Circulating tumor cells, tumor- and endothelium- derived extracellular vesicles, but not circulating endothelial cells associate with poor prognosis in colorectal cancer

Elevated tumor-derived EV (tdEV) and Circulating Tumor Cell (CTC) load in patients with metastatic cancer is associated with poor clinical outcome. In this study, we investigated whether endothelium-derived extracellular vesicles (edEVs) can be detected in the blood of metastatic colorectal cancer (mCRC) patients and whether there is an association with prognosis.

The open-source ACCEPT software was used to enumerate edEVs, tdEVs and other objects from digitally stored CellSearch^® images obtained after Circulating Endothelial Cell (CEC) and CTC enrichment from blood of 395 mCRC patients, before the initiation of a new therapy. Patients had participated in the prospective phase III CAIRO2 study. ACCEPT classified objects, CTC and CEC counts and patient information were used in univariable and multivariable analysis to determine their relation with Progression-Free Survival (PFS) and Overall Survival (OS).

edEVs are present in blood of mCRC patients at 5-10 fold higher frequencies than CECs. A significantly shorter PFS and OS was observed for patients with ≥ 3 CTCs/ 7.5 mL, ≥ 40 tdEVs/ 7.5 mL and ≥ 287 edEVs/ 4.0 mL. The Hazard Ratio HR (95% CI) of PFS for increased CTCs, tdEVs and edEVs was 1.4 (1.1-1.9), 2.0 (1.5-2.6) and 1.7 (1.2-2.5), respectively. Similarly, the HR of OS for increased CTCs, tdEVs and edEVs was 2.2 (1.7-3.0), 2.7 (2.0-3.5) and 2.1 (1.5-2.8), respectively. There was no cut-off value for CECs leading to a dichotomization of patients with a significant HR. Both tdEVs and edEVs remained significant predictors of OS in multivariable analysis.

edEVs and tdEVs are independent prognostic factors for OS in mCRC patients.