Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Ein Kerem, P.O. Box 12000, Jerusalem, 91120, Israel.
Breast Cancer Res Treat. 2013 Apr;138(2):407-13. doi: 10.1007/s10549-013-2453-x. Epub 2013 Feb 28.
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.
信号转导子和转录激活子 3（STAT3）是众多致癌信号通路的汇聚点。在乳腺癌细胞系和异种移植模型中，激活的 STAT3 参与乳腺癌的发生，而人类研究表明，磷酸化（酪氨酸 705）-STAT3 是乳腺癌预后良好的标志物。为了解决这个矛盾，我们假设在临床上，磷酸化 STAT3 对辅助化疗的获益具有预测作用；因此，本研究的目的是确定磷酸化 STAT3 状态作为乳腺癌患者辅助化疗获益预测因子的有用性。对乳腺癌标本的组织微阵列进行磷酸化 STAT3 的免疫组织化学分析。磷酸化 STAT3 的表达模式与接受或未接受辅助化疗的患者的病理参数和总生存进行回顾性相关。在可解释磷酸化 STAT3 的 375 个组织标本中，有 134 个（36%）显示磷酸化 STAT3 核表达阳性。在接受辅助治疗的 234 名患者中，显示磷酸化 STAT3 核表达阳性的肿瘤患者的十年总生存率高于显示磷酸化 STAT3 核表达阴性的肿瘤患者（P=0.001）。在未接受辅助化疗的患者中，磷酸化 STAT3 核状态与总生存的增加无关（P=0.54）。在多变量分析中，无论接受何种化疗方案，磷酸化 STAT3 阳性仅与接受辅助化疗的患者的总体生存改善相关（死亡风险比，0.35[95%CI 0.188-0.667]；P=0.001）。这些发现支持磷酸化 STAT3 作为接受辅助化疗的乳腺癌患者良好预后标志物的作用。磷酸化 STAT3 是否具有辅助化疗获益的预测作用，需要在前瞻性、随机、对照研究中进行验证。
