Liu Shiwei, Duan Xuening, Xu Ling, Ye Jingming, Cheng Yuanjia, Liu Qian, Zhang Hong, Zhang Shuang, Zhu Sainan, Li Ting, Liu Yinhua
Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
Department of Pathology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
Tumour Biol. 2016 Apr;37(4):4873-81. doi: 10.1007/s13277-015-4325-y. Epub 2015 Nov 2.
Aberrant activation of the hedgehog (Hh) signaling pathway has shown predictive significance for treatment response and prognostic effect for survival in human tumors. However, the associations of the Hh signaling pathway with response to neoadjuvant therapy (NAT) and survival after NAT in breast cancer are unknown. Therefore, we investigated the correlation of pretherapeutic nuclear expression of glioma-associated oncogene homolog 1 (Gli1), a key transcriptional factor of the Hh signaling pathway, with pathological complete response (pCR) and event-free survival (EFS) in HER2-positive breast cancer treated with trastuzumab-based NAT. High nuclear Gli1 expression (OR 0.19; 95 % CI 0.07-0.54; P = 0.002) and positive hormone receptor (HR) status (OR 0.36; 95 % CI 0.14-0.90; P = 0.028) were independent and negative predictors of pCR in multivariate analysis. High nuclear Gli1 expression was significantly associated with lower pCR rates in both HR-positive and HR-negative tumors (P = 0.014 and 0.024, respectively). For survival analyses, multivariate analysis indicated that high nuclear Gli1 expression was the only independent predictor of poorer EFS in both the entire population (hazard ratio 2.97; 95 % CI 1.18-7.44; P = 0.020) and patients with non-pCR (hazard ratio 3.98; 95 % CI 1.35-11.68; P = 0.012). Our study is the first to demonstrate the associations of high nuclear Gli1 expression with resistance to trastuzumab-based NAT and subsequent worse prognosis in HER2-positive disease. These findings suggest that the nuclear Gli1 protein may be a novel target of NAT for HER2-positive breast cancer.
刺猬信号通路（Hh）的异常激活已显示出对人类肿瘤治疗反应的预测意义以及对生存的预后影响。然而，Hh信号通路与乳腺癌新辅助治疗（NAT）反应及NAT后生存的关联尚不清楚。因此，我们研究了Hh信号通路关键转录因子胶质瘤相关致癌基因同源物1（Gli1）的治疗前核表达与接受曲妥珠单抗为基础的NAT的HER2阳性乳腺癌患者的病理完全缓解（pCR）和无事件生存期（EFS）之间的相关性。在多变量分析中，高核Gli1表达（比值比0.19；95%可信区间0.07 - 0.54；P = 0.002）和激素受体（HR）阳性状态（比值比0.36；95%可信区间0.14 - 0.90；P = 0.028）是pCR的独立负向预测因素。高核Gli1表达在HR阳性和HR阴性肿瘤中均与较低的pCR率显著相关（分别为P = 0.014和0.024）。对于生存分析，多变量分析表明，高核Gli1表达是整个研究人群（风险比2.97；95%可信区间1.18 - 7.44；P = 0.020）和非pCR患者（风险比3.98；95%可信区间1.35 - 11.68；P = 0.012）中EFS较差的唯一独立预测因素。我们的研究首次证明高核Gli1表达与HER2阳性疾病中基于曲妥珠单抗的NAT耐药及随后更差的预后相关。这些发现提示核Gli1蛋白可能是HER2阳性乳腺癌NAT的一个新靶点。
