Validation of blood-based biomarkers for risk assessment of lung cancer among individuals with no smoking history in the PLCO Cohort

Project Summary While most cases of lung cancer are related to tobacco use, with effective tobacco control, lung cancer in those with light or no smoking history is becoming a greater public health concern. It is estimated that lung cancer in those who have never smoked (LCINS) would be the fifth-leading cause of cancer death worldwide and the seventh-leading cause in the United States. No widely accepted early detection strategy exists for those who are not high risk for lung cancer based on a tobacco use history. Efforts to broaden low-dose CT based lung cancer screening to those at lower risk have been likely met with increasing rates of overdiagnosis. Our team has an extensive track record of developing and validating blood-based biomarkers for cancer risk, including a 4-protein biomarker panel (4MP) that has been extensively validated to improve prediction of lung cancer risk over clinical risk factors alone. Here we demonstrate that the 4MP and a newly validated 4-metabolite biomarker panel (4MetP) have similar performance in LCITNS. Our translational objective of this proposal is to test the predictive performance of the 4MP and 4MetP, individually and in combination with clinical risk models, for 1- year risk prediction of lung cancer among those no smoking history. We hypothesize that a composite panel of the 4MP, 4MetP, with addition of clinical risk characteristics, can identify those with no smoking history and at a high enough risk that they may benefit from lung cancer screening. Samples from those with no smoking history from several MD Anderson cohorts and the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial will be utilized to build a composite panel consisting of blood-based biomarkers and clinical characteristics to identify those at risk for lung cancer. Aim 1: Evaluate the predictive performance of the 4MP and 4MetP for 1-year risk of lung cancer among never-smoking individuals. We will build on preliminary data and evaluate the performance of the 4MP and 4MetP in cohorts of LCINS and matched controls from MD Anderson. We will measure the 4MP and 4MetP in 12-month prediagnostic LCINS samples from the PLCO (n=74) as well as ten times the number of unmatched controls to externally validate the biomarker panels. We will assess the performance of these panels and any composite biomarker panel to predict 1-year risk of developing lung cancer as well as risk of lung cancer mortality. Aim 2: Assess whether an algorithm that consider repeat biomarker testing improves sensitivity and lead-time detection of lung cancer among never-smoking participants in the PLCO cohort. We will obtain all available longitudinally collected samples from the cases and controls specified in Aim 1. We will evaluate whether an individualized algorithm accounting for biomarker trends can improve upon a single threshold measurement to improve diagnostic performance.