School of Medicine, University of Glasgow, Glasgow, UK.
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
J Natl Cancer Inst. 2018 Jun 1;110(6):616-627. doi: 10.1093/jnci/djx255.
Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.
A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.
In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy.
The IKKα, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.
芳香化酶抑制剂可改善绝经后激素受体阳性乳腺癌患者的无病生存期，优于他莫昔芬。Tamoxifen 和 Exemestane Adjuvant Multinational（TEAM）试验比较了依西美坦单药治疗与他莫昔芬序贯治疗后的依西美坦治疗。该试验未能显示治疗组之间存在统计学上的显著差异。建立了一个强大的转化研究计划来研究预测生物标志物。
使用 TEAM 试验（n=9766）的患者组织（n=4631）的子集进行了回顾性组织微阵列构建。对生物标志物进行了免疫组织化学分析，分为三组：MAPK 通路、NF-kappa B 通路和雌激素受体（ER）磷酸化。使用 Kaplan-Meier 曲线和对数秩分析分析与无复发生存率（RFS）和治疗方案的关系，分析复发时间为 2.5 年和 10 年。所有统计检验均为双侧。
在单因素分析中，ER167（危险比[HR] = 0.71，95%置信区间[CI] = 0.59 至 0.85，P <.001）、IKKα（HR = 0.74，95% CI = 0.60 至 0.92，P =.005）、Raf-1338（HR = 0.64，95% CI = 0.52 至 0.80，P <.001）和 p44/42 MAPK202/204（HR = 0.77，95% CI = 0.64 至 0.92，P =.004）与接受序贯治疗的患者 10 年时的 RFS 显著相关。当将 IKKα、Raf-1338 和 ER167 组合成累积预后评分时，相关性得到了加强（HR = 0.64，95% CI = 0.52 至 0.77，P <.001）。所有 IKKα、Raf-1338 和 ER167 评分均为阴性的患者，倾向于接受依西美坦单药治疗（比值比=0.56，95% CI = 0.35 至 0.90）。多变量分析显示，IKKα、Raf-1338 和 ER167 评分（P =.001）是接受序贯治疗的患者 10 年 RFS 的独立预后因素。
IKKα、Raf-1338 和 ER167 评分是序贯治疗中较低复发的独立预测生物标志物。阴性表达可能进一步为依西美坦单药治疗提供预测价值。
