Abstract P5-15-10: Eribulin mesylate (eribulin) showed inhibitory effects on epithelial-mesenchymal transition (EMT) in tumors of metastatic breast cancer patients. -First preliminary report of a prospective study-
Authors: Utsumi T , Hayashi T , Kobayashi N , Hikichi M , Ushimado K , Ri Y , Nakano S , Fujii K , Ando T 
Published: March 2017

Background: EMT is thought to contribute to metastasis in patients with breast cancer, leading to their poor prognosis. Pivotal phase III trials have demonstrated that eribulin improved overall survival in patients with triple negative metastatic breast cancer (MBC). Preclinical studies have shown that eribulin suppressed EMT and this phenomenon could be one of reason for an improved prognosis of MBC patients treated with eribulin. However, there is no direct clinical data on the effect of eribulin treatment on EMT in tumors of MBC patients. We designed a prospective study to clarify if eribulin treatment suppresses EMT in tumors of MBC patients.

Patients and methods: Patients with recurrent or MBC were treated with eribulin (1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle). Dose reductions were allowed according to eribulin's prescribing information. Treatment continued until disease progress, unacceptable toxic effects, or discontinuation requests from patients or physicians. Breast cancer tissue samples were obtained from all patients before and on day 15±4 of 1st cycle of eribulin treatment. The quantitative analysis of mRNA levels of EMT markers (E-cadherin, cytokelatin18, cytokelatin19, N-cadherin, vimentin, ZEB1, Slug, Snail, and Twist) were carried out by qPCR. Primary outcome measure was to assess the change from baseline to day 15±4 in mRNA levels of EMT related markers in tumor tissue. This study was approved by the Ethic Committee of Fujita Health University.

Results: Eleven patients were enrolled. Median age of the patients was 63 years old (44-72). Of the 11 tumors, 6 were luminal B and 5 were triple negative (TN). Median number of prior chemotherapy regimen for recurrent or metastatic disease was 0 (0-3). Four patients were treated with dose reduced eribulin (1.1 mg/m2) and administration of eribulin on day 8 during 1st cycle of the treatment were skipped in 2 patients. To identify meaningful EMT markers, differences in expression levels of each EMT marker were investigated between TN and luminal B tumors. At baseline mRNA levels of N-cadherin and vimentin were higher in TN tumors than in luminal B tumors, 8.12±10.78 vs 1.02±0.68, 5.13±4.50 vs 0.88±0.47, respectively. After the treatment, a decrease of expression of N-cadherin and vimentin was more frequent in TN tumors (100% and 80%, respectively) than in luminal B tumors (33.3% and 16.7%, respectively). Frequency of a decrease of expression of ZEB1, Slug, Snail, and Twist in TN tumors and luminal B tumors were 80% (TN) vs 83.3% (luminal B), 80% vs 16.7%, 40% vs 66.7%, and 100% vs 50%, respectively.

Conclusions: This is the first prospective study to investigate the effect of eribulin treatment on expression of EMT markers in tumors of MBC patients. We demonstrated that eribulin treatment suppressed EMT in tumors. Our results suggested that eribulin showed antitumor effect by improving the tumor microenvironment. In our study, eribulin seems to have different effects on EMT pathway in individual cases. Our findings may provide a light to a scientific basis for solving underlying mechanisms for improvement of overall survival of patients with MBC treated with eribulin.

Citation Format: Utsumi T, Hayashi T, Kobayashi N, Hikichi M, Ushimado K, Ri Y, Nakano S, Fujii K, Ando T. Eribulin mesylate (eribulin) showed inhibitory effects on epithelial-mesenchymal transition (EMT) in tumors of metastatic breast cancer patients. -First preliminary report of a prospective study- [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-10.