Abstract
Background: Metastatic spreading is promoted by cancer cell seeding from the primary tumor into the bloodstream. In patients with metastatic breast cancer (MBC), the clinical relevance of circulating tumor cell clusters (CTC-clusters) has been extensively reported, while their study in earlier stages is limited. Several methods, besides the FDA-cleared CellSearch®, limited to the detection of epithelial-enriched clusters, can be used for the detection of CTC-clusters. We hypothesize that resorting to marker-independent approaches can improve CTC-cluster detection. Methods: Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, ScreenCell® filters. The number of CTC-clusters was compared among the technologies and analyzed in relation to patient characteristics and outcome. Results: In spiked-in samples, the 3 technologies showed similar capability of recover epithelial mammospheres, whereas, in a series of 19 clinical samples processed in parallel with the CellSearch® and CellSieve™ filters (that allow the detection of both epithelial and non-epithelial clusters), CTC-clusters were detected in 53% of samples with the CellSearch®, versus 79% and 84% with the CellSieve™, when considering only epithelial or both epithelial and non-epithelial clusters, respectively. Next, blood samples from 37 non-metastatic breast cancer (NMBC) and 23 MBC patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification of clusters based on cytomorphological criteria. At baseline, CTC-clusters were detected in 70% of NMBC cases and in 20% of MBC patients (median number= 2, range 0–20, versus 0, range 0‑15, P =0.0015). Among NMBC patients, clusters were slightly higher in women with node-positive than node‑negative status (0 versus 3, P =0.1110 ) and were more frequently observed in women with luminal‑like and triple-negative tumors than in patients with HER2-positive disease (median CTC-cluster number =4, 5, and 0 for luminal‑like, triple-negative, and HER2-positive BC, respectively, P =0.0467). Conclusions: We demonstrated that CTC-cluster detection can be improved by a marker-independent enrichment and identification, and we reported that CTC-clusters are more frequently detected in NMBC than in MBC patients, suggesting that dissemination of CTC-clusters is an early event in BC natural history.
Update Breast Cancer 2019 Part 4 – Diagnostic and Therapeutic Challenges of New, Personalised Therapies for Patients with Early Breast Cancer
