Clinical Utility of Biomarkers Driven Management of Indeterminate Pulmonary Nodules

PROJECT SUMMARY

The goal of this application is to test the clinical utility of a biomarker-informed approach to the evaluation and

management of indeterminate pulmonary nodules (IPNs). The study is designed to address this major and

growing unmet need given the adoption of lung cancer screening in the US and abroad and the common

occurrence of incidentally identified IPNs. We have developed and validated in external cohorts a high sensitivity

hs-CYFRA 21-1 biomarker assay and quantitative imaging features that together improve the current non-

invasive assessment of IPNs. In this proposal we hypothesize that a prediction model that integrates clinical

variables, hs-CYFRA 21-1 serum concentration, and quantitative imaging signature will show clinical utility by

reducing costly and invasive procedures while shortening time to diagnosis. To test this hypothesis, we propose

the following specific aims: First, we will test the clinical utility of a biomarker-informed strategy in a first of its

kind randomized clinical trial of IPN management. We will enroll 440 individuals with intermediate risk IPNs (10-

70% risk for cancer) at four institutions with the goal of reducing the number of invasive procedures and time to

diagnosis. In the control arm, participants will follow the standard of care and in the intervention arm the

biomarker results, expressed as a post-test probability for lung cancer, will be given to providers and participants

to inform nodule management. Second, to further our work in identifying new candidate biomarkers for better

risk stratification, we will apply a workflow for evaluation of candidates and validate the best candidates for entry

into a similar future trial to that proposed in Aim 1. In a set of prospectively collected specimens, evaluated

retrospectively in a blinded fashion (ProBE design), we will test the improvement in diagnostic accuracy of

candidate biomarkers in patients with IPNs of intermediate risk for lung cancer based on the Mayo risk model. A

blood biomarker signature from Abbott laboratories will be tested alone and in combination with a validated

radiomics score to determine if together they reclassify at least 20% of those at intermediate risk (10-70%) based

on the Mayo risk model alone into either a lower risk (70%) group. We will determine the

optimal and most cost-effective Mayo model + biomarker combination or sequence needed to achieve the critical

decision thresholds in the management of IPNs. At the end of this project, we will have: a) demonstrated for the

first time the clinical utility of a biomarker informed approach to IPN management and acquired additional

outcomes data for a larger follow-on randomized multicenter trial, b) validated the incremental diagnostic

accuracy of new candidate biomarkers for the management of IPNs, and c) opened a new avenue for rapid

testing of the most effective combination(s) of candidates.