Role of aneuploid circulating tumor cells and CD31⁺ circulating tumor endothelial cells in predicting and monitoring anti-angiogenic therapy efficacy in advanced NSCLC

Prognosticating the efficacy of anti-angiogenic therapy through longitudinal monitoring and early detection of treatment resistance in cancer patients remain highly challenging. In this study, co-detection and comprehensive phenotypic and karyotypic molecular characterization of aneuploid circulating tumor cells (CTCs) and circulating tumor endothelial cells (CTECs) were conducted on non-small cell lung cancer (NSCLC) patients receiving bevacizumab plus chemotherapy. Prognostic values of the cell-based significant univariate risk factors identified by Cox regression analyses were progressively investigated. Subjects showing an increase in total post-therapeutic platelet endothelial cell adhesion molecule-1 (CD31)(-) CTCs and CD31(+) CTECs exhibited a significantly reduced median progression-free survival (mPFS) and overall survival. Further stratification analyses indicated that pretherapeutic patients bearing vimentin (Vim)(+) CTECs (mesenchymal M-type) at baseline revealed a significantly shortened mPFS compared with patients with Vim(-) CTECs. Post-therapeutic patients harboring epithelial cell adhesion molecule (EpCAM)(+) CTCs and CTECs (epithelial E-type), regardless of Vim expression or not, showed a significantly reduced mPFS. Post-therapeutic patients possessing de novo EpCAM(+)/Vim(+) (hybrid E/M-type) CTECs displayed the shortest mPFS. Patients harboring either pre- or post-therapeutic EpCAM(-)/Vim(-) null CTECs (N-type) exhibited a better response to therapy compared to patients harboring EpCAM(+) and/or Vim(+) CTECs. The presented results support the notion that baseline Vim(+) CTECs and post-therapeutic EpCAM(+) CTCs and CTECs are predictive biomarkers for longitudinal monitoring of response to anti-angiogenesis combination regimens in NSCLC patients.