Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response.
Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response.
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DOI：
10.1158/1078-0432.ccr-16-1896
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发表时间：
2017-06-01
期刊：
影响因子：
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通讯作者：
Scandura JM
中科院分区：
文献类型：
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作者：
Schneider BJ;Shah MA;Klute K;Ocean A;Popa E;Altorki N;Lieberman M;Schreiner A;Yantiss R;Christos PJ;Palmer R;You D;Viale A;Kermani P;Scandura JM
肿瘤抑制基因 (TSG) 的表观遗传沉默是在癌症中观察到的一种获得性异常，通常与 DNA 甲基化相关。我们假设用 5-阿扎胞苷进行预处理（引发）将通过重新激活 TSG 来提高化疗的疗效。本研究旨在确定局部晚期食管/胃腺癌 (EGC) 患者在 EOX（表柔比星、奥沙利铂、卡培他滨）新辅助化疗前 5-阿扎胞苷的耐受剂量。符合条件的患者未经治疗、局部晚期、可切除 EGC、ECOG 0-2 和足够的器官功能。在每个 21 天周期的 EOX 之前，皮下给予 5-阿扎胞苷（V，75mg/m2）3（剂量水平，DL 1）或 5（DL 2）天（E 50 mg/m2，O 130 mg/m2，X 625 mg/m2 BIDx21 d）。标准 3+3 方法指导 V 剂量递增。通过数字液滴、亚硫酸氢盐 qPCR 测量基线和切除时收集的肿瘤样本中对照和生物标志物区域的 DNA 甲基化。所有受试者均接受了残余肿瘤的完全切除（R0）。 12 名患者中的 3 名 (25%) 实现了手术完全缓解，5 名患者获得部分缓解。总体回应率为 67%。最常见的毒性是胃肠道和血液学毒性。在所有剂量水平下均观察到生物标志物基因的低甲基化，并随治疗反应变化趋势。新辅助 VEOX 耐受性良好，具有显着的临床和表观遗传反应，初步证据表明化疗前用 V 启动可能会增强化疗疗效。推荐的 II 期试验方案是 5-阿扎胞苷 75 mg/m2，持续 5 天，然后每 21 天进行一次 EOX 化疗。
Epigenetic silencing of tumor suppressor genes (TSGs) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pre-treatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally-advanced esophageal/gastric adenocarcinoma (EGC). Eligible patients had untreated, locally-advanced, resectable EGC, ECOG 0–2 and adequate organ function. 5-azacitidine (V, 75mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E 50 mg/m2, O 130 mg/m2, X 625 mg/m2 BIDx21 d). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection. All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and five had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response. Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days.