25O - pSTAT3 in luminal breast cancer. Integrated RNA-protein pooled analysis and results from the BIG 2-98 phase III trial.

Date 04 May 2017
Event IMPAKT 2017
Session Best abstracts session – Oral abstracts
Topics Breast Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Amir Sonnenblick
Authors A. Sonnenblick1, R. Salgado2, T. Peretz1, P. Francis3, J.P.A. Crown4, E.D. Azambuja2, A. Lieveke2, M. Piccart2, J.F. Bromberg5, C. Sotiriou2
  • 1Oncology, Sharett Institute of Oncology, Hadassah - Hebrew University Medical Center, Jerusalem/IL
  • 2Oncology, Jules Bordet Institute, B-1000 - Brussels/BE
  • 3Oncology, Peter MacCallum Cancer Centre, Melbourne/AU
  • 4Oncology, Irish Clinical Oncology Research Group, B-1000 - Dublin/IE
  • 5Oncology, Memorial Sloan Kettering Cancer Center, New york/US

Abstract

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Purpose: To gain better insight into the prognostic role of the STAT3 signaling pathway in estrogen receptor positive (ER positive) breast cancer, we evaluated the pSTAT3 proteomic and gene signature status and investigated its impact on outcome in a pooled analysis and in a large adjuvant phase III trial.

Patients and Methods: By analyzing gene expression and matched proteomic data in ER-positive tumors from the TCGA repository, we developed gene signatures that reflect the level of expression of phosphorylated-STAT3 (pSTAT3), capturing their corresponding level of pathway activation. Using pooled analysis of gene-expression data from over 7,000 breast cancer (BC) patients, we then assessed their association with prognosis. We further validated the pSTAT3 prognostic effect using primary tumors tissue microarrays from the Breast International Group (BIG) 2-98, phase III, prospective randomized trial. Immunohistochemistry (IHC) of pSTAT3 were performed blinded to clinical outcome. Evaluation was performed for tumoral and stromal components separately and the association between pSTAT3 and clinical outcome was assessed using univariate and multivariate Cox modeling.

Results: Our pooled analysis showed that the pSTAT3 signature score was elevated in luminal A cancers and not in luminal B (Kruskal–Wallis test p<10e-10 for all subtypes). pSTAT3 signature was significantly associated with improved relapse free survival (RFS) (Log rank p<10e-10). This pattern remained significant when the analysis was performed in luminal ER-positive BC patients treated with endocrine therapy. Of interest, pSTAT3 signature was also able to identify patients with improved RFS irrespective of the luminal molecular subtype (Log rank: luminal A p=0.026; luminal B p=0.006). pSTAT3 staining by IHC in tumor or stroma was positive in 174 of 610 (28.5%) ER positive samples from the BIG 2-98. With a median follow-up of 10.1 years, pSTAT3 was associated with reduced disease free survival in ER-positive/HER2-negative breast cancer (Cox Univariate HR:0.66 95%CI: 0.44 to 0.98; p=0.04).

Conclusion: pSTAT3 is associated with improved outcome in patients with luminal breast cancer.

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