Duchnowska Renata, Wysocki Piotr J, Korski Konstanty, Czartoryska-Arłukowicz Bogumiła, Niwińska Anna, Orlikowska Marlena, Radecka Barbara, Studziński Maciej, Demlova Regina, Ziółkowska Barbara, Merdalska Monika, Hajac Łukasz, Myśliwiec Paulina, Zuziak Dorota, Dębska-Szmich Sylwia, Lang Istvan, Foszczyńska-Kłoda Małgorzata, Karczmarek-Borowska Bożenna, Żawrocki Anton, Kowalczyk Anna, Biernat Wojciech, Jassem Jacek
Military Institute of Medicine, Oncology Department, Warsaw, Poland.
West Pomeranian Cancer Center, Szczecin, Poland.
Oncotarget. 2016 Jan 5;7(1):550-64. doi: 10.18632/oncotarget.6375.
Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015).
the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.
乳腺癌中拉帕替尼耐药的分子机制尚未完全明确。本研究旨在将参与表皮生长因子受体（ErbB）家族信号通路的特定蛋白表达与拉帕替尼的临床疗效相关联。研究组包括270例接受拉帕替尼和卡培他滨治疗的HER2阳性晚期乳腺癌患者。对原发性乳腺癌样本中磷酸化腺苷单磷酸激活蛋白（p-AMPK）、丝裂原活化蛋白激酶（p-MAPK）、磷酸化（p）-p70S6K、细胞周期蛋白E、磷酸酶和张力蛋白同源物的免疫组化表达进行分析。确定每个生物标志物无进展生存期（PFS）的最佳判别值，并进行多变量分析。199例患者中至少检测了一种生物标志物。p-p70S6K的表达与较长的PFS独立相关（风险比[HR]0.45；95%置信区间[CI]：0.25-0.81；p=0.009），而细胞周期蛋白E与较短的PFS相关（HR 1.83；95%CI：1.06-3.14；p=0.029）。p-MAPK（HR 1.61；95%CI 1.13-2.29；p=0.009）和细胞周期蛋白E（HR 2.99；95%CI：1.29-6.94；p=0.011）的表达与较短的总生存期相关，而雌激素受体的表达（HR 0.65；95%CI 0.43-0.98；p=0.041）与较长的总生存期相关。p-AMPK的表达对治疗反应（HR 3.31；95%CI 1.48-7.44；p=0.004）和疾病控制（HR 3.07；95%CI 1.25-7.58；p=0.015）产生负面影响。
拉帕替尼的疗效似乎与下游信号通路——AMPK/mTOR和Ras/Raf/MAPK的活性相关。有必要进一步研究以评估这些数据的临床实用性，并确定拉帕替尼与MAPK通路抑制剂联合使用的潜在作用。
