Abstract OT1-01-07: A phase 2 study of eribulin followed by doxorubicin and cyclophosphamide as preoperative therapy for HER2-negative inflammatory breast cancer
Authors: Overmoyer B , Goel S , Regan M , Hirshfield-Bartek J , Schlosnagel E , Yeh E , Qin L , Bellon J , Nakhlis F , Jacene H , Winer E 
Published: March 2017

Abstract
Background: HER2 negative(neg) inflammatory breast cancer(IBC) exhibits relative resistance to chemotherapy evidenced by pCR(pathologic complete response rate) rates of 12-25% with preoperative taxane/anthracycline regimens. Eribulin(Eisai®) inhibits microtubular function via sequestration of tubulin into nonfunctional aggregates, thus being effective against taxane-resistant cancer. Preclinical data shows 2 mechanisms of action: reversion of EMT(epithelial to mesenchymal transition) and normalization of tumor vascularity. Treatment of triple negative breast cancer(TNBC) cell-lines with eribulin results in downregulation of mesenchymal markers with concomitant increase in expression of classical epithelial markers(Yoshida BJC 2014). In PDX models, eribulin improved blood perfusion in central region of tumors, increased vessel density, reduced vessel diameter, and reduced hypoxia. IBC is highly angiogenic, with increased microvessel density, higher fraction of proliferating endothelial cells and greater expression of pro-angiogenic genes compared with non-IBC(McCarthy CCR 2002). This preoperative study(EAC) exploits the angiogenic properties of IBC with the treatment scheme of eribulin(E) followed by doxorubicin/cyclosphosphamide(AC) in newly diagnosed HER2neg IBC.
Methods: Pts with HER2neg Stage III (cT4d,any N,M0) IBC are eligible if they have not received prior therapy for BC, have adequate organ function, cardiac ejection fraction &gt; 50%, and willing to undergo 2 research biopsies (rbx) of the affected breast. Following baseline rbx, pts receive cycle 1, day(d)1 eribulin 1.4 mg/m2. A 2nd rbx occurs on d8, prior to dosing of E. Following 3 more cycles of E(1.4mg/m2 d1,d8,every 21d), pts receive 4 cycles of dose-dense AC(A-60 mg/m2,C-600mg/m2 every 14d). Pts with adequate disease response undergo mastectomy/axillary lymph node dissection followed by chest wall/regional lymph node radiation. Adjuvant endocrine therapy is used if hormone receptor positive. An imaging sub-study evaluates tumor perfusion via DCE-MRI pre and post 1st dose E.
Correlatives: To investigate whether E induces reversion of EMT in IBC, expression of 10 EMT-related genes are determined in each rbx, and normalization of tumor vessel phenotype are assessed by expression of 15 angiogenesis-related genes in rbx by RT-qPCR. Gene expression will be repeated on residual tumor at mastectomy. An imaging sub-study of DCE-MRI (10 pts) will assess vascular remodeling via changes in Ktrans , ve and vp determination of IBC region of interest, core and rim and changes in the iAUC computed pre and post 1st dose E.
Statistics: The primary endpoint is pCR. A Simon two-stage design is used. If the proportion of pts having pCR is &lt; 0.10 then EAC is considered minimally effective, versus alternative hypothesis that EAC is worthy of further study if proportion pCR &gt; 0.30. In the 1st stage, if &lt; 2/16 pts have pCR, the study is stopped; if &gt; 3 pts have pCR, the study proceeds. In the 2nd stage, EAC is rejected if &lt; 4 of 25 pts have a pCR(α=0.10;β=0.10). Up to 25 pts will be enrolled. Secondary endpoints are residual cancer burden, disease-free survival, time to treatment failure and overall survival. Clinical trial information: NCT02623972.
Citation Format: Overmoyer B, Goel S, Regan M, Hirshfield-Bartek J, Schlosnagel E, Yeh E, Qin L, Bellon J, Nakhlis F, Jacene H, Winer E. A phase 2 study of eribulin followed by doxorubicin and cyclophosphamide as preoperative therapy for HER2-negative inflammatory breast cancer [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 OT1-01-07.