In breast cancer, increased immune infiltrate prior to neoadjuvant chemotherapy predicts improved pathologic complete response (pCR) and improved survival, however almost half of breast tumors have no CD8+ T cell infiltrate. Evidence has emerged that conventional breast cancer chemotherapy can increase CD8+ T cells (doxorubicin) and decrease the immunosuppressive regulatory CD4+ T cells (paclitaxel and cyclophosphamide); therefore discovering well tolerated agents that further enhance the anti-tumor immune function of these chemotherapies may further improve response in breast cancer patients. The oral agent bexarotene (a retinoic receptor agonist) showed a 20% disease response as a single agent in metastatic breast cancer and has been shown to increase CD8+ T cell tumor infiltration and decrease CD8+ T cell apoptosis in vitro. The goal of this study is to demonstrate whether this well tolerated oral agent can enhance the anti-tumor response of conventional chemotherapy through increasing intratumoral CD8+ T cells in TgMMTV-neu transgenic mice that are immunologically competent and genetically similar to human luminal B breast cancer.
Two of the most active chemotherapies in human breast cancer, doxorubicin and paclitaxel, each could inhibit tumor growth by 70-80% and increase CD8+ T cell tumor infiltrate by approximately 40% in tumor bearing TgMMTV-neu mice, a third breast cancer chemotherapy cyclophosphamide increased CD8+ tumor infiltrate by 45% (p = 0.011) but did not show a statistically significant decrease in tumor volume. When TgMMTV-neu mice with ∼100 mm3 tumors were treated with 50 mg/m2 bexarotene for four weeks they demonstrated a 44% increase in CD8+ tumor infiltrate (p = 0.05) and 60% decrease in mean tumor growth (p = 0.03) compared to control. However, the addition of bexarotene to chemotherapy was superior to chemotherapy alone, and significantly more effective than bexarotene alone. This enhanced anti-tumor function was even seen with cyclophosphamide that by itself had not inhibited tumor growth. Adding bexarotene to weekly doxorubicin decreased tumor growth by 98% (p = 0.008 compared to doxorubicin alone), adding bexarotene to weekly paclitaxel decreased tumor growth by 86% (p = 0.02 compared to paclitaxel alone), and adding bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p = 0.04 compared to cyclophosphamide alone). Further studies are now ongoing to identify the anti-tumor role of bexarotene particularly its immune modulatory role. These results suggest that the addition of bexarotene, a relatively well-tolerated oral agent, may modify the immune environment and improve tumor response to chemotherapy in breast cancer possibly improving response to neoadjuvant chemotherapy.