XIAP is the most potent inhibitor of both the extrinsic and intrinsic cell death pathways, which is linked to chemotherapy resistance and tumor aggressiveness. We analyzed the correlations between XIAP expression in invasive breast cancers and clinicopathological parameters including metastasis-free survival (MFS) and pathological complete response (pCR) to chemotherapy.
Breast cancer databases comprising gene expression profiles with clinicopathological annotations from 8,636 non-redundant non-metastatic, non-inflammatory, primary, invasive patients were analyzed for XIAPexpression (binary variable, ”high” vs.“low” by using median as cut-off). XIAP immunohistochemistry was conducted in a cohort of post-chemotherapy mastectomy samples.
High XIAP mRNA expression was associated with pathological ductal type, pT1 tumor size, ER-positive, PR-positive, HR+/HER2-, luminal A and B PAM50 subtypes. Analysis of MFS (3,454 non-stage 4) revealed shorter MFS (p = 8.1E-03, log-rank test) associated with “XIAP-high” group. The hazard ratio for metastatic relapse was 1.20 (95%CI 1.05-1.38, p = 8.17E-03, Wald test) in “XIAP-high” vs.“XIAP-low” group.In multivariate analysis, two variables (GGI and pT) remained significant, whereas the TN subtype and XIAPexpression tended to be (p = 0.059). The prognostic value of XIAPwas significant in the multivariate analysis including two major signatures (70-gene signature, Recurrence Score), suggesting independent prognostic value. The same analysis, but in each molecular subtype separately, showed significant difference in the TN subtype (p = 1.0E-03).Univariate analysis of pCR to anthracycline-based neoadjuvant chemotherapy (1,203 patients) identified 20% pCR in the “XIAP-high” group vs.26% in the “XIAP-low” group (p = 0.015, logit function). Immunohistochemistry revealed high XIAP cytoplasmic staining only in invasive tumors and identified correlates with variables like grade, T, N, M and subtype status.
XIAP-high” tumors are more prone to metastatic relapse and resistance to chemotherapy, suggesting the therapeutic benefit of targeting XIAP in the neoadjuvant setting.
Department of Defense W81XWH-17-1-0297 (to G.R. Devi) and Duke School of Medicine Bridge Fund (to G.R.Devi).
All authors have declared no conflicts of interest.