Blood microRNA testing in participants with suspicious low-dose CT findings: follow-up of the BioMILD lung cancer screening trial

Abstract

Background: The proper management of suspicious radiologic findings is crucial to optimize the effectiveness of low-dose computed tomography (LDCT) lung cancer screening trials. In the BioMILD study, we evaluated the utility of combining a plasma 24-microRNA signature classifier (MSC) and LDCT to define the individual risk and personalize screening strategies. Here we aim to assess the utility of repeated MSC testing during annual screening rounds in 1024 participants with suspicious LDCT findings.

Methods: The primary outcome was two-year lung cancer incidence in relation to MSC test results, reported as relative risk (RR) with 95% confidence interval (CI). Lung cancer incidence and mortality were estimated using extended Cox models for time-dependent covariates, yielding the respective hazard ratios (HR). Clinicaltrials.gov ID: NCT02247453.

Findings: With a median follow-up of 8.5 years, the full study set included 1403 indeterminate LDCT (CTind) and 584 positive LDCT (CT+) results. A lung cancer RR increase in MSC+ compared to MSC- participants was observed in both the CTind (RR: 2.5; 95% CI: 1.4-4.32) and CT+ (RR: 2.6; 95% CI: 1.81-3.74) groups and was maintained when considering stage I or resectable tumors only. A 98% negative predictive value in CTind/MSC- and a 30% positive predictive value in CT+/MSC+ lesions were recorded. At seven years' follow-up, MSC+ participants had a cumulative HR of 4.4 (95% CI: 3.0-6.4) for lung cancer incidence and of 8.1 (95% CI: 2.7-24.5) for lung cancer mortality.

Interpretation: Our study shows that MSC can be reliably performed during LDCT screening rounds to increase the accuracy of lung cancer risk and mortality prediction and supports its clinical utility in the management of LDCT findings of uncertain malignancy.

Funding: Italian Association for Cancer Research; Italian Ministry of Health; Horizon2020; National Cancer Institute (NCI); Gensignia LifeScience.

Keywords: Biomarkers; Early detection; LDCT screening.

Fig. 1

Flow chart of the study design. BioMILD screening participants were selected according to the low-dose computed tomography (LDCT) result at the first and subsequent screening rounds (A). At each screening round the selected participants were stratified according to the combined results of LDCT and the microRNA signature classifier (MSC) test (B). LDCT divided patients into CT negative (CT−), CT indeterminate (CTind) and CT positive (CT+), while MSC divided patients into MSC positive (MSC+) and MSC negative (MSC−).

Fig. 2

Swimmer plot reporting the MSC test results over time along with lung cancer diagnosis and mortality. For the 125 patients who developed incident lung tumors during the BioMILD study, the MSC test results at annual recall and at cancer diagnosis were considered. Overall mortality and lung cancer-specific mortality are indicated with black lines starting from the time of lung cancer diagnosis.

Fig. 3

Extended Kaplan–Meier curves stratified by yearly MSC test repetition. Lung cancer incidence (A) and mortality (B) in MSC+ and MSC− BioMILD screening participants. Cox models with hazard ratio (HR) and 95% confidence interval (95% CI) for time-dependent covariates were adopted.