Of the African American ever-smokers who were PLCO1.7%-positive and USPSTF-negative, the criteria missed from the USPSTF were those with pack-years less than 30 (67.7%), quit time of greater than 15 years (22.5%), and age less than 55 years (13.0%).ConclusionsThe PLCOm2012 model was found to be preferable over the USPSTF criteria at identifying African American ever-smokers for lung cancer screening. The broader use of this model in racially diverse populations may help overcome disparities in lung cancer screening and outcomes.     

Impact of Low-Dose Computed Tomography Screening for Primary Lung Cancer on Subsequent Risk of Brain Metastasis

IntroductionBrain metastasis (BM) is one of the most common metastases from primary lung cancer (PLC). Recently, the National Lung Screening Trial revealed the efficacy of low-dose computed tomography (LDCT) screening on LC mortality reduction. Nevertheless, it remains unknown if early detection of PLC through LDCT may be potentially beneficial in reducing the risk of subsequent metastases. Our study aimed to investigate the impact of LDCT screening for PLC on the risk of developing BM after PLC diagnosis.MethodsWe used the National Lung Screening Trial data to identify 1502 participants who were diagnosed with PLC in 2002 to 2009 and have follow-up data for BM. Cause-specific competing risk regression was applied to evaluate an association between BM risk and the mode of PLC detection—that is, LDCT screen-detected versus non-LDCT screen-detected. Subgroup analyses were conducted in patients with early stage PLC and those who underwent surgery for PLC.ResultsOf 1502 participants, 41.4% had PLC detected through LDCT screening versus 58.6% detected through other methods, for example, chest radiograph or incidental detection. Patients whose PLC was detected with LDCT screening had a significantly lower 3-year incidence of BM (6.5%) versus those without (11.9%), with a cause-specific hazard ratio (HR) of 0.53 (p = 0.001), adjusting for age at PLC diagnosis, PLC stage, PLC histology, and smoking status. This significant reduction in BM risk among PLCs detected through LDCT screening persisted in subgroups of participants with early stage PLC (HR = 0.47, p = 0.002) and those who underwent surgery (HR = 0.37, p = 0.001).ConclusionsEarly detection of PLC using LDCT screening is associated with lower risk of BM after PLC diagnosis on the basis of a large population-based study.     

Population-Based Relative Risks for Lung Cancer Based on Complete Family History of Lung Cancer

IntroductionPublished risk estimates for diagnosis of lung cancer based on family history are typically focused on close relatives, rather than a more diverse or complete family history. This study provides estimates of relative risk (RR) for lung cancer based on comprehensive family history data obtained from a statewide cancer registry linked to a high-quality genealogy data resource that is extensive and deep. The risk estimates presented avoid common recall, recruitment, ascertainment biases, and are based on an individual’s (proband’s) lung cancer family history constellation (pattern of lung cancer affected relatives); numerous constellations are explored.MethodsWe used a population-based genealogic resource linked to a statewide electronic Surveillance Epidemiology and End Results program cancer registry to estimate RR for lung cancer for an individual based on their lung cancer family history. The family history data available for a proband included degree of relationship (first- to third-degree), paternal or maternal family lung cancer history, number of lung cancer–affected relatives, and age at diagnosis of affected relatives. More than 1.3 million probands with specific constellations of lung cancer were analyzed. To estimate RRs for lung cancer, the observed number of lung cancer cases among probands with a specific family history constellation was compared to the expected number using internal cohort-specific rates.ResultsA total of 5048 lung cancer cases were identified. Significantly elevated RR was observed for any number of lung cancer–affected relatives among first-, second-, or third-degree relatives. RRs for lung cancer were significantly elevated for each additional lung cancer first-degree relative (FDR) ranging from RR = 2.57 (confidence interval [CI] 95%: 2.39, 2.76) for 1 or more FDR to RR = 4.24 (CI 95%: 1.56, 9.23) for 3 or more FDRs affected. In an absence of FDR family history, increased risk for lung cancer was significant for increasing numbers of affected second-degree relatives (SDRs) ranging from 1.41 (CI 95%: 1.30, 1.52) for 1 or more SDRs to 4.76 (CI 95%: 1.55, 11.11) for 4 or more SDRs. In the absence of affected FDRs and SDRs, there were significantly increased risks based on lung cancer–affected third-degree relatives (TDRs) ranging from 1.18 (CI 95%: 1.11, 1.24) for 1 or more affected TDRs to 1.55 (CI 95%: 1.03, 2.24) for 4 or more affected TDRs. RRs were significantly increased with earlier age at diagnosis of a FDR, and equivalent risks for maternal compared to paternal history were observed.ConclusionsThis study provides population-based estimates of lung cancer risk based on a proband’s complete family history (lung cancer constellation). Many individuals at two to five or more times increased risk for lung cancer are identified. Estimates of RR for lung cancer based on family history are arguably relevant clinically. The constellation RR estimates presented could serve in individual decision-making to direct resource use for lung cancer screening, and could be pivotal in decision-making for screening, treatment, and post-treatment surveillance.     

Potential Impact of Criteria Modifications on Race and Sex Disparities in Eligibility for Lung Cancer Screening

IntroductionLow-dose computed tomography (LDCT) screening reduces lung cancer mortality, but current eligibility criteria underestimate risk in women and racial minorities. We evaluated the impact of screening criteria modifications on LDCT eligibility and lung cancer detection.MethodsUsing data from a Lung Nodule Program, we compared persons eligible for LDCT by the following: U.S. Preventive Services Task Force (USPSTF) 2013 criteria (55–80 y, ≥30 pack-years of smoking, and ≤15 y since cessation); USPSTF2021 criteria (50–80 y, ≥20 pack-years of smoking, and ≤15 y since cessation); quit duration expanded to less than or equal to 25 years (USPSTF2021-QD25); reducing the pack-years of smoking to more than or equal to 10 years (USPSTF2021-PY10); and both (USPSTF2021-QD25-PY10). We compare across groups using the chi-square test or analysis of variance.ResultsThe 17,421 individuals analyzed were of 56% female sex, 69% white, 28% black; 13% met USPSTF2013 criteria; 17% USPSTF2021; 18% USPSTF2021-QD25; 19% USPSTF2021-PY10; and 21% USPSTF2021-QD25-PY10. Additional eligible individuals by USPSTF2021 (n = 682) and USPSTF2021-QD25-PY10 (n = 1402) were 27% and 29% black, both significantly higher than USPSTF2013 (17%, p < 0.0001). These additional eligible individuals were 55% (USPSTF2021) and 55% (USPSTF2021-QD25-PY10) of female sex, compared with 48% by USPSTF2013 (p < 0.05). Of 1243 persons (7.1%) with lung cancer, 22% were screening eligible by USPSTF13. USPSTF2021-QD25-PY10 increased the total number of persons with lung cancer by 37%. These additional individuals with lung cancer were of 57% female sex (versus 48% with USPSTF2013, p = 0.0476) and 24% black (versus 20% with USPSTF2013, p = 0.3367).ConclusionsExpansion of LDCT screening eligibility criteria to allow longer quit duration and fewer pack-years of exposure enriches the screening-eligible population for women and black persons.     

High-Ambient Air Pollution Exposure Among Never Smokers Versus Ever Smokers With Lung Cancer

IntroductionAir pollution may play an important role in the development of lung cancer in people who have never smoked, especially among East Asian women. The aim of this study was to compare cumulative ambient air pollution exposure between ever and never smokers with lung cancer.MethodsA consecutive case series of never and ever smokers with newly diagnosed lung cancer were compared regarding their sex, race, and outdoor and household air pollution exposure. Using individual residential history, cumulative exposure to outdoor particulate matter (PM_2.5) in a period of 20 years was quantified with a high-spatial resolution global exposure model.ResultsOf the 1005 patients with lung cancer, 56% were females and 33% were never smokers. Compared with ever smokers with lung cancer, never smokers with lung cancer were significantly younger, more frequently Asian, less likely to have chronic obstructive pulmonary disease or a family history of lung cancer, and had higher exposure to outdoor PM_2.5 but lower exposure to secondhand smoke. Multivariable logistic regression analysis revealed a significant association with never-smoking patients with lung cancer and being female (OR = 4.01, 95% confidence interval [CI]: 2.76–5.82, p < 0.001), being Asian (OR_{Asian versus non-Asian} = 6.48, 95% CI: 4.42–9.50, p < 0.001), and having greater exposure to air pollution (OR_{ln_PM2.5} = 1.79, 95% CI: 1.10–7.2.90, p = 0.019).ConclusionsCompared with ever-smoking patients with lung cancer, never-smoking patients had strong associations with being female, being Asian, and having air pollution exposures. Our results suggest that incorporation of cumulative exposure to ambient air pollutants be considered when assessing lung cancer risk in combination with traditional risk factors.     

Stage Migration and Lung Cancer Incidence After Initiation of Low-Dose Computed Tomography Screening

IntroductionDespite evidence from clinical trials of favorable shifts in cancer stage and improvements in lung cancer-specific mortality, the effectiveness of lung cancer screening (LCS) in clinical practice has not been clearly revealed.MethodsWe performed a multicenter cohort study of patients diagnosed with a primary lung cancer between January 1, 2014, and September 30, 2019, at one of four U.S. health care systems. The primary outcome variables were cancer stage distribution and annual age-adjusted lung cancer incidence. The primary exposure variable was receipt of at least one low-dose computed tomography for LCS before cancer diagnosis.ResultsA total of 3678 individuals were diagnosed with an incident lung cancer during the study period; 404 (11%) of these patients were diagnosed after initiation of LCS. As screening volume increased, the proportion of patients diagnosed with lung cancer after LCS initiation also rose from 0% in the first quartile of 2014 to 20% in the third quartile of 2019. LCS did not result in a significant change in the overall incidence of lung cancer (average annual percentage change [AAPC]: −0.8 [95% confidence interval (CI): −4.7 to 3.2]) between 2014 and 2018. Stage-specific incidence rates increased for stage I cancer (AAPC = 8.0 [95% CI: 0.8–15.7]) and declined for stage IV disease (AAPC = −6.0 [95% CI: −11.2 to −0.5]).ConclusionsImplementation of LCS at four diverse health care systems has resulted in a favorable shift to a higher incidence of stage I cancer with an associated decline in stage IV disease. Overall lung cancer incidence did not increase, suggesting a limited impact of overdiagnosis.     

The Role of Smoking Status on the Progression‐Free Survival of Non‐Small Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First‐Line EGFR Tyrosine Kinase Inhibitor Versus Platinum Doublet Chemotherapy: A Meta‐Analysis of Prospective Randomized Trials

Background.

Univariate analyses from several randomized phase III trials seemed to suggest ever-smokers with advanced mutated epidermal growth factor receptor (EGFRm) non-small cell lung cancer (NSCLC) did not seem to benefit from EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment when compared with platinum-doublet chemotherapy as measured by progression-free survival (PFS).

Methods.

A literature-based meta-analysis of PFS outcomes as measured by log-transformed pooled hazard ratio (HR) was performed using a random-effect model. Pooled HRs for smoking status, age, gender, ethnicity, type of EGFR mutation, and EGFR TKI were obtained. Comparison of the pooled HR was performed by metaregression analysis.

Results.

Among the 1,649 EGFRm NSCLC patients analyzed from 7 prospective randomized trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, LUX Lung-3, LUX Lung-6, and ENSURE), 83.7% were Asians, and 30.0% were ever-smokers. An equal percentage of ever-smokers received doublet chemotherapy (30.2%) or EGFR TKI (30.0%). The pooled HR for PFS was 0.29 (95% confidence interval [CI]: 0.21–0.39) for never-smokers and 0.54 (95% CI: 0.38–0.76) for ever-smokers (p < .007 by metaregression). The pooled PFS HR for exon 19 deletion was 0.25 (95% CI: 0.19–0.31) and 0.44 for exon 21 substitution (95% CI: 0.34–0.57) (p < .001 by metaregression analysis). The pooled PFS HR was 0.33 (95% CI: 0.24–0.46) for Asians and 0.48 for non-Asians (95% CI: 0.28–0.84) (p = .261 by metaregression analysis).

Conclusion.

EGFRm NSCLC patients derived significant PFS benefit from TKI over platinum-doublet chemotherapy as first-line treatment regardless of smoking status; however, PFS benefit is significantly better in never-smokers by metaregression analysis.     

Racial Differences in Lung Cancer Screening Beliefs and Screening Adherence

BackgroundOne challenge in high-quality lung cancer screening (LCS) is maintaining adherence with annual and short-interval follow-up screens among high-risk individuals who have undergone baseline low-dose CT (LDCT). This study aimed to characterize attitudes and beliefs toward lung cancer and LCS and to identify factors associated with LCS adherence.MethodsWe administered a questionnaire to 269 LCS participants to assess attitudes and beliefs toward lung cancer and LCS. Clinical data including sociodemographics and screening adherence were obtained from the LCS Program Registry.ResultsAfrican-American individuals had significantly greater lung cancer worries compared with Whites (6.10 vs. 4.66, P < .001). In making the decision to undergo LCS, African-American participants described screening convenience and cost as very important factors significantly more frequently than Whites (60% vs. 26.8%, P< .001 and 58.4% vs. 37.8%, P = .001; respectively). African-American individuals with greater than high school education had significantly higher odds of LCS adherence (aOR 2.55; 95% CI, 1.14-5.60) than Whites with less than high school education. Participants who described screening convenience and cost as “very important” had significantly lower odds of completing screening follow-up after adjusting for demographic and other factors (aOR 0.56; 95% CI, 0.33-0.97 and aOR 0.54; 95% CI, 0.33-0.91, respectively).ConclusionRacial differences in beliefs about lung cancer and LCS exist among African-American and White individuals enrolled in an LCS program. Cost, convenience, and low educational attainment may be barriers to LCS adherence, specifically among African-American individuals.ImpactMore research is needed on how barriers can be overcome to improve LCS adherence.     

Mutational Profile from Targeted NGS Predicts Survival in LDCT Screening–Detected Lung Cancers

BackgroundThe issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials could be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. The mutation profile of LDCT screening–detected lung tumors is currently unknown.MethodsTargeted next-generation sequencing was performed on 94 LDCT screening–detected lung tumors. Associations with clinicopathologic features, survival, and the risk profile of a plasma microRNA signature classifier were analyzed.ResultsThe mutational spectrum and frequency observed in screening series was similar to that reported in public data sets, although a larger number of tumors without mutations in driver genes was detected. The 5-year overall survival (OS) rates of patients with and without mutations in the tumors were 66% and 100%, respectively (p = 0.015). By combining the mutational status with the microRNA signature classifier risk profile, patients were stratified into three groups with 5-year OS rates ranging from 42% to 97% (p < 0.0001) and the prognostic value was significant after controlling for stage (p = 0.02).ConclusionTumor mutational status along with a microRNA-based liquid biopsy can provide additional information in planning clinical follow-up in lung cancer LDCT screening programs.     

Management of Lung Cancer Screening Results Based on Individual Prediction of Current and Future Lung Cancer Risks

ObjectivesWe propose a risk-tailored approach for management of lung cancer screening results. This approach incorporates individual risk factors and low-dose computed tomography (LDCT) image features into calculations of immediate and next-screen (1-y) risks of lung cancer detection, which in turn can recommend short-interval imaging or 1-year or 2-year screening intervals.MethodsWe first extended the “LCRAT+CT” individualized risk calculator to predict lung cancer risk after either a negative or abnormal LDCT screen result. To develop the abnormal screen portion, we analyzed 18,129 abnormal LDCT results in the National Lung Screening Trial (NLST), including lung cancers detected immediately (n = 649) or at the next screen (n = 235). We estimated the potential impact of this approach among NLST participants with any screen result (negative or abnormal).ResultsApplying the draft National Health Service (NHS) England protocol for lung screening to NLST participants referred 76% of participants to a 2-year interval, but delayed diagnosis for 40% of detectable cancers. The Lung Cancer Risk Assessment Tool+Computed Tomography (LCRAT+CT) risk model, with a threshold of less than 0.95% cumulative lung cancer risk, would also refer 76% of participants to a 2-year interval, but would delay diagnosis for only 30% of cancers, a 25% reduction versus the NHS protocol. Alternatively, LCRAT+CT, with a threshold of less than 1.7% cumulative lung cancer risk, would also delay diagnosis for 40% of cancers, but would refer 85% of participants for a 2-year interval, a 38% further reduction in the number of required 1-year screens beyond the NHS protocol.ConclusionsUsing individualized risk models to determine management in lung cancer screening could substantially reduce the number of screens or increase early detection.     

Incidence of Smoking-Related Second Primary Cancers After Lung Cancer in Germany: An Analysis of Nationwide Cancer Registry Data

IntroductionApproximately 80% of lung cancer cases in Germany are attributable to smoking. Patients with a lung cancer diagnosis may remain at increased risk of developing smoking-related second primary cancers (SPCs).MethodsAnonymous data from 11 population-based cancer registries covering approximately 50% of the German population were pooled for the analysis. Included patients were diagnosed with having an index lung cancer between 2002 and 2013, aged 30 to 99 years old at diagnosis, and survived for at least 6 months. We calculated standardized incidence ratios (SIRs)—stratified by age, sex, region, and period—comparing the incidence of smoking-related and other SPCs to the general population.ResultsOf the 135,589 lung cancer survivors (68.2% male; mean follow-up 30.8 mo) analyzed, 5298 developed an SPC. In males, the risk was particularly high for SPCs of the larynx (SIR = 3.70, 95% confidence interval [CI]: 3.14–4.34), pharynx (3.17, 2.61–3.81), and oral cavity (2.86, 2.38–3.41). For females, SIRs were notably elevated for the esophagus (4.66, 3.15–6.66), oral cavity (3.14, 2.03–4.63), and urinary tract (2.68, 2.04–3.45). When combining all smoking-related cancer sites, SIR was 1.41 in males (95% CI: 1.36–1.47) and 1.81 in females (95% CI: 1.68–1.94). We observed that males had a 1.46-fold (95% CI: 1.37–1.56) and females a 1.33-fold (95% CI: 1.20–1.47) increased risk for smoking-related compared with other cancers.ConclusionsPatients with primary lung cancer were at increased risk for developing a smoking-related SPC. Therefore, the advantages of increased patient surveillance and the benefits of smoking cessation strategies should be considered.     

Circulating Inflammation Proteins Associated With Lung Cancer in African Americans

IntroductionLung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs.MethodsWe adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays.ResultsWe identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99–4.22], interferon γ [OR: 1.55; 95% CI: 1.10–2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10–9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92–3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20–2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96–4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09–2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38–0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12–2.21], and tumor necrosis factor β [OR: 0.52; 95% CI: 0.37–0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences.ConclusionsOur results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.     

Potential Impact of Including Time to First Cigarette in Risk Models for Selecting Ever-Smokers for Lung Cancer Screening

IntroductionSelecting individuals on the basis of model-predicted risks has been reported to improve lung cancer screening efficiency. On the basis of case-control studies, time to first cigarette (TTFC), a nicotine dependency measurement, has been a strong independent predictor of lung cancer risk. Our objective was to verify the TTFC–lung cancer association in the prospective National Lung Screening Trial and evaluate whether adding TTFC can improve lung cancer risk-prediction models.MethodsUsing Cox models, we examined associations between TTFC (≤5, 6–14, 15–29, 30–59, and ≥60 minutes) and lung cancer incidence and death in 18,729 National Lung Screening Trial participants, adjusting for smoking and other lung cancer risk factors comprehensively. We estimated 5-year individual lung cancer incidence by using models without and with TTFC and dichotomized into screening or no-screening groups based on risk thresholds of 1% and 2%. Area under the receiver operating curve values were calculated for models without and with TTFC.ResultsSmokers with a TTFC of 60 minutes or more had a much lower standardized 5-year lung cancer incidence risk—1.54% (1.52%–1.56%) for TTFC 60 minutes or more versus 4.07% (4.04%–4.09%) for TTFC 5 minutes or less—and lung cancer death risk—0.59% (0.57%–0.61%) for TTFC 60 minutes or more versus 2.26% (2.23%–2.28%) for TTFC 5 minutes or less (p trend < 0.001). Adding TTFC to the lung cancer incidence model improved the area under the receiver operating curve by 0.0079 (95% confidence interval = 0.0019–0.0138 [p = 0.0085]). Among 8994 smokers without a lung cancer diagnosis, 180 (2.00%) and 155 (1.67%) more people would be assigned to the no-screening group by adding TTFC to the model (p values for percent changes <0.001) at the 1% and 2% risk thresholds, respectively.ConclusionIncluding TTFC, which can be elicited by a single question at very low cost and noninvasively question, into risk models might better identify smokers with lower risk and could therefore be a safe, convenient tool to improve identification of those who benefit less from lung cancer screening.