Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University & County Council of Östergötland, SE-581 85, Linköping, Sweden.
Breast Cancer Res Treat. 2013 Jan;137(2):397-406. doi: 10.1007/s10549-012-2376-y. Epub 2012 Dec 15.
The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor α (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.
PI3K/Akt/mTOR 生长信号通路的频繁改变被认为是乳腺癌对内分泌治疗产生耐药的机制之一，部分原因是通过调节雌激素受体 α（ER）的活性。为了改善个体化治疗，需要可靠的治疗预测生物标志物。我们对 912 例绝经后淋巴结阴性乳腺癌患者的原发肿瘤进行了回顾性免疫组化分析，这些患者被随机分为他莫昔芬组或无辅助治疗组。评估磷酸化（p）Akt 丝氨酸（s）473、p-mTOR s2448 和 ER 磷酸化 s167 和 s305 是否为预后和他莫昔芬治疗效果的潜在生物标志物。高 p-mTOR 表达预示着对他莫昔芬的反应降低，在 ER+/孕激素受体（PgR）+亚组中最为明显（他莫昔芬与无他莫昔芬：风险比（HR），0.86；95%置信区间（CI），0.31-2.38；P = 0.78），而低 p-mTOR 表达预示着他莫昔芬受益（HR，0.29；95%CI，0.18-0.49；P = 0.000002）。此外，核 p-Akt-s473 以及 p-ER-s167 和/或 s305 的表达与他莫昔芬疗效呈交互作用，具有统计学意义。包括 p-Akt、p-mTOR 和 p-ER 在内的阳性通路标志物组合评分与他莫昔芬获益显著相关（交互作用检验；P = 0.029）。生长信号通路与 ER 信号之间的串扰被认为会影响激素受体阳性乳腺癌中他莫昔芬的反应。这些结果支持这一假设，因为过度活跃的通路与他莫昔芬反应降低显著相关。一种用于治疗前交叉对话标志物的临床检测将是朝着个体化辅助内分泌治疗迈进的一步，无论是否添加 PI3K/Akt/mTOR 通路抑制剂。
