Clinical validation of a cell-free DNA fragmentome assay for augmentation of lung cancer early detection.

Lung cancer screening via annual low-dose computed tomography (LDCT) has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by an LDCT. Changes in genome-wide cell-free DNA (cfDNA) fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples, and then validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer, and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a five-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths.

A Nasal Swab Classifier to Evaluate the Probability of Lung Cancer in Patients With Pulmonary Nodules.

BACKGROUND: Accurate assessment of the probability of lung cancer (pCA) is critical in patients with pulmonary nodules (PNs) to help guide decision-making. We sought to validate a clinical-genomic classifier developed using whole-transcriptome sequencing of nasal epithelial cells from patients with a PN ≤ 30 mm who smoke or have previously smoked. RESEARCH QUESTION: Can the pCA in individuals with a PN and a history of smoking be predicted by a classifier that uses clinical factors and genomic data from nasal epithelial cells obtained by cytologic brushing? STUDY DESIGN AND METHODS: Machine learning was used to train a classifier using genomic and clinical features on 1,120 patients with PNs labeled as benign or malignant established by a final diagnosis or a minimum of 12 months of radiographic surveillance. The classifier was designed to yield low-, intermediate-, and high-risk categories. The classifier was validated in an independent set of 312 patients, including 63 patients with a prior history of cancer (other than lung cancer), comparing the classifier prediction with the known clinical outcome. RESULTS: In the primary validation set, sensitivity and specificity for low-risk classification were 96% and 42%, whereas sensitivity and specificity for high-risk classification was 58% and 90%, respectively. Sensitivity was similar across stages of non-small cell lung cancer, independent of subtype. Performance compared favorably with clinical-only risk models. Analysis of 63 patients with prior cancer showed similar performance as did subanalyses of patients with light vs heavy smoking burden and those eligible for lung cancer screening vs those who were not. INTERPRETATION: The nasal classifier provides an accurate assessment of pCA in individuals with a PN ≤ 30 mm who smoke or have previously smoked. Classifier-guided decision-making could lead to fewer diagnostic procedures in patients without cancer and more timely treatment in patients with lung cancer.

Outcomes From More Than 1 Million People Screened for Lung Cancer With Low-Dose CT Imaging.

BACKGROUND: Lung cancer screening (LCS) with low-dose CT (LDCT) imaging was recommended in 2013, making approximately 8 million Americans eligible for LCS. The demographic characteristics and outcomes of individuals screened in the United States have not been reported at the population level. RESEARCH QUESTION: What are the outcomes among people screened and entered in the American College of Radiology's Lung Cancer Screening Registry compared with those of trial participants? STUDY DESIGN AND METHODS: This was a cohort study of individuals undergoing baseline LDCT imaging for LCS between 2015 and 2019. Predictors of adherence to annual screening were computed. LDCT scan interpretations by Lung Imaging Reporting and Data System (Lung-RADS) score, cancer detection rates (CDRs), and stage at diagnosis were compared with National Lung Cancer Screening Trial data. RESULTS: Adherence was 22.3%, and predictors of poor adherence included current smoking status and Hispanic or Black race. On baseline screening, 83% of patients showed negative results and 17% showed positive screening results. The overall CDR was 0.56%. The percentage of people with cancer detected at baseline was higher in the positive Lung-RADS categories at 0.4% for Lung-RADS category 3, 2.6% for Lung-RADS category 4A, 11.1% for Lung-RADS category 4B, and 19.9% for Lung-RADS category 4X. The cancer stage distribution was similar to that observed in the National Lung Cancer Screening Trial, with 53.5% of patients receiving a diagnosis of stage I cancer and 14.3% with stage IV cancer. Underreporting into the registry may have occurred. INTERPRETATION: This study revealed both the positive aspects of CT scan screening for lung cancer and the challenges that remain. Findings on CT imaging were correlated accurately with lung cancer detection using the Lung-RADS system. A significant stage shift toward early-stage lung cancer was present. Adherence to LCS was poor and likely contributes to the lower than expected cancer detection rate, all of which will impact the outcomes of patients undergoing screening for lung cancer.

Development and Validation of a Risk Assessment Model for Pulmonary Nodules Using Plasma Proteins and Clinical Factors.

BACKGROUND: Deficiencies in risk assessment for patients with pulmonary nodules (PNs) contribute to unnecessary invasive testing and delays in diagnosis. RESEARCH QUESTION: What is the accuracy of a novel PN risk model that includes plasma proteins and clinical factors? How does the accuracy compare with that of an established risk model? STUDY DESIGN AND METHODS: Based on technology using magnetic nanosensors, assays were developed with seven plasma proteins. In a training cohort (n = 429), machine learning approaches were used to identify an optimal algorithm that subsequently was evaluated in a validation cohort (n = 489), and its performance was compared with the Mayo Clinic model. RESULTS: In the training set, we identified a support vector machine algorithm that included the seven plasma proteins and six clinical factors that demonstrated an area under the receiver operating characteristic curve of 0.87 and met other selection criteria. The resulting risk reclassification model (RRM) was used to recategorize patients with a pretest risk of between 10% and 84%, and its performance was assessed across five risk strata (low, ≤ 10%; moderate, 10%-34%; intermediate, 35%-70%; high, 71%-84%; very high, > 85%). Stratification by the RRM decreased the proportion of intermediate-risk patients from 26.7% to 10.8% (P < .001) and increased the low-risk and high-risk strata from 16.8% to 21.9% (P < .001) and from 3.7% to 12.1% (P < .001), respectively. Among patients classified as low risk by the RRM and Mayo Clinic model, the corresponding true-negative to false-negative ratios were 16.8 and 19.5, respectively. Among patients classified as very high risk by the RRM and Mayo Clinic model, the corresponding true-positive to false-positive ratios were 28.5 and 17.0, respectively. Compared with the Mayo Clinic model, the RRM provided higher specificity at the low-risk threshold and higher sensitivity at the very high-risk threshold. INTERPRETATION: The RRM accurately reclassified some patients into low-risk and very high-risk categories, suggesting the potential to improve PN risk assessment.

Lung Cancer Screening.

Lung cancer screening with low-dose computed tomography (LDCT) reduces lung cancer deaths by early detection. The United States Preventive Services Task Force recommends lung cancer screening with LDCT in adults of age 50 years to 80 years who have at least a 20 pack-year smoking history and are currently smoking or have quit within the past 15 years. The implementation of a lung-cancer-screening program is complex. High-quality screening requires the involvement of a multidisciplinary team. The aim of a screening program is to find balance between mortality reduction and avoiding potential harms related to false-positive findings, overdiagnosis, invasive procedures, and radiation exposure. Components and processes of a high-quality lung-cancer-screening program include the identification of eligible individuals, shared decision-making, performing and reporting LDCT results, management of screen-detected lung nodules and non-nodule findings, smoking cessation, ensuring adherence, data collection, and quality improvement.

Characteristics of Persons Screened for Lung Cancer in the United States : A Cohort Study.

BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was recommended by the U.S. Preventive Services Task Force (USPSTF) in 2013, making approximately 8 million Americans eligible for screening. The demographic characteristics and adherence of persons screened in the United States have not been reported at the population level. OBJECTIVE: To define sociodemographic characteristics and adherence among persons screened and entered into the American College of Radiology's Lung Cancer Screening Registry (LCSR). DESIGN: Cohort study. SETTING: United States, 2015 to 2019. PARTICIPANTS: Persons receiving a baseline LDCT for LCS from 3625 facilities reporting to the LCSR. MEASUREMENTS: Age, sex, and smoking status distributions (percentages) were computed among persons who were screened and among respondents in the 2015 National Health Interview Survey (NHIS) who were eligible for screening. The prevalence between the LCSR and the NHIS was compared with prevalence ratios (PRs) and 95% CIs. Adherence to annual screening was defined as having a follow-up test within 11 to 15 months of an initial LDCT. RESULTS: Among 1 159 092 persons who were screened, 90.8% (n = 1 052 591) met the USPSTF eligibility criteria. Compared with adults from the NHIS who met the criteria (n = 1257), screening recipients in the LCSR were older (34.7% vs. 44.8% were aged 65 to 74 years; PR, 1.29 [95% CI, 1.20 to 1.39]), more likely to be female (41.8% vs. 48.1%; PR, 1.15 [CI, 1.08 to 1.23]), and more likely to currently smoke (52.3% vs. 61.4%; PR, 1.17 [CI, 1.11 to 1.23]). Only 22.3% had a repeated annual LDCT. If follow-up was extended to 24 months and more than 24 months, 34.3% and 40.3% were adherent, respectively. LIMITATIONS: Underreporting of LCS and missing data may skew demographic characteristics of persons reported to be screened. Underreporting of adherence may result in underestimates of follow-up. CONCLUSION: Approximately 91% of persons who had LCS met USPSTF eligibility criteria. In addition to continuing to target all eligible adults, men, those who formerly smoked, and younger eligible patients may be less likely to be screened. Adherence to annual follow-up screening was poor, potentially limiting screening effectiveness. PRIMARY FUNDING SOURCE: None.

Evaluating the Patient With a Pulmonary Nodule: A Review.

IMPORTANCE: Pulmonary nodules are identified in approximately 1.6 million patients per year in the US and are detected on approximately 30% of computed tomographic (CT) images of the chest. Optimal treatment of an individual with a pulmonary nodule can lead to early detection of cancer while minimizing testing for a benign nodule. OBSERVATIONS: At least 95% of all pulmonary nodules identified are benign, most often granulomas or intrapulmonary lymph nodes. Smaller nodules are more likely to be benign. Pulmonary nodules are categorized as small solid (<8 mm), larger solid (≥8 mm), and subsolid. Subsolid nodules are divided into ground-glass nodules (no solid component) and part-solid (both ground-glass and solid components). The probability of malignancy is less than 1% for all nodules smaller than 6 mm and 1% to 2% for nodules 6 mm to 8 mm. Nodules that are 6 mm to 8 mm can be followed with a repeat chest CT in 6 to 12 months, depending on the presence of patient risk factors and imaging characteristics associated with lung malignancy, clinical judgment about the probability of malignancy, and patient preferences. The treatment of an individual with a solid pulmonary nodule 8 mm or larger is based on the estimated probability of malignancy; the presence of patient comorbidities, such as chronic obstructive pulmonary disease and coronary artery disease; and patient preferences. Management options include surveillance imaging, defined as monitoring for nodule growth with chest CT imaging, positron emission tomography-CT imaging, nonsurgical biopsy with bronchoscopy or transthoracic needle biopsy, and surgical resection. Part-solid pulmonary nodules are managed according to the size of the solid component. Larger solid components are associated with a higher risk of malignancy. Ground-glass pulmonary nodules have a probability of malignancy of 10% to 50% when they persist beyond 3 months and are larger than 10 mm in diameter. A malignant nodule that is entirely ground glass in appearance is typically slow growing. Current bronchoscopy and transthoracic needle biopsy methods yield a sensitivity of 70% to 90% for a diagnosis of lung cancer. CONCLUSIONS AND RELEVANCE: Pulmonary nodules are identified in approximately 1.6 million people per year in the US and approximately 30% of chest CT images. The treatment of an individual with a pulmonary nodule should be guided by the probability that the nodule is malignant, safety of testing, the likelihood that additional testing will be informative, and patient preferences.

Executive Summary: Screening for Lung Cancer: Chest Guideline and Expert Panel Report.

BACKGROUND: Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not. METHODS: Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development and Evaluation approach. Meta-analyses were performed where appropriate. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached. RESULTS: The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements. CONCLUSIONS: Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.

Screening for Lung Cancer: CHEST Guideline and Expert Panel Report.

BACKGROUND: Low-dose chest CT screening for lung cancer has become a standard of care in the United States, in large part because of the results of the National Lung Screening Trial (NLST). Additional evidence supporting the net benefit of low-dose chest CT screening for lung cancer, and increased experience in minimizing the potential harms, has accumulated since the prior iteration of these guidelines. Here, we update the evidence base for the benefit, harms, and implementation of low-dose chest CT screening. We use the updated evidence base to provide recommendations where the evidence allows, and statements based on experience and expert consensus where it does not. METHODS: Approved panelists reviewed previously developed key questions using the Population, Intervention, Comparator, Outcome format to address the benefit and harms of low-dose CT screening, and key areas of program implementation. A systematic literature review was conducted using MEDLINE via PubMed, Embase, and the Cochrane Library on a quarterly basis since the time of the previous guideline publication. Reference lists from relevant retrievals were searched, and additional papers were added. Retrieved references were reviewed for relevance by two panel members. The quality of the evidence was assessed for each critical or important outcome of interest using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Meta-analyses were performed when enough evidence was available. Important clinical questions were addressed based on the evidence developed from the systematic literature review. Graded recommendations and ungraded statements were drafted, voted on, and revised until consensus was reached. RESULTS: The systematic literature review identified 75 additional studies that informed the response to the 12 key questions that were developed. Additional clinical questions were addressed resulting in seven graded recommendations and nine ungraded consensus statements. CONCLUSIONS: Evidence suggests that low-dose CT screening for lung cancer can result in a favorable balance of benefit and harms. The selection of screen-eligible individuals, the quality of imaging and image interpretation, the management of screen-detected findings, and the effectiveness of smoking cessation interventions can impact this balance.

Proposed Quality Metrics for Lung Cancer Screening Programs: A National Lung Cancer Roundtable Project.

Lung cancer screening with a low radiation dose chest CT scan is the standard of care for screening-eligible individuals. The net benefit of screening may be optimized by delivering high-quality care, capable of maximizing the benefit and minimizing the harms of screening. Valid, feasible, and relevant indicators of the quality of lung cancer screening may help programs to evaluate their current practice and to develop quality improvement plans. The purpose of this project was to develop quality indicators related to the processes and outcomes of screening. Potential quality indicators were explored through surveys of multidisciplinary lung cancer screening experts. Those that achieved predefined measures of consensus for each of the validity, feasibility, and relevance domains are proposed as quality indicators. Each of the proposed indicators is described in detail, with guidance on how to define, measure, and improve program performance within the indicator.

Phenotypes and Subphenotypes of Patients With COVID-19: A Latent Class Modeling Analysis.

BACKGROUND: Since COVID-19 was identified, its clinical and biological heterogeneity has been recognized. Identifying COVID-19 phenotypes might help guide basic, clinical, and translational research efforts. RESEARCH QUESTION: Does the clinical spectrum of patients with COVID-19 contain distinct phenotypes and subphenotypes? STUDY DESIGN AND METHODS: We included adult patients (≥ 18 years) positive for laboratory-confirmed SARS-CoV-2 infection from a prospective COVID-19 registry database in the Cleveland Clinic Health System in Ohio and Florida. The patients were split into training and testing sets. Using latent class analysis (LCA), we first identified phenotypic clusters of patients with COVID-19 based on demographics, comorbidities, and presenting symptoms. We then identified subphenotypes of hospitalized patients with additional blood biomarker data measured on hospital admission. The associations of phenotypes/subphenotypes and clinical outcomes were investigated. Multivariable prediction models were established to predict assignment to the LCA-defined phenotypes and subphenotypes and then evaluated on an independent testing set. RESULTS: We analyzed data for 20,572 patients. Seven phenotypes were identified on the basis of different profiles of presenting COVID-19 symptoms and existing comorbidities, including the following groups: young, no symptoms; young, symptoms; middle-aged, no symptoms; middle-aged, symptoms; middle-aged, comorbidities; old, no symptoms; and old, symptoms. The rates of inpatient hospitalization for the phenotypes were significantly different (P < .001). Five subphenotypes were identified for the subgroup of hospitalized patients, including the following subgroups: young, elevated WBC and platelet counts; middle-aged, lymphopenic with elevated C-reactive protein; middle-aged, hyperinflammatory; old, leukopenic with comorbidities; and old, hyperinflammatory with kidney dysfunction. The hospital mortality and the times from hospitalization to ICU transfer or death were significantly different (P < .001). The models for predicting the LCA-defined phenotypes and subphenotypes showed high discrimination (concordance index, 0.92 and 0.91). INTERPRETATION: Hypothesis-free LCA-defined phenotypes and subphenotypes of patients with COVID-19 can be identified. These may help clinical investigators conduct stratified analyses in clinical trials and assist basic science researchers in characterizing the pathobiology of the spectrum of COVID-19 presentations.

Association of Exercise Behavior with Overall Survival in Stage I-IIIA Lung Cancer.

Rationale: Exercise assessments may help predict outcomes for patients with diagnosed lung cancer. Objectives: We examined the relationship between prediagnosis exercise behavior and clinical outcomes among patients with stage I-IIIA lung cancer. Methods: In a retrospective cohort study of patients with stage I-IIIA lung cancer at Kaiser Permanente Colorado who had at least one Exercise Vital Sign assessment-a questionnaire tool to help promote exercise in chronic disease management-within the year before diagnosis, we defined exercise behavior as active (any min/wk of moderate-to-vigorous-intensity physical activity) or inactive (no moderate-to-vigorous physical activity). The outcomes were 1) overall survival (OS) and 2) acute healthcare use (AHCU). We used the Kaplan-Meier method, Cox proportional hazard model, and negative binomial regression model to analyze the effects of exercise on outcomes, adjusting for demographic, socioeconomic, clinical, and lung-cancer characteristics. Results: Among 552 patients with lung cancer, 230 (42%) were identified as physically active before their diagnosis of cancer. There was no significant difference in the stage distribution between active and inactive patients. The median survival times were 2.4 years for the active group and 1.8 years for inactive patients (P < 0.001). The mean rates (standard deviations) of AHCU were 1.09 (1.55) and 2.31 (5.61) per person-year for active and inactive groups, respectively (P < 0.01). Active exercise, compared with inactivity, was associated with better OS (hazard ratio, 0.52 [0.39-0.69]) and lower AHCU (rate ratio, 0.63 [0.49-0.80]) in unadjusted analyses; in adjusted analyses, active exercise was associated with better OS (hazard ratio, 0.62 [0.45-0.86]), but AHCU was not lower by a statistically significant amount (rate ratio, 0.82 [0.65-1.04]). Conclusions: Prediagnosis active exercise was associated with better OS after diagnosis of stage I-IIIA lung cancer. Exercise assessments may help predict outcomes, risk-stratify patients for curative-intent therapy, and identify those who would benefit from increased physical activity and exercise.

Lung Cancer Screening.

Lung cancer is the leading cause of US cancer-related deaths. Lung cancer screening with a low radiation dose chest computed tomography scan is now standard of care for a high-risk eligible population. It is imperative for clinicians and surgeons to evaluate the trade-offs of benefits and harms, including the identification of many benign lung nodules, overdiagnosis, and complications. Integration of smoking cessation interventions augments the clinical benefits of screening. Screening programs must develop strategies to manage screening-detected findings to minimize potential harms. Further research should focus on how to improve patient selection, minimize harms, and facilitate access to screening.