COX-2 drives metastatic breast cells from brain lesions into the cerebrospinal fluid and systemic circulation.

Breast cancer is among the most common malignancies that metastasize to the brain, with 15% to 20% of patients with metastatic breast cancer eventually developing brain metastases. We previously reported a method to enumerate tumor cells in the cerebrospinal fluid (CSF) of patients with breast cancer with central nervous system (CNS) metastases, a setting that lacks sufficiently informative biomarkers. Here, we show that breast cancer cells can spontaneously disseminate into the CSF from brain lesions in mice in a COX-2-dependent manner and can escape from the CNS to systemic circulation. Enumeration of tumor cells in the peripheral blood (circulating tumor cells, CTC) and CSF (cerebrospinal fluid tumor cells, CSFTC) of nine breast cancer patients with brain metastases revealed dynamic changes in tumor cell burden in both the peripheral blood and CSF compartments that correlated with clinical disease progression. Interestingly, four of the enrolled patients exhibited rapid intercompartmental transitioning of the disease reflected in the CTC and CSFTC counts that preceded corresponding evidence by clinical imaging or neurologic symptoms. Two of these patients had systemic disease recurrence involving the primary malignant site. Intercompartmental cycling of tumor cells may represent an important mechanism for disease persistence and recurrence that may involve tumor self-seeding. Our findings demonstrate the involvement of COX-2 in the genesis of CSFTCs and suggest that COX-2 inhibitors should be investigated in patients with breast cancer with brain metastases for their ability to reduce CSFTC counts and prevent systemic recurrence.