ABSTRACT
BACKGROUND: The objectives of the current study were to develop an initial blood-based circulating tumor DNA (ctDNA) gene signature and to validate the clinical test performance in patients with early primary and secondary lung cancer. METHODS: Between January 2009 and October 2014, a total of 211 patients with known or suspected lung cancer donated their blood prior to surgery and were followed up to May 2018. ctDNA was extracted from plasma and from corresponding formalin-fixed, paraffin-embedded tissues. The blood was analyzed in a blinded manner and pathology reports were issued that were blinded to the blood test results. The reference standard was histopathology confirmed cancer in the resected surgical specimens as reported according to World Health Organization criteria and staged using the eighth edition of the TNM Classification of Malignant Tumors criteria. RESULTS: Of 211 consenting patients, 19 (9.0%) were excluded, leaving 192 participants, consisting of 95 men (49%) and with a mean age of 63 years (SD, 15 years). The clinical test performance for the blood-based diagnostic signature demonstrated a sensitivity of 75% (95% CI, 67%-81%), specificity of 89% (95% CI, 70%-98%), positive predictive value of 98% (95% CI, 93%-100%), and negative predictive value of 35% (95% CI, 24%-48%) when compared with conventional clinical histopathology reporting of the resected tissue. CONCLUSIONS: The results of the current study suggested that blood-based ctDNA analysis of cancer mutations is a specific, noninvasive test for the diagnosis of cancer.
Subject(s)
Biomarkers, Tumor/blood , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Mutation/genetics , Female , Humans , Lung Neoplasms/blood , Lung Neoplasms/genetics , Male , Middle Aged , Neoplasm Staging/methods , Neoplastic Cells, Circulating/pathology , Prognosis , Sensitivity and SpecificityABSTRACT
BACKGROUND: Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery. METHODS: Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX systemTM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens. RESULTS: Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41-76%) and 41% (95% CI, 24-59%), with a specificity of 53% for both. CONCLUSIONS: The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer.