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

被引:30
作者
Messaritakis, Ippokratis [1 ]
Nikolaou, Michalis [2 ]
Koinis, Fillipos [5 ]
Politaki, Eleni [1 ]
Koutsopoulos, Anastasios [3 ]
Lagoudaki, Eleni [3 ]
Vetsika, Eleni-Kyriaki [5 ]
Georgoulias, Vassilis [1 ,4 ]
Kotsakis, Athanasios [5 ]
机构
[1] Univ Crete, Sch Med, Lab Tumor Cell Biol, Iraklion, Greece
[2] Marika Iliadi Hosp Athens, Dept Internal Med, Med Oncol Unit, Athens, Greece
[3] Univ Gen Hosp Heraklion, Dept Pathol, Iraklion, Greece
[4] IASO Gen Hosp Athens, Dept Med Oncol 1, Athens, Greece
[5] Univ Gen Hosp Larissa, Dept Med Oncol, Thessaly, Greece
关键词
DLL3; Vimentin; SCLC; CTCs; STEM-CELLS; NEUROENDOCRINE; SURVIVAL; PROGRESSION; EXPRESSION; PATHWAY;
D O I
10.1016/j.lungcan.2019.06.025
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-naive 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.
引用
收藏
页码:33 / 39
页数:7
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