P1-15-01: Oral Fluoropyrimidine (UFT and S-1) May Augment the Efficacy of Aromatase Inhibitor Via the Down-Regulation of Estrogen Receptor in Estrogen-Responsive Breast Cancer Xenografts.
Authors: Nukatsuka M , Saito H , Nakagawa F , Abe M , Uchida J , Shibata J , Matsuo K-I , Noguchi S , Kiniwa M 
Published: June 2012

Breast cancer patients has tended to be more personalized by biomarkers, such as estrogen receptor (ER), HER-2 and other risk factors. Adjuvant endocrine therapy is recommended for all ER-positive breast cancer patients, and the addition of adjuvant chemotherapy to endocrine therapy has been shown to further improve the prognosis of ER-positive breast cancer patients. Addition of an oral fluoropyrimidine, UFT was shown to improve the outcome of patients with luminal A cancer. Based on these studies, the present preclinical study was designed to evaluate a new combination therapy comprised of the aromatase inhibitor anastrozole (ANA) and the oral fluoropyrimidines, UFT and S-1 against luminal A human breast cancer cell line MCF-7/Arom 14, which was stably transfected with the cDNA of human aromatase. MCF-7/Arom 14 cells showed a high aromatase activity (111.6±69.6 fmole/mg protrin/hr) in vivo. Testosterone failed to induce cell growth of parent MCF-7. But, MCF-7/Arom 14 cells were potentiated by both testosterone and E2 in vitro, and ANA and 5-fluorouracil (5-FU) inhibited cell growth at concentrations of 0.005 to 10 and 0.2 to 5 μM, respectively. The combination of 5-FU and ANA additively inhibited cell growth. MCF-7/Arom 14 was implantable in vivo, but it failed to grow in he absence of E2 or testosterone releasing pellet (Tes-P). The growth of MCF-7/Arom 14 was significantly inhibited by ANA and S-1 or UFT alone vs Control (Tes-P alone) in vivo. The combination of ANA with S-1 or UFT administered using a 21-day consecutive, metronomic-like regimen. On day 22, relative tumor volume (RTV) treated by ANA and UFT or ANA and S-1 was significantly lower than either mono-therapy by Welch's t-test. Based on RTV change the period required for the RTV to reach 3 was estimated, and its differences between control was designated as growth delay period (GDP). GDP of combination-therapy was 2 to 4 times longer than either mono-therapy.

To investigate the mechanisms by which fluoropyrimidines enhance the antitumor activity of ANA, the protein and mRNA expression levels of ER-a in tumor tissue after treatment with S-1, ANA, and the typical chemotherapeutic agents doxorubicin (ADM) or paclitaxel (TXL) were analyzed by immuno-histostain and RT-PCR, respectively. The protein and mRNA expression of ER-a were markedly decreased by S-1 or S-1+ANA, but not for ADM or TXL. The reduced ER-a level might increase antitumor activity of ANA in addition to the decreased estrogen production. As activity of dihydropyrimidine dehydrogenase (DPD) in breast cancer is higher, UFT or S-1 which is resistant against DPD would be suitable compared other 5-FU derivatives. Therefore, the combination of ANA and S-1 might yield a greater benefit than other chemotherapeutic agents in postmenopausal women with Luminal A breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-15-01.