MAPK信号分子对HER-2阳性乳腺癌新辅助化疗疗效预测及预后价值探讨

目的：探讨有丝分裂原活化蛋白激酶（mitogen-activatedproteinkinase，MAPK）通路分子在人表皮生长因子受体2（humanepithelialgrowthfactorreceptor2，HER-2）阳性乳腺癌含蒽环类新辅助化疗中的疗效预测及预后价值。方法：回顾性分析广东医学院附属南山医院2007-05-1020120910，接受含蒽环类新辅助化疗（曲妥珠单抗新辅助靶向治疗患者除外）〉2个周期、化疗后可手术的113例女性HER-2阳性乳腺癌患者，采用免疫组织化学的方法，检测肿瘤原发灶空芯针穿刺活检标本及手术标本中MAPK的表达情况及其磷酸化状态（pMAPK）变化，分析分子表达及其变化与新辅助化疗疗效及患者预后的关系。结果：新辅助化疗后临床完全缓解20例（17．7％），其中病理完全缓解14例（12．4％），部分缓解60例（53．1％），疾病稳定30例（26．5％），疾病进展3例（2．7％）。中位随访37．2个月（8～72个月），复发转移事件60例，总死亡事件32例，3年无复发生存率为51．3％，总生存率为67．6％。空心针标本MAPK和pMAPK的阳性率分别为81．4％（92／113）和69．9％（79／113）；手术标本中pMAPK的阳性率分别为78．8％（89／113）和43．4％（49／113）。MAPK表达水平于化疗后未发生明显改变，pMAPK发生明显下降，平均下降（20±6．2）％，MAPK的磷酸化状态在化疗前后差异有统计学意义，t＝2．103，P=0．031。单因素分析提示，MAPK的磷酸化水平下降与化疗疗效有关x2=29．342，P=0．027。Cox多因素回归生存分析提示，MAPK的磷酸化水平下降为患者无复发生存率（RR=0．461，95％CI=0．262～0．813，P=0．009）和总生存率（RR=0．273，95％CI=0．121～0．618，P=0．002）的独立影响因素。结论：HER-2阳性乳腺癌蒽环类新辅助化疗后MAPK磷酸化水平下降与化疗疗效相关，并且磷酸化水平下降是其独立的预后指标。但其确切的疗效预测及预后意义尚需大样本前瞻性临床研究。

Clinical evaluation of the predictive and prognostic significance of MAPK biomarkers in the HER-2-positive breast cancer patients with neoadjuvant chemotherapy

OBJECTIVE： To evaluate the predictive and prognostic significance of mitogen-activated protein Kinase （MAPK） pathway-related biomarkers in the HER-2-positive breast cancer patients with neoadjuvant chemotherapy. METHODS： To analyze the clinical data of one hundred and thirteen HER 2 positive breast cancer patients treated in our hospital from May 10,2007 to September 10,2012. All the patients were diagnosed by core needle biopsy as invasive ductal breast cancer and treated with not less than two cycles of anthracycline-based neoadjuvant chemotherapy before operation （patients with Trustuzumab-targeted therapy were excluded）. Biomarkers of MAPK and pMAPK were evaluated by IHC in the core needle biopsy specimens and postoperative tumor tissue. The relationship between the predictive and prognostic significance and the biomarkers expression status was analyzed. RESULTS： Among 113 patients, 20 （17. 7 %） cases were clinical complete remission after neoadjuvant chemotherapy, 14（12.4% ） pathological complete remission, 60（53.1 % ） clinical partial remission,30（26.5%） stable disease and 3 cases （2.7%） progression disease. The mean follow up time was 37.2 months, 60 cases had local recurrence and distant metastasis, 32 cases for death. Three-year relapse-free survival（RFS） was 51. 3%and overall survival（OS） was 67. 6%. The positive expression rates of MAPK and pMAPK were 81.4% and 69.9% in the core needle biopsy specimens and 78.8% and 43.4% in the postoperative tumor tissue respectively, pMAPK expression was decreased significantly （t=2. 103 ,P=0. 031）. Decrease of pMAPK expression was related to the treatment effect on single factor analysis（x2 = 29. 342, P = 0. 027） and a strong prognostic factor for RFS（RR= 0. 461,95;CI=0. 262-0. 813,P=0. 009） and OS（RR=0. 273,95;CI=0. 121-0. 618,P=0. 002）on Cox regression multivariate survival analysis. CONCLUSIONS： Decrease of pMAPK expression is related to the treatment effect of anthracycline-based neoadjuvant chemotherapy and can be utilized as an independent prognostic factor in HER-2-positive breast cancer patients and prospective clinical studies are needed for the definition of the predictive and prognostic significance of pMAPK for these patients.