Bcl-2 expression in circulating tumor cells (CTCs) of patients with small cell lung cancer (SCLC) receiving front-line treatment

Introduction: To investigate the presence of Bcl-2(+)CTCs in chemotherapy-naive SCLC patients and their clinical relevance during front-line treatment. Methods: Peripheral blood was obtained from 66 consecutive-patients before chemotherapy administration, after one-cycle and at relapse. CTCs were detected by CellSearch and immunofluorescence using anti-Bcl-2, antiM30, anti-cytokeratins(CK), anti-CD45 and anti-vimentin(Vim) antibodies. Results: Before treatment, CTCs were detected in 62.1% and 72.7% of patients using the CellSearch and immunofluorescence (Bcl-2(+)/CD45(-)), respectively. One-treatment cycle significantly decreased both CTCs' detection rate(p < 0.001) and their absolute number (p < 0.001). On relapse, both the number of positive-patients and the absolute number of CTC subpopulations were significantly increased, compared to post-1st cycle (CellSearch: p = 0.002 and immunofluorescence: p < 0.001). Immunofluorescence revealed an important CTC heterogeneity (Bcl-2(+)/Vim(+), Bcl2(+)/Vim(-), Bcl2(+)/CK+, Bcl2(+)/CK- and Bcl2(+)/M30(-) CTCs). Moreover, 50.0% of patients without detectable CTCs by CellSearch had detectable Bcl-2(+)/CD45(-) cells. Multivariate analysis revealed a significant association between Bcl-2(+)/CD45(-) cells at baseline and PFS (HR = 4.5;p = 0.005) and OS (HR: 4.3; p = 0.001). Bcl-2(+)/CD45 cells after one-treatment cycle were significantly associated with shorter OS (HR: 13.9; p = 0.007). Conclusions: These results demonstrate an important phenotypic CTCs heterogeneity based on the co-expression of Bcl-2, CK, Vim and M30 in SCLC patients. The changes of Bcl-2(+)/CD45(-) CTCs during treatment seem to be a dynamic biomarker associated with treatment efficacy and patients' clinical outcome.