Clinical Trials and Statistics Unit (ICR-CTSU), Division of Clinical Studies, The Institute of Cancer Research, London, SM2 5NG, UK.
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
Breast Cancer Res Treat. 2019 May;175(1):149-163. doi: 10.1007/s10549-018-05110-x. Epub 2019 Jan 24.
The prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).
Of the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini-Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (p).
Phospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (p = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (p > 0.05 for all).
This PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.
评估 MAPK/AKT/ERα 磷酸化轴（pT202/T204MAPK、pT308AKT、pS473AKT、pS118ERα 和 pS167ERα）在原发性肿瘤中的预后和预测价值，以确定这些标志物是否可以区分接受他莫昔芬辅助内分泌治疗 2-3 年后转换为依西美坦的患者与继续单独使用他莫昔芬治疗的患者的反应。
在 IES 中，4724 例患者中有 1506 例在参与 PathIES 的亚组中心（N=89）中进行管理。这些中心招募了 1282 例（85%，1282/1506）女性入组 PathIES，其中 1036 例有磷酸化标志物数据。所有磷酸化标志物均通过免疫组织化学染色进行分析。多变量 Cox 比例风险模型对疾病无进展生存（DFS）和总生存（OS）的磷酸化标志物进行了调整，以适应临床病理因素。通过交互检验确定治疗对生物标志物表达的影响。采用 Benjamini-Hochberg 调整进行多重检验，假发现率为 10%（p）。
发现磷酸化 T202/T204MAPK、pS118ERα 和 pS167ERα 均相关（p=0.0002）。当控制已建立的临床病理因素时，这些标志物与 DFS 或 OS 均无关。磷酸化标志物与 DFS 或 OS 的治疗策略之间的交互项在统计学上均无显著性差异（p>0.05）。
这项 PathIES 研究证实了以前描述的绝经后乳腺癌患者 AKT、MAPK 和 ERα 活性磷酸化位点标志物之间的关联。在磷酸化标志物和临床结局之间未发现预后相关性，也未发现这些标志物在转换治疗的患者与单独使用他莫昔芬治疗的患者之间对临床结局具有预测性。
