Characterization of DLL3-positive Circulating Tumor Cells (CTCs) in Patients with Small Cell Lung Cancer (SCLC) and Evaluation of Their Clinical Relevance During Front-line Treatment

Objectives: The aim of the study was to characterize and evaluate the presence of DLL3-positive Circulating Tumor Cells (CTCs) in SCLC patients receiving front-line chemotherapy and assess their clinical relevance.

Materials And Methods: Peripheral blood was obtained from treatment-naïve patients with SCLC (n = 108 patients), after one etoposide/platinum cycle (n = 68 patients) and on disease progression (n = 48 patients). Immunofluorescence staining using antibodies against the DLL3, cytokeratins (CK), CD45 and vimentin (Vim) was used for the detection and characterization of CTCs.

Results: Before treatment, 74.1% of patients had detectable DLL3/CD45 CTCs. One-treatment cycle significantly decreased both the detection rate (p < 0.001) and the absolute number (p < 0.001) of DLL3/CD45 CTCs. Triple immunofluorescence staining using anti-CK, anti-Vim and anti-DLL3 antibodies revealed an important CTC heterogeneity since DLL3 could be detected in Vim, Vim, CK and CK CTCs. On disease progression, both the detection rate and the absolute number of DLL3/CD45 CTCs were significantly increased compared to post-1 cycle values (p < 0.001 and p = 0.002, respectively). In addition, 22.7% of patients had detectable DLL3/CD45 cells which could not be captured by the CellSearch assay. In multivariate analysis, the detection of DLL3+/CD45- CTCs at baseline was significantly associated with decreased progression-free survival (HR = 10.8; p = 0.005) whereas their detection on disease progression was associated with decreased overall survival (HR: 28.2; p = 0.016).

Conclusions: These findings demonstrate an important heterogeneity of CTCs, based on the expression of CK, Vim and DLL3, in patients with SCLC and the changes of DLL3/CD45 CTCs during treatment seem to be a dynamic biomarker associated with patients' clinical outcome.