Clinical Utility of a Plasma-Based miRNA Signature Classifier Within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study

Abstract

A B S T R A C T PurposeRecent screening trial results indicate that low-dose computed tomography (LDCT) reduces lung cancer mortality in high-risk patients. However, high false-positive rates, costs, and potential harms highlight the need for complementary biomarkers. The diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicenter Italian Lung Detection (MILD) trial. Patients and MethodsPlasma samples from 939 participants, including 69 patients with lung cancer and 870 disease-free individuals (n ϭ 652, LDCT arm; n ϭ 287, observation arm) were analyzed by using a quantitative reverse transcriptase polymerase chain reaction-based assay for MSC. Diagnostic performance of MSC was evaluated in a blinded validation study that used prespecified risk groups. ResultsThe diagnostic performance of MSC for lung cancer detection was 87% for sensitivity and 81% for specificity across both arms, and 88% and 80%, respectively, in the LDCT arm. For all patients, MSC had a negative predictive value of 99% and 99.86% for detection and death as a result of disease, respectively. LDCT had sensitivity of 79% and specificity of 81% with a false-positive rate of 19.4%. Diagnostic performance of MSC was confirmed by time dependency analysis. Combination of both MSC and LDCT resulted in a five-fold reduction of LDCT false-positive rate to 3.7%. MSC risk groups were significantly associated with survival ( 1 2 ϭ 49.53; P Ͻ .001). ConclusionThis large validation study indicates that MSC has predictive, diagnostic, and prognostic value and could reduce the false-positive rate of LDCT, thus improving the efficacy of lung cancer screening.

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…• Selection of miRNA with significantly altered expression as potential biomarkers performance of plasma microRNAs as complementary biomarkers for LDCT screening in a cohort of current or former smokers, older than 50 years [6]. They retrospectively evaluated plasma miRNA signatures in samples from 939 participants, including 69 patients with lung cancer and 870 diseasefree individuals.…”

“…However, a high rate of false positive results associated with LDCT screening opened a debate over the cost-effectiveness of LDCT screening programs and the potential harms related to overdiagnosis and radiation-induced cancers. In view of personalised medicine, the potential role for specific, miRNAbased biomarkers to complement the radiological modalities and increase the total sensitivity and specificity of the lung cancer screening process is currently being investigated [6,7].…”

Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

“…Boeri et al recently validated their miRNA signature in a large cohort of individuals with lung cancer [26], highlighting the potential for application in other cancers. We adopted this method to overcome the limitations associated with global normalization approaches.…”

Implementing Low-Dose Computed Tomography Screening for Lung Cancer in Canada: Implications of Alternative At-Risk Populations, Screening Frequency, and Duration

“…The incremental number of invasive procedures is quite low, although additional diagnostic ct imaging is more frequent. A recent report on the use of a biomarker-a plasma-based microrna signature classifier-during the mild ldct screening trial 34 demonstrated that the combination of the microrna signature classifier and ldct reduced the false-positive rate to 3.7% 43 . If a microrna signature classifier or another biomarker is confirmed to be effective in reducing false-positive screen rates, it would, in many cases, avoid the need for follow-up ct imaging and unnecessary invasive procedures and would reduce costs.…”