Identification of Atypical Circulating Tumor Cells with Prognostic Value in Metastatic Breast Cancer Patients

BackgroundCirculating tumor cells (CTCs) have a strong potential as a quasi-non-invasive tool to set up precision medicine strategy for cancer patients. Tremendous efforts have been made to develop the second-generation of “filtration-based” technologies to detect CTCs, revealing a surprising heterogeneity among those cells. Here, we performed the largest and simultaneous analysis of all atypical circulating tumor cells (aCTCs) detected with a filtration-based technology, in a cohort of metastatic breast cancer (mBC) patients, and correlated their presence with clinicopathological and survival data.MethodsThe PERMED-01 study enrolled patients with mBC refractory to systemic therapy. We prospectively analyzed aCTCs present at the time of inclusion in the study, using the Screencell®Cyto device (n=91). Subsets cut-offs were established and evaluated for correlation with clinicopathological data, including progression-free survival (PFS) and overall survival (OS).ResultsThe median number of aCTCs found in mBC was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in mBC patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter PFS and OS in multivariate analyses. For 23 cases, the analysis was completed with advanced immunofluorescence staining and showed that CTM and g-aCTCs displayed a hybrid phenotype for epithelial and mesenchymal markers.ConclusionsThis study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels when using a Screencell®Cyto device. It reveals the g-aCTC subset as a prognostic factor and a potential stratification tool that might help to orientate late-stage mBC patients’ therapeutic care.