title: Nuclear Gli1 expression is associated with pathological complete response and event-free survival in HER2-positive breast cancer treated with trastuzumab-based neoadjuvant therapy.
abstract: 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.
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Liu
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China. 18600441365@163.com.
authors.forename: Xuening
authors.initials: X
authors.lastname: Duan
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Jingming
authors.initials: J
authors.lastname: Ye
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medical Statistics, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Sainan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Breast Disease Center, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, People's Republic of China.
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab / Q000008:administration & dosage*; D000071676:Zinc Finger Protein GLI1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000068878:Trastuzumab; D000071676:Zinc Finger Protein GLI1; C400551:GLI1 protein, human; C508053:ERBB2 protein, human
keywords: Gli1; HER2; Hedgehog; Neoadjuvant therapy; Predictive; Prognostic