Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.
Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin.
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DOI：
10.18632/oncotarget.11317
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发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Kopetz S
中科院分区：
文献类型：
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作者：
Overman MJ;Morris V;Moinova H;Manyam G;Ensor J;Lee MS;Eng C;Kee B;Fogelman D;Shroff RT;LaFramboise T;Mazard T;Feng T;Hamilton S;Broom B;Lutterbaugh J;Issa JP;Markowitz SD;Kopetz S
启动子CpG岛（CIMP）的高甲基化与化疗耐药密切相关，并与称为CIMP高的结直肠癌（crc）亚群的发病机制有关。这项针对CRC的I/II期研究（II期部分仅限于cmp -高CRC），每三周用阿扎胞替丁（75 mg/m2/天D1-5皮下注射）和CAPOX（卡培替滨和奥沙利铂）治疗氟嘧啶/奥沙利铂难治患者。26名患者（pts）参加了这项研究：15名患者（12名接受MTD治疗）处于I期，11名患者处于II期。未观察到剂量限制性毒性。共有14分是cimp高。记者没有看到任何回应。cimp高状态与疗效终点[稳定疾病（SD）或无进展生存期（PFS）]或基线vimentin甲基化水平无关。波形蛋白甲基化随时间的变化与疗效结果无关。基线甲基化的vimentin与肿瘤体积相关（P<0.001），较高的基线甲基化水平与疾病的稳定相关（P=0.04）。在cimp高的患者中，阿扎胞苷和CAPOX耐受性良好，疾病稳定率高，但没有客观反应。血清甲基化的vimentin可能与包括低甲基化药物的方案的益处相关，尽管本研究无法分离生物标志物的潜在预后或预测作用。
Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.