Systematic review and critique of circulating miRNAs as biomarkers of stage I-II non-small cell lung cancer.

Selected circulating microRNAs (miRNAs) have been suggested for non-invasive
screening of non-small cell lung cancer (NSCLC), however the numerous proposed
miRNA signatures are inconsistent.
Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in
serum/plasma samples, we searched the databases “Pubmed”, “Medline”, “Scopus”,
“Embase” and “WOS” and systematically reviewed the publications reporting
quantitative data on the efficacy [sensitivity, specificity and/or area under the curve
(AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20
studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls,
and were of medium quality according to Quality Assessment of Diagnostic Accuracy
Studies checklist. In these studies, the patient cohorts as well as the control groups
were heterogeneous for demographics and clinicopathological characteristics;
moreover, numerous pre-analytical and analytical variables likely influenced miRNA
determinations, and potential bias of hemolysis was often underestimated. We
identified four circulating miRNAs scarcely influenced by hemolysis, each featuring
high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-
223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity
(> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step
screening for stage I-II NSCLC using first the above panel of serum miRNAs with
high sensitivity and high AUC, and subsequently the panel with high specificity, the
estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and
other circulating miRNAs suggested for stage I-II NSCLC screening require validation
in multiple independent studies before they can be proposed for clinical application.