Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic
and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the
prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving
first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this
study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma
cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated
by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant
features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had
a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95%
confidence limits (CL) = 1.24–3.68; p-value = 0.006). Conversely, an inverse relationship between CTC
median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that
in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate
patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in
the overall population. In the subgroup of SD patients, both biomarkers identified patients at high
risk of poor prognosis who might deserve additional/alternative therapeutic interventions.