Abstract 2277: Loss of nuclear localized and tyrosine phosphorylated Stat5: A predictor of poor clinical outcome and increased risk of antiestrogen therapy failure in breast cancer
Authors: Peck Amy R. , Witkiewicz Agnieszka K. , Liu Chengbao , Stringer Ginger A. , Klimowicz Alexander C. , Pequignot Edward , Freydin Boris , Tran Thai H. , Yang Ning , Rosenberg Anne L. , Hooke Jeffrey A. , Kovatich Albert J. , Nevalainen Marja T. , Shriver Craig D. , Hyslop Terry , Sauter Guido , Rimm David L. , Magliocco Anthony M. , Rui Hallgeir 
Published: June 2012

Abstract
Stat5 transcription factor is activated by prolactin in the mammary gland and is necessary for mammary gland development, differentiation and lactation. Previous work based on tissue microarrays has suggested that nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) is a marker of prognosis in node-negative breast cancer. The purpose of this study was to validate the prognostic value of Nuc-pYStat5 in whole tissue sections and expand the analyses to a quantitative immunofluoresence-based assay. In addition, we explored Nuc-pYStat5 as a predictor of response to antiestrogen therapy. Levels of Nuc-pYStat5 were analyzed in five archival materials of breast cancer by traditional diaminobenzidine-chromogen immunohistochemistry (DAB-IHC) and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. In two prognostic cohorts of node-negative breast cancer patients not receiving systemic adjuvant therapy, Nuc-pYStat5 was an independent marker of cancer-specific survival (CSS) when adjusted for common pathology parameters in multivariate analyses. Corresponding results were obtained both by standard DAB-IHC with pathologist scoring of whole tissue sections (Material I; n=233) and by quantitative immunofluorescence of a tissue microarray (Material II; n=291) and using two distinct monoclonal antibodies. A breast tissue progression array (Material III; n=130) revealed loss of Nuc-pYStat5 in invasive ductal carcinoma (IDC) compared to normal breast epithelia or ductal carcinoma in situ (DCIS), with greatest loss of Nuc-pYStat5 in lymph node metastases. Importantly, loss of Nuc-pYStat5, detected by DAB-IHC (Material IV; n=221), was associated with increased risk of antiestrogen therapy failure as measured by CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in patients treated with antiestrogen monotherapy (Material V; n=97) identified a subset of patients with low Nuc-pYStat5 at a 7.4-fold elevated risk of dying from breast cancer (CSS univariate Cox regression HR=7.36 (2.94-18.42), p&lt;0.001, n=53). Importantly, low levels of Nuc-pYStat5 also predicted therapy failure in multivariate analyses (multivariate Cox regression, CSS HR=21.55 (5.61-82.77), p&lt;0.001; TTR HR=7.30 (2.34-22.78), p=0.001; n=53) independent of ER/PR status and lymph node status. We conclude that Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. Furthermore, this study suggests that Nuc-pYStat5 may become useful as a predictive marker of response to systemic adjuvant hormone therapy if confirmed by prospective studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2277. doi:10.1158/1538-7445.AM2011-2277