Abstract P3-08-08: SOX11 is a potential prognostic marker of high-risk breast ductal carcinoma in situ
Authors: Ladha FA , Kai K , Lu W , Yang F , Tang X , Wistuba II , Sen S , Thompson A 
Published: May 2019

Ductal carcinoma in situ (DCIS) comprises 20-25% of screen-detected breast cancers and, like invasive ductal carcinoma (IDC), is heterogenous in terms of the underlying biology, presentation, and outcome. While there are limited potential biomarkers of outcome for DCIS, estrogen receptor (ER)- positive, progesterone receptor (PR)- positive, and HER2- negative DCIS appears to have a better prognosis compared to ER- negative, PR- negative, and HER2- positive DCIS. The aim of this study was to identify additional clinically relevant markers to stratify DCIS according to risk of relapse or progression to invasive disease. In order to determine the driver genes involved in DCIS evolution, we utilized transcriptional data sets (GSE788, GSE16873), containing data from both normal mammary glands (NMG) and DCIS. Upon performing class comparison (NMG vs DCIS), we identified 297 over-expressed genes and 187 under-expressed genes. The over-expressed genes represented mitotic and proliferative features annotated as mitotic spindle and condensed chromosomes, while the under-expressed genes were associated with loss of epithelial features annotated as epithelial cell differentiation and development. The 484 differentially expressed genes were further correlated with recurrence events using Kessler's breast cancer data set to identify genes contributing to the aggressive features across IDC and subsequently associated with DCIS. Genes correlating with recurrence events were selected. Of the 484 genes, 99 genes were found to be significantly associated with recurrence events of IDC (with P&lt;0.003). Among these 99 genes, component genes of the Oncotype DCIS score and genes reported as relevant to DCIS biology were included for Nanostring transcriptomic analysis. The final number of genes-of-interest were 58, including 5 housekeeping genes. 40 DCIS lesions and 8 NMG tissue were macro- dissected from formalin- fix paraffin- embedded blocks (FFPE) and extracted transcripts were subjected for Nanostring analysis. Gene expression data was clustered in an unsupervised manner using R software. Two sample clusters were identified: an ER/PR- negative cluster and an ER/PR- positive cluster. Over-expression of transcription factor SOX11, along with HER2, was exclusively seen in the ER/PR- negative cluster. This cluster was further categorized into HER2-low/SOX11+ and HER2-high/SOX11+ groups. These RNA expression findings are undergoing confirmation by immunohistochemistry (IHC) of the FFPE tumor sections. An independent series of 15 DCIS cases that have recurred as DCIS or progressed to IDC were analyzed by IHC, revealing SOX11 expression only present in cases displaying a high proportion of HER2+ expression. SOX11 is exclusively expressed in ER/PR-negative DCIS and is a candidate clinical marker for recurrence of DCIS or progression to IDC.

Citation Format: Ladha FA, Kai K, Lu W, Yang F, Tang X, Wistuba II, Sen S, Thompson A. SOX11 is a potential prognostic marker of high-risk breast ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-08.