Abstract P4-01-01: Combination Treatment with Fulvestrant and Various Cytotoxic Agents Has a Synergistic Effect in ER-Positive Breast Cancer Cell Lines In Vitro and In Vivo.
Authors: Ikeda H , Taira N , Nogami T , Shien T , Doihara H , Miyoshi S. 
Published: April 2011

Abstract
Background: Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers since they can be treated with anti-estrogen therapies. However, ER-positive breast cancers have low sensitivity to chemotherapy and the survival benefitof chemotherapy is limited. Microtubule associated protein-tau (MAPT) plays an important role in taxane sensitivity. In a previous study we showed that ER signaling influenced MAPT expression and that fulvestrant, an estrogen receptor antagonist, downregulated MAPT and reversed resistance to taxane in MAPT-and ER-positive breast cancer cells (SABCS 2009, Abstract 2118). In clinical treatment for breast cancer, the advantages and disadvantages of combination treatment with endocrine therapy and chemotherapy have long been discussed. Several studies have shown that endocrine therapy has an antagonistic effect on chemotherapy, which suggests that concurrent use of a hormone drug and a chemotherapeutic agent should be avoided clinically. However, most of these studies used tamoxifen (TAM) and anthracycline regimens. The effects of combination treatment using new hormone therapies, such as aromatase inhibitors or fulvestrant, and chemotherapeutic agents have not been examined thoroughly. In this study we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents in vitro and in vivo.
Methods: In vitro, the effects of different combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-FU) and three hormone drugs (TAM, 4-hydroxytamoxifen (4OH-TAM), and fulvestrant) were examined in ER-positive breast cancer cell lines (MCF-7, ZR75-1) using CalcuSyn software. The cells were also exposed to hormone drugs and changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1 (MRP1), and MAPT were examined. In vivo, xenografts were created using MCF-7 cells transplanted into BALB/c nu/nu mice. Tumor sizes were evaluated after the mice were treated with tamoxifen alone, fulvestrant alone, docetaxel alone, and combinations of these drugs.
Results: Combination treatment with fulvestrant and all chemotherapeutic agents in vitro showed a synergistic effect regardless of the fulvestrant dose. In contrast, TAM showed an antagonistic effect with all the chemotherapeutic agents, with the strongest antagonism occurring at a low dose of TAM. 4OH-TAM showed an antagonistic effect with doxorubicin and 5-FU, and a synergistic effect with taxanes and vinorelbine. In the analysis of chemoresistant factors, Bcl2 and MAPT were downregulated by fulvestrant, but upregulated by TAM and 4OH-TAM. In vivo, the combination of fulvestrant and docetaxel showed the strongest inhibitory effect on tumor growth.
Conclusion: TAM and 4OH-TAM had different effects in combination with chemotherapeutic agents. Fulvestrant downregulated ER and chemoresistant factors such as Bcl2 and MAPT, which are regulated via ER. Fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents in vitro and in vivo. These results suggest that combination therapy with fulvestrant and chemotherapeutic agents may be effective for ER-positive breast cancers.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-01.