Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study

BackgroundEribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy.MethodsPatients with primary triple negative breast cancer ≥2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study.ResultsIn stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR.ConclusionsDespite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation.Trial registrationEU Clinical Trial Register, EudraCT number 2012-004956-12.

背景 甲磺酸艾立布林（Eribulin mesylate, E）获批用于既往接受过蒽环类与紫杉类药物治疗的转移性乳腺癌患者。本研究提出假设：甲磺酸艾立布林同样可使符合新辅助化疗指征的患者获益。
方法 入组原发肿瘤直径≥2cm的三阴性乳腺癌患者，给予多柔比星60mg/m²联合紫杉醇200mg/m²方案（AT方案）治疗4周期，随后予以甲磺酸艾立布林1.4mg/m²治疗4周期。本研究主要终点为病理完全缓解（pathological complete response, pCR）率；次要终点与探索性终点分别为临床/代谢缓解率、安全性，以及生物标志物分析。本研究采用两阶段Simon设计，第一阶段计划入组13例患者，若其中有4例达到pCR，则继续第二阶段入组，最终计划纳入43例患者。
结果 本研究第一阶段共入组13例女性患者，中位年龄43岁；其中9例（69%）肿瘤直径为2~5cm，8例（61%）存在淋巴结阳性。主要的3级不良事件为中性粒细胞减少（分别与AT方案和甲磺酸艾立布林相关的病例数为4例和2例）。AT方案序贯甲磺酸艾立布林治疗后，11例（85%）患者达到临床完全缓解+部分缓解，3例（23%）达到病理完全缓解。基线时、AT方案治疗后及甲磺酸艾立布林治疗后的最大标准摄取值（maximum standardized uptake value, SUVmax）中位值分别为13、3和1.9。AT方案治疗后及甲磺酸艾立布林治疗后分别有2例和3例患者达到完全代谢缓解（complete metabolic response, CMR）。值得注意的是，5例达到完全代谢缓解的患者中有2例（40%）在术后病理达到pCR。配对的治疗前后肿瘤标本免疫组化检测显示，β-连环蛋白、细胞周期蛋白D1、Zeb-1及c-myc的表达水平降低，而N-钙粘蛋白的表达未出现调控变化。由于未达到预设的pCR患者例数要求，本研究在第一阶段即提前终止。
结论 尽管本研究提前终止，但AT方案序贯术前甲磺酸艾立布林治疗在三阴性乳腺癌患者中展现出临床与生物学活性。此外，本研究观察到β-连环蛋白通路核心蛋白的调控，该调控似乎不涉及上皮间质转化过程，这一发现有待进一步研究验证。
试验注册 欧盟临床试验登记库（EU Clinical Trial Register），EudraCT编号：2012-004956-12。