Department of Clinical Medicine and Gastroenterology, St James's Hospital and Trinity College Dublin, James's Street, Dublin 8, Ireland.
Endocr Relat Cancer. 2010 Sep 23;17(4):847-56. doi: 10.1677/ERC-09-0204. Print 2010 Dec.
Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene - human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolization (n=14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (n=28), doxorubicin (n=14), 5-fluorouracil (n=18), and etoposide/cisplatinum (n=16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P<0.001; tumor grade, P<0.001; tumor differentiation, P<0.001; CA9, P=0.004; Akt, P=0.01; HIF-1, P<0.001; p53, P<0.0001; and hMLH1, P=0.005. Markers associated with treatment response included overall group: Akt and PTEN (P=0.05 and 0.05 respectively); streptozotocin: Akt (P=0.07), TS (P=0.02), and PTEN (P=0.017); doxorubicin: Ki-67 (P=0.05), Akt (P=0.06), and CA9 (P=0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05-0.8)). For patients receiving only systemic chemotherapy (n=46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (P=0.008) and hLMH1 (0.07); doxorubicin: Akt (P=0.09), CA9 (P=0.09), and hLMH1 (P=0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1).
胃肠胰神经内分泌肿瘤（GEP-NET）对细胞毒药物的反应率各不相同；最近的试验表明，多达 70%的患者缺乏客观反应率。在 GEP 的治疗中，鉴定预测治疗的生物标志物将是有益的。选择具有已知或可疑预测细胞毒药物或预后反应能力的标记物（Ki-67、p53、多药耐药蛋白 1（MDR1）、Akt、胸苷酸合成酶（TS）、磷酸酶和张力蛋白同源物（PTEN）、CA9、分化簇 34（CD34）、血管内皮生长因子（VEGF）、缺氧诱导因子（HIF）-1、错配修复基因-人类 mutL 同源物 1（hLMH1）和 Bcl-2），在 60 名接受化疗（n=46）或化疗栓塞（n=14）治疗不可切除的晚期和/或转移性 GEP 且无治疗经验的患者中，采用免疫组化进行分析，并与预后（生存率和反应率）相关。治疗包括系统化疗（n=28），阿霉素（n=14），5-氟尿嘧啶（n=18）和依托泊苷/顺铂（n=16），或化疗栓塞（n=9），阿霉素（n=5）。在整个队列中与总生存率相关的因素包括 Ki-67（P<0.001）；肿瘤分级（P<0.001）；肿瘤分化（P<0.001）；CA9（P=0.004）；Akt（P=0.01）；HIF-1（P<0.001）；p53（P<0.0001）和 hMLH1（P=0.005）。与治疗反应相关的标志物包括：总组：Akt 和 PTEN（P=0.05 和 0.05）；链脲佐菌素：Akt（P=0.07）、TS（P=0.02）和 PTEN（P=0.017）；阿霉素：Ki-67（P=0.05）、Akt（P=0.06）和 CA9（P=0.02）。多变量分析显示，Akt 与治疗无反应显著相关（客观反应（OR）：0.2（0.05-0.8））。对于仅接受系统化疗的患者（n=46），PTEN（0.04）和 hLMH1（0.03）与治疗反应相关，对于单个分子，链脲佐菌素：PTEN（P=0.008）和 hLMH1（P=0.07）；阿霉素：Akt（P=0.09）、CA9（P=0.09）和 hLMH1（P=0.09）。这些结果表明 GEP-NET 中有许多新的预后生物标志物，此外，化疗反应与选择的标记物（如 CA9、Akt、PTEN、TS 和 hLMH1）的简单组合相关。
