title: Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer.
abstract: Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188-0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.
authors: Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Ein Kerem, P.O. Box 12000, Jerusalem, 91120, Israel. amirsonn@gmail.com
authors: Amir
authors: A
authors: Sonnenblick
authors: Beatrice
authors: B
authors: Uziely
authors: Hovav
authors: H
authors: Nechushtan
authors: Luna
authors: L
authors: Kadouri
authors: Eithan
authors: E
authors: Galun
authors: Jonathan H
authors: JH
authors: Axelrod
authors: Daniela
authors: D
authors: Katz
authors: Hagit
authors: H
authors: Daum
authors: Tamar
authors: T
authors: Hamburger
authors: Bela
authors: B
authors: Maly
authors: Tanir M
authors: TM
authors: Allweis
authors: Tamar
authors: T
authors: Peretz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015999:Multivariate Analysis; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate