Nuclear Gli1 expression is associated with pathological complete response and event-free survival in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant therapy

摘要

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.