Cell-Free DNA Fragmentomes in the Diagnostic Evaluation of Patients With Symptoms Suggestive of Lung Cancer

Abstract

BackgroundThe diagnostic workup of individuals suspected of having lung cancer can be complex and protracted because conventional symptoms of lung cancer have low specificity and sensitivity.Research QuestionAmong individuals with symptoms of lung cancer, can a blood-based approach to analyze cell-free DNA (cfDNA) fragmentation (the DNA evaluation of fragments for early interception [DELFI] score) enhance evaluation for the possible presence of lung cancer?Study Design and MethodsAdults were referred to Bispebjerg Hospital (Copenhagen, Denmark) for diagnostic evaluation of initial imaging anomalies and symptoms consistent with lung cancer. Numbers and types of symptoms were extracted from medical records. cfDNA from plasma samples obtained at the prediagnostic visit was isolated, sequenced, and analyzed for genome-wide cfDNA fragmentation patterns. The relationships among clinical presentation, cancer status, and DELFI score were examined.ResultsA total of 296 individuals were analyzed. Median DELFI scores were higher for those with lung cancer (n = 98) than those without cancer (n = 198; 0.94 vs 0.19; P < .001). In a multivariate model adjusted for age, smoking history, and presenting symptoms, the addition of the DELFI score improved the prediction of lung cancer for those who demonstrated symptoms (area under the receiver operating characteristic curve, 0.74-0.94).InterpretationThe DELFI score distinguishes individuals with lung cancer from those without cancer better than suspicious symptoms do. These results represent proof-of-concept support that fragmentation-based biomarker approaches may facilitate diagnostic resolution for patients with concerning symptoms of lung cancer. The diagnostic workup of individuals suspected of having lung cancer can be complex and protracted because conventional symptoms of lung cancer have low specificity and sensitivity. Among individuals with symptoms of lung cancer, can a blood-based approach to analyze cell-free DNA (cfDNA) fragmentation (the DNA evaluation of fragments for early interception [DELFI] score) enhance evaluation for the possible presence of lung cancer? Adults were referred to Bispebjerg Hospital (Copenhagen, Denmark) for diagnostic evaluation of initial imaging anomalies and symptoms consistent with lung cancer. Numbers and types of symptoms were extracted from medical records. cfDNA from plasma samples obtained at the prediagnostic visit was isolated, sequenced, and analyzed for genome-wide cfDNA fragmentation patterns. The relationships among clinical presentation, cancer status, and DELFI score were examined. A total of 296 individuals were analyzed. Median DELFI scores were higher for those with lung cancer (n = 98) than those without cancer (n = 198; 0.94 vs 0.19; P < .001). In a multivariate model adjusted for age, smoking history, and presenting symptoms, the addition of the DELFI score improved the prediction of lung cancer for those who demonstrated symptoms (area under the receiver operating characteristic curve, 0.74-0.94). The DELFI score distinguishes individuals with lung cancer from those without cancer better than suspicious symptoms do. These results represent proof-of-concept support that fragmentation-based biomarker approaches may facilitate diagnostic resolution for patients with concerning symptoms of lung cancer. Take-home PointsStudy Question: Can the blood-based DNA evaluation of fragments for early interception (DELFI) method for cancer detection distinguish between individuals who do and do not have lung cancer better than symptoms suspicious for lung cancer alone do?Results: DELFI scores improved the identification of patients with lung cancer when combined with symptoms suggestive of the disease.Interpretation: The DELFI method distinguishes between lung cancer and no cancer in a symptomatic cohort, implying potential clinical usefulness to streamline the diagnostic workup for patients with symptoms suggestive of lung cancer. Study Question: Can the blood-based DNA evaluation of fragments for early interception (DELFI) method for cancer detection distinguish between individuals who do and do not have lung cancer better than symptoms suspicious for lung cancer alone do? Results: DELFI scores improved the identification of patients with lung cancer when combined with symptoms suggestive of the disease. Interpretation: The DELFI method distinguishes between lung cancer and no cancer in a symptomatic cohort, implying potential clinical usefulness to streamline the diagnostic workup for patients with symptoms suggestive of lung cancer. Delayed diagnosis of lung cancer is an abiding concern in clinical medicine.1Ellis P.M. Vandermeer R. Delays in the diagnosis of lung cancer.J Thorac Dis. 2011; 3: 183-188PubMed Google Scholar, 2Walter F.M. Rubin G. Bankhead C. et al.Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study.Br J Cancer. 2015; 112: S6-S13Crossref PubMed Scopus (147) Google Scholar, 3Vidaver R.M. Shershneva M.B. Hetzel S.J. Holden T.R. Campbell T.C. 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S.M. et for lung cancer with low-dose computed and review for the US 2021; PubMed Scopus Google Scholar these a blood-based that could improve the evaluation of patients with symptoms suggestive of lung cancer may have clinical have evaluated as lung cancer and and of cancer: and 2014; PubMed Scopus Google Scholar, T. et and lung cancer early of the 2021; PubMed Scopus Google Scholar, et for early stage non-small cell lung to low-dose computed Oncol. 2021; Scopus (10) Google Scholar The of genome-wide of fragmentation of cell-free DNA (cfDNA) in plasma developed as a approach to the detection of S. A. J. et cell-free DNA fragmentation in patients with PubMed Scopus Google Scholar, D. S. et and of lung cancer cell-free DNA 2021; 12: PubMed Scopus Google Scholar, K. et cancer cell-free DNA PubMed Scopus Google Scholar In a proof-of-concept DNA evaluation of fragments for early interception (DELFI) was to lung cancer with sensitivity at D. 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