Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.
Breast Cancer Res Treat. 2021 Jan;185(2):371-380. doi: 10.1007/s10549-020-05940-8. Epub 2020 Sep 25.
Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy.
In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group.
91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011).
Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.
紫杉醇耐药仍然是治疗乳腺癌的主要挑战。我们的临床前研究表明，乳腺癌中的 TEKT4 种系变异与紫杉醇耐药相关，并增加长春瑞滨的敏感性。本临床试验比较了紫杉醇和长春瑞滨在乳腺癌新辅助化疗中的疗效。
这是一项开放标签、单中心、Ⅱ期临床试验，入组了携带 TEKT4 种系变异的人表皮生长因子受体 2（HER2）阴性、ⅡB 期至ⅢC 期乳腺癌女性患者，随机分为紫杉醇加表柔比星（PE）或长春瑞滨加表柔比星（NE）组。主要终点是病理完全缓解（pCR）率，次要终点是客观缓解率（ORR）和安全性。对包含 484 个与乳腺癌相关基因的panel 进行靶向测序，以鉴定每组中与 pCR 相关的体细胞突变。
91 例患者被分配至 PE 组（46 例）或 NE 组（45 例）。NE 组的 pCR 率略有增加（22.2%比 8.7%，P=0.074）。NE 和 PE 的 ORR 分别为 82.2%和 76.1%。有趣的是，在激素受体（HR）阳性亚组中，NE（15.4%）的 pCR 率明显高于 PE（0%）（P=0.044）。两种方案均耐受良好，报道的 3 级和 4 级毒性反应发生率与预期相符。生物标志物分析表明，UNC13D 突变预测了 NE 组的 pCR 率（P=0.011）。
尽管主要终点未达到，但 NE 可能为 HR 阳性患者或同时携带 UNC13D 突变的患者带来临床获益。
