Abstract
CT screening for lung cancer reduces mortality, but will cost Medicare ∼2 billion dollars due in part to high false positive rates. Molecular biomarkers could augment current risk stratification used to select smokers for screening. Gene methylation in sputum reflects lung field cancerization that remains in lung cancer patients post-resection. This population was used in conjunction with cancer-free smokers to evaluate classification accuracy of a validated eight-gene methylation panel in sputum for cancer risk. Sputum from resected lung cancer patients (n=487) and smokers from Lovelace (n=1380) and PLuSS (n=718) cohorts was studied for methylation of an 8-gene panel. Area under a receiver operating characteristic curve was calculated to assess the prediction performance in logistic regressions with different sets of variables. The prevalence for methylation of all genes was significantly increased in the ECOG-ACRIN patients compared to cancer-free smokers as evident by elevated odds ratios that ranged from 1.6 to 8.9. The gene methylation panel showed lung cancer prediction accuracy of 82–86% and with addition of clinical variables improved to 87–90%. With sensitivity at 95%, specificity increased from 25% to 54% comparing clinical variables alone to their inclusion with methylation. The addition of methylation biomarkers to clinical variables would reduce false positive screens by ruling out one-third of smokers eligible for CT screening and could increase cancer detection rates through expanding risk assessment criteria.
Highlights
Lung cancer (LC) remains the leading cause of cancer-related death for men and women in the US [1]
Classification accuracy of the methylation panel was similar when relaxing the Medicare inclusion criteria for CT to include all ECOG-ACRIN cases that smoked compared to all cancer-free subjects from Lovelace Smokers Cohort (LSC) and Pittsburgh PLuSS Cohort (PLuSS)
The retrospective nature of this study design allowed us to define the classification accuracy of the biomarker panel in a sample size of cases (n = 487) that was comparable to that detected by the National LungScreening trial (NLST) screening trial of 53,439 smokers [7]
Summary
Lung cancer (LC) remains the leading cause of cancer-related death for men and women in the US [1]. The current study addressed whether our validated gene methylation panel could be extended to improve the existing risk prediction model used to recommend people for a CT screen To accomplish this goal we used three cohorts of people: ECOG-ACRIN5597 trial participants who had a confirmed Stage I diagnosis of LC (based on pathology following surgical resection), the Lovelace Smokers Cohort ([LSC], current and former smokers at high risk for LC), and the PLuSS Smokers cohort ( current and former smokers at high risk for LC). We initially evaluated the utility of the eight gene panel to classify risk for LC by comparing gene methylation prevalence at baseline in the ECOG-ACRIN5597 patients who met the Medicare guidelines to receive a CT screen to screen eligible subjects from two cancer-free smoker cohorts (LSC and PLuSS) described previously [21]. The performance of our methylation panel was assessed in all ECOG-ACRIN5597 patients who provided baseline sputum compared to LSC or PLuSS current or former smokers irrespective of meeting eligibility for receiving a CT screen
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