Role of circulating tumor cell clusters in breast cancer.

Breast cancer (BC) in the metastatic state has disseminated to lungs, bones and brain resulting in a poor prognosis and high mortality. Cancer cells separate from the primary lesion and intravasate as circulating tumor cells (CTCs) to generate distal metastases following extravasation and colonization of target tissues. CTCs are infrequently detectable at low numbers in nonmetastatic BC but occur at higher cell counts in metastatic BC, where they are an independent predictor of shorter disease-free survival and overall survival. CTCs exist as single cells or as homotypic or heterotypic clusters with reportedly higher metastatic potential as demonstrated by murine patient-derived xenograft (PDX)/cell line-derived xenograft (CDX) models and correlation with a poorer survival in patients. Homotypic clusters are made of cancer cells only, in contrast to heterotypic clusters that incorporate stromal or immune cells along with cancer cells. However, experimental animal models with highly active CTCs and rapid formation of metastases are a poor representation of clinical BC with one metastasis-inducing CTC among 60 million cancer cells and a time to metastasis of several years. CTC clusters are rapidly cleared from the circulation but within the time frame of the PDX/CDX models, these cell aggregates will not be able to grow, extravasate and generate additional metastases, nor will their disaggregation prevent metastasis. The generation of CTC clusters is most likely due to larger originating tumors that contain accordingly large and leaky tumor vessels that allow the release of several associated tumor cells instead of single CTCs. Tumor size and microvascular density are well-known prognostic parameters in BC.