title: Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study.
abstract: OBJECTIVE
  Recent 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.
  
  
  METHODS
  Plasma samples from 939 participants, including 69 patients with lung cancer and 870 disease-free individuals (n = 652, LDCT arm; n = 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.
  
  
  RESULTS
  The 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 (χ1(2) = 49.53; P < .001).
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Gabriella Sozzi, Mattia Boeri, Carla Verri, Paola Suatoni, Luca Roz, Davide Conte, Michela Grassi, Tumor Genomics Unit; Ugo Pastorino, Thoracic Surgery Unit; Alfonso Marchiano, Radiology Unit, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale dei Tumori; Marta Rossi, Francesca Bravi, Eva Negri, Carlo La Vecchia, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri"; Francesca Bravi and Carlo La Vecchia, University of Milan, Milan; and Nicola Sverzellati, University of Parma, Parma, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.forename: Mattia
authors.initials: M
authors.lastname: Boeri
authors.forename: Marta
authors.initials: M
authors.lastname: Rossi
authors.forename: Carla
authors.initials: C
authors.lastname: Verri
authors.forename: Paola
authors.initials: P
authors.lastname: Suatoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Bravi
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.forename: Davide
authors.initials: D
authors.lastname: Conte
authors.forename: Michela
authors.initials: M
authors.lastname: Grassi
authors.forename: Nicola
authors.initials: N
authors.lastname: Sverzellati
authors.forename: Alfonso
authors.initials: A
authors.lastname: Marchiano
authors.forename: Eva
authors.initials: E
authors.lastname: Negri
authors.forename: Carlo
authors.initials: C
authors.lastname: La Vecchia
authors.forename: Ugo
authors.initials: U
authors.lastname: Pastorino
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D016009:Chi-Square Distribution; D005189:False Positive Reactions; D005260:Female; D020869:Gene Expression Profiling; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008403:Mass Screening / Q000379:methods*; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000401:mortality; D013997:Time Factors; D014057:Tomography, X-Ray Computed
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs