Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and predominately affects young and minority women. TNBC is characterized by a high recurrence rate, with about 34% of TNBC patients relapsing around 2.6 years. This type of breast cancer lacks targeted therapy options and is limited to chemotherapy treatment options. The purpose of our study was to determine whether gut microbiota populations correlate with chemotherapeutic responsiveness and may be a predictive biomarker of outcome. Moreover, we want to determine the impact of targeting the microbiome on chemotherapy efficacy. In this study, 8-week old female BALB/c mice were injected with TNBC 4T1-luciferase cells into their L4/5 mammary fat pad. Once tumors developed, mice were either untreated (control group), treated with 1 x weekly 2.5 mg/kg IV doxorubicin (DOX), or treated with doxorubicin + antibiotics (mixture of streptomycin, ampicillin, and colistin in the drinking water to ablate host bacterial populations). Tumors were collected at the end of the study. Fecal samples were collected at time point 0 weeks (T0; before therapy when tumors were approximately 100 mm3) and time point 4 weeks (T4; after treatment). We subdivided the doxorubicin treated group into DOX-responders (tumors stopped growing or shrank) or DOX-nonresponders (tumors continued to grow on treatment). Tumors from the DOX-responders and DOX + antibiotics groups were significantly smaller and mice from these groups displayed reduced lung weight, suggesting decreased lung metastatic burden. 16S-bacterial sequencing analysis was performed on breast tumor tissue and feces. We demonstrate that at T0, elevated fecal Ruminococcus correlates with DOX-nonresponsiveness. Furthermore, at T4, we show increased fecal abundance of Oscillospira and Bacteroidales are associated with better therapeutic outcome. Protein analysis of primary 4T1 breast tumor tissue indicate a significant elevation of apoptosis (cleaved caspase-3 protein levels) in DOX-responders and DOX + antibiotic treated mice. We also stained breast tumor tissue and lung tissue for bacteria to confirm presence of microbiota by immunohistochemistry. Taken together our data demonstrates that chemotherapy efficacy is modulated by the microbiome. Moreover, fecal microbiota populations could be used as a predictive biomarker of chemotherapeutic responsiveness and suggests that modulation of the gut microbiome through dietary or probiotic interventions may affect therapeutic outcomes.
Citation Format: Alaa Bawaneh, Adam S. Wilson, Kenysha YJ Clear, Akiko Chiba, Katherine L. Cook. Gut microbiota population may be used to predict chemotherapeutic responsiveness in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 650.