Adamczyk Agnieszka, Grela-Wojewoda Aleksandra, Domagała-Haduch Małgorzata, Ambicka Aleksandra, Harazin-Lechowska Agnieszka, Janecka Anna, Cedrych Ida, Majchrzyk Kaja, Kruczak Anna, Ryś Janusz, Niemiec Joanna
Department of Applied Radiobiology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
Department of Systemic and Generalized Malignancies, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Cracow Branch, Cracow, Poland.
J Cancer. 2017 Jan 1;8(1):131-139. doi: 10.7150/jca.16239. eCollection 2017.
Resistance to trastuzumab (which is a standard therapy for breast cancer patients with HER2 overexpression) is associated with higher risk of progression or cancer death, and might be related to activation of signalling cascades (PI3K/AKT/mTOR, Ras/Raf/MAPK) and decreased level of their inhibitors.
Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p.H1047R and p.E545K) by qPCR, and (2) expression of Ki-67, EGFR, MUC4, HER3 and PTEN by immunohistochemistry.
Lower Ki-67LI was observed in EGFR-immunonegative and in PTEN-immunopositive tumours. MUC4-immunonegative tumours more frequently were PTEN- and HER3-immunonegative. Favourable metastasis-free survival was observed in patients with tumours characterized by Ki-67LI≤50% (p=0.027), HER3 immunonegativity or PTEN immunopositivity (vs. tumours with HER3 expression and lack of PTEN expression, p=0.043), additionally, the trend was observed for patients with pN0+pN1 pathological tumour stage (vs. pN2+pN3) (p=0.086). Cox model revealed that independent negative prognostic factors were: (i) Ki-67LI>50% (p=0.014, RR=4.6, 95% CI 1.4-15.4), (ii) HER3 immunopositivity together with PTEN immunonegativity (p=0.034, RR=3.7, 95% CI 1.1-12.5).
The results of our study suggest that combined analysis of HER3 and PTEN expression might bring information on trastuzumab sensitivity in the group of HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting.
对曲妥珠单抗（HER2过表达乳腺癌患者的标准治疗药物）产生耐药与疾病进展或癌症死亡风险升高相关，可能与信号级联反应（PI3K/AKT/mTOR、Ras/Raf/MAPK）的激活及其抑制剂水平降低有关。
选取118例接受根治性局部治疗并在辅助治疗中使用曲妥珠单抗的HER2过表达乳腺癌患者的福尔马林固定石蜡包埋肿瘤标本，用于评估：（1）通过定量聚合酶链反应检测PIK3CA基因突变（p.H1047R和p.E545K）；（2）通过免疫组织化学检测Ki-67、表皮生长因子受体（EGFR）、黏蛋白4（MUC4）、HER3和磷酸酶及张力蛋白同源物（PTEN）的表达。
在EGFR免疫阴性和PTEN免疫阳性的肿瘤中观察到较低的Ki-67标记指数（Ki-67LI）。MUC4免疫阴性的肿瘤更常见PTEN和HER3免疫阴性。在Ki-67LI≤50%（p=0.027）、HER3免疫阴性或PTEN免疫阳性的肿瘤患者中观察到较好的无转移生存期（与HER3表达且缺乏PTEN表达的肿瘤患者相比，p=0.043），此外，在病理肿瘤分期为pN0+pN1的患者中观察到这种趋势（与pN2+pN3相比）（p=0.086）。Cox模型显示，独立的阴性预后因素为：（i）Ki-67LI>50%（p=0.014，风险比[RR]=4.6，95%置信区间[CI]1.4-15.4）；（ii）HER3免疫阳性且PTEN免疫阴性（p=0.034，RR=3.7，95%CI 1.1-12.5）。
我们的研究结果表明，对HER3和PTEN表达进行联合分析可能为辅助治疗中接受曲妥珠单抗治疗的HER2阳性乳腺癌患者群体的曲妥珠单抗敏感性提供信息。
