Assessment of multidrug resistance in breast cancer with [11C] tariquidar PET

Multidrug resistance (MDR) is a major challenge for successful systemic treatment of breast cancer. Among others, MDR by overexpression of P-glycoprotein (Pgp) has been demonstrated to result in poor response to standard of care chemotherapeutics for breast cancer (i.e. taxans, anthracyclines). Pgp expression in tumor specimens of breast cancer patients has been reported in up to 41% of all cases and is a negative predictive factor for response to neoadjuvant chemotherapy. Moreover, Pgp expression in breast cancer was found to be induced in response to chemotherapy. Following the idea of personalized medicine the identification of subgroups likely to respond to chemotherapy or suitable for co-treatment with third-generation Pgp inhibitors such as tariquidar is a clinical relevant objective. Positron emission tomography (PET) imaging with [ 11C]tariquidar provides a non-invasive method to quantify Pgp expression levels. In a preclinical study we recently demonstrated 50-60% higher binding of [ 11C]tariquidar in Pgp overexpressing doxorubicin-resistant breast cancer xenografts compared to doxorubicin- sensitive ones. In the proposed project we aim to translate our preclinical set-up to the clinic and evaluate [ 11C]tariquidar as a PET tracer to visualize Pgp expression levels in breast cancer patients. The study will be performed as a prospective cohort diagnostic test accuracy study in 30 breast cancer patients scheduled for neoadjuvant chemotherapy, 15 of which with Pgp-positive and 15 with Pgp-negative tumors as confirmed by immunohistochemistry (IHC) analysis of tumor specimens obtained for diagnosis of breast cancer. Patients will be evaluated by a [ 11C]tariquidar PET scan as part of their staging examination before chemotherapy. After neoadjuvant chemotherapy an additional [ 11C]tariquidar PET scan will be performed as part of the re-staging assessment (optional). Patients will then undergo standard of care breast tumor surgery. Tumor specimens from breast tumor surgery will be assessed for Pgp expression by IHC. We aim to answer the following questions: 1. Can [ 11C]tariquidar PET discriminate patients with Pgp-positive breast tumors from Pgp-negative tumors? 2. Can induction of Pgp expression by neoadjuvant chemotherapy be quantified by [ 11C]tariquidar PET? 3. Is positive [ 11C]tariquidar PET a negative predictive marker for response to neoadjuvant chemotherapy as evaluated by RECIST criteria?

The blood-brain barrier (BBB) is the interface between blood and the brain. It essentially consists of brain capillary endothelial cells linked by tight junctions. At the BBB high levels of efflux transporters, such a P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are expressed, which can transport a wide variety of different drugs and thereby restrict their brain distribution. The most common form of primary brain tumors are neuroepithelial tumors called gliomas because they arise from glial cells. The pharmacological treatment of gliomas is often complicated by the impermeability of the BBB to clinically available anticancer drugs. There is evidence that the BBB may become disrupted in central necrotic parts of high-grade gliomas, leading to higher anticancer drug concentrations as compared with tumor-free brain tissue. It is however less known to which extent a BBB disruption exists in low-grade glioma. In the present study we used the non-invasive imaging technique positron emission tomography (PET) to study regional brain distribution and BBB integrity of a small, drug-like molecule ([11C]tariquidar) in patients with neuroepithelial tumors of the central nervous system. Previous work has shown that [11C]tariquidar is effluxed by ABCB1 and ABCG2 at the BBB and can therefore be considered representative of many anticancer agents for potential use in glioma treatment (e.g. tyrosine kinase inhibitors). Seven patients (WHO Grade I-III) were included into the study and underwent [11C]tariquidar PET scans of the brain. We examined the distribution of [11C]tariquidar to central parts of the tumor, to the rim of the tumor and to tumor-free brain tissue. Our results indicated very low distribution of [11C]tariquidar to the brain, most likely due to efflux transport by ABCB1 and ABCG2. There were no major differences in [11C]tariquidar distribution to tumor and tumor-free brain tissue, indicating integrity and functionality of the BBB in tumor tissue and most likely inability of certain anticancer drugs to reach the tumor tissue in sufficiently high and therapeutically effective concentrations.