Heterogeneity of circulating tumor cells (CTCs) in patients with recurrent small cell lung cancer (SCLC) treated with pazopanib

Abstract

Objectives: To investigate the effect of pazopanib on different CTCs subpopulations in patients with recurrent SCLC and evaluate their clinical relevance.

Methods: Peripheral blood was obtained before the administration of pazopanib (n=56 patients), after the first cycle (n=35 patients) and at disease progression (n=45 patients). CTCs were detected by CellSearch and double immunofluorescent staining using antibodies against the cytokeratins (CK), TTF-1, CD56 and VEGFR2.

Results: Before treatment, CTCs could be detected in 50% of patients by CellSearch; phenotypic characterization of CTCs demonstrated that 50%, 46.6% and 27.6% of patients had CD45^-/TTF1⁺, CD45^-/CD56⁺ and TTF-1⁺/CD56⁺ CTCs, respectively. Additionally, 59% of CTCs were TTF-1⁺/VEGFR2⁺ and 53% CK⁺/VEGFR2⁺. One pazopanib cycle resulted to a significant decrease of the number of CTCs (CellSearch: p=0.043) and CK⁺/VEGFR2⁺ cells (p=0.027). At the time of PD, both the total number of CTCs (p=0.027) and the number of the different subpopulations were significantly increased compared to post-1st cycle values; this increased CTCs number was associated with a significant increase of TTF-1⁺/VEGFR2⁺ (p=0.028) and CK⁺/VEGFR2⁺ CTCs (p=0.018). In multivariate analysis, only the number of CTCs as assessed by CellSearch after one treatment cycle was significantly associated with OS (HR: 0.21; p=0.005).

Conclusions: Pazopanib has a significant effect on different subpopulations of CTCs in patients with relapsed SCLC; the detection of VEGFR2⁺ CTCs during treatment could be a surrogate marker associated with resistance to pazopanib.

Keywords: CD56; CTCs; CellSearch; Immunofluorescence; Pazopanib; SCLC; TTF-1; VEGFR2.