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The issue of overdiagnosis in low-dose computed tomography (LDCT) screening trials could be addressed by the development of complementary biomarkers able to improve detection of aggressive disease. The mutation profile of LDCT screening–detected lung tumors is currently unknown.Targeted next-generation sequencing was performed on 94 LDCT screening–detected lung tumors. Associations with clinicopathologic features, survival, and the risk profile of a plasma microRNA signature classifier were analyzed.The mutational spectrum and frequency observed in screening series was similar to that reported in public data sets, although a larger number of tumors without mutations in driver genes was detected. The 5-year overall survival (OS) rates of patients with and without mutations in the tumors were 66% and 100%, respectively (p = 0.015). By combining the mutational status with the microRNA signature classifier risk profile, patients were stratified into three groups with 5-year OS rates ranging from 42% to 97% (p < 0.0001) and the prognostic value was significant after controlling for stage (p = 0.02).Tumor mutational status along with a microRNA-based liquid biopsy can provide additional information in planning clinical follow-up in lung cancer LDCT screening programs.