Cros J, Hentic O, Rebours V, Zappa M, Gille N, Theou-Anton N, Vernerey D, Maire F, Lévy P, Bedossa P, Paradis V, Hammel P, Ruszniewski P, Couvelard A
Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France U1149 - University Paris DiderotParis, France.
Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
Endocr Relat Cancer. 2016 Aug;23(8):625-33. doi: 10.1530/ERC-16-0117. Epub 2016 Jun 28.
Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.
替莫唑胺（TEM）在高分化胰腺神经内分泌肿瘤（WDPNETs）中显示出令人鼓舞的结果。肿瘤内低O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）表达和MGMT启动子甲基化与胶质母细胞瘤患者在基于TEM的化疗下更好的预后相关。我们旨在评估MGMT表达和MGMT启动子甲基化是否有助于预测WDPNET患者基于TEM的化疗疗效。对2006年至2012年间接受TEM治疗的50%以上出现病情进展的WDPNET和/或肝脏受累的连续患者进行了回顾性研究。根据实体瘤疗效评价标准（RECIST）1.1指南评估肿瘤反应。通过免疫化学（H评分，0-300）评估MGMT的核表达，通过焦磷酸测序评估MGMT启动子甲基化。分析了43例1级WDPNET（n=6）或2级（n=36）患者（21例男性，58岁（27-84岁））。客观缓解、疾病稳定和进展率分别见于17例患者（39.5%）、18例患者（41.9%）和8例患者（18.6%）。低MGMT表达（≤50）与放射学客观缓解（P=0.04）和更好的无进展生存期（PFS）相关（HR=0.35（0.15-0.81），P=0.01）。治疗18个月时，MGMT评分高达100时疾病控制率仍令人满意（74%），但随着表达升高而下降。高MGMT启动子甲基化与低MGMT表达和更长的PFS相关（HR=0.37（0.29-1.08），P=0.05）。低MGMT评分（≤50）似乎可预测客观肿瘤反应，而中等MGMT评分（50-100）似乎与疾病长期稳定相关。
