P11.22.A ABC EFFLUX TRANSPORTERS ARE EXPRESSED AT THE BLOOD-BRAIN TUMOR BARRIER IN HUMAN BRAIN METASTASES

Abstract BACKGROUND Brain metastases (BM) are a common complication of many solid cancers, and their incidence is expected to rise as systemic treatments continue to improve and prolong patient survival. The efficacy of systemic therapies against BM is often hindered by the blood-brain barrier (BBB). The BBB restricts the brain entry of many drugs, in part due to active efflux by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). The expression and functionality of these drug-transporting proteins at the BBB can vary. Previous work in mouse models has demonstrated that ABC transporters can restrict chemotherapy efficacy against glioblastoma (GBM) and melanoma BM, even when the BBB is compromised. However, while their expression has been clearly established in GBM patients, their presence in the various types of human BM is less well documented. We therefore set out to comprehensively assess the expression of ABCB1 and ABCG2 in human tissue of the most common BM. MATERIAL AND METHODS A retrospective pathology study has been conducted through PALGA, the nationwide network and registry of histopathology and cytopathology in the Netherlands. Data provided by PALGA were year of birth, age at diagnosis, localization of the lesion, and diagnosis, as made by the local pathologist. Tissue of the nine most common origins of brain metastases was requested: non-small cell lung carcinoma (NSCLC), small-cell lung carcinoma (SCLC), Her2 positive-, Her2 negative- and triple-negative breast cancer, melanoma, renal clear cell carcinoma, colon carcinoma, and ovarian carcinoma. Per origin, 10 pairs of the primary tumor and matched BM of the same patient were requested for comparison. Whenever possible, tissue was selected to be treatment-naïve to avoid potential confounding effects of systemic therapy on ABC transporter expression. Using immunohistochemistry, tissues were stained for ABCB1, ABCG2, IgG - as a proxy for barrier leakage - and the endothelial cell marker CD31. RESULTS In general, we find expression of ABCB1 and ABCG2 in the vasculature associated with brain metastases of all investigated primary origins. Expression levels did vary within and across different lesions. Interestingly, in some cases, we observed expression in the tumor-associated vasculature of primary tumors but not in the adjacent tumor-free tissue, suggesting a local tumor-induced expression of drug efflux transporters. CONCLUSION The brain metastasis associated vasculature expresses ABCB1 and ABCG2, which can impede the delivery of systemic therapies to brain metastases. Supported by Dutch Cancer Society (KWF) project grant 14736.