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.

Abstract

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-1st 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.

• Authors: Ippokratis Messaritakis, Michalis Nikolaou, Fillipos Koinis, Eleni Politaki, Anastasios Koutsopoulos, Eleni Lagoudaki, Eleni-Kyriaki Vetsika, Vassilis Georgoulias, Athanasios Kotsakis
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 135 Pg. 33-39 (09 2019) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 31447000 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Biomarkers, Tumor
• DLL3 protein, human
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Vimentin

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers
• Biomarkers, Tumor
• Cell Line, Tumor
• Disease Management
• Female
• Fluorescent Antibody Technique
• Gene Expression
• Humans
• Immunophenotyping
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Leukocytes, Mononuclear
• Lung Neoplasms (diagnosis, genetics, metabolism, therapy)
• Male
• Membrane Proteins (genetics, metabolism)
• Neoplasm Staging
• Neoplastic Cells, Circulating (metabolism)
• Proportional Hazards Models
• Small Cell Lung Carcinoma (diagnosis, genetics, metabolism, therapy)
• Vimentin (genetics, metabolism)