Background Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.

中文翻译：

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难治性小肠腺癌和CpG岛甲基化表型（CIMP）高结直肠癌的nab-紫杉醇II期研究。

背景启动子CpG岛的超甲基化[CpG岛甲基化子表型（CIMP）]代表了大肠癌（CRC）发生的独特途径，其特征是缺乏染色体不稳定和腺瘤性息肉病（APC）突变率低。两者均与紫杉烷抗性相关。同样，小肠腺癌（SBA）是一种罕见的肿瘤，其APC突变率也很低。这项II期研究评估了SBA和CIMP高CRC中紫杉烷的敏感性。患者和方法主要目标是1.1版实体瘤的缓解率评估标准。资格包括东部合作肿瘤小组的工作状态为0/1，难治性疾病以及SBA或CIMP高转移性CRC。最初以每3​​周260 mg / m2的剂量服用Nab-紫杉醇，但由于毒性降低至220 mg / m2。结果自2012年11月至2014年10月，共招募了21例CIMP高CRC患者和13例SBA。疗效评估人群（接受至少三剂治疗的患者）包括15例CIMP高CRC患者和10例SBA患者。常见的3级或4级毒性是疲劳（12％），中性粒细胞减少症（9％），高热性中性粒细胞减少症（9％），脱水（6％）和血小板减少症（6％）。在CIMP高的CRC队列中未观察到应答，在SBA队列中未观察到两个部分应答。SBA队列中位无进展生存期显着高于CIMP高CRC队列中（3.2个月对2.1个月，P = 0.03）。在CIMP高CRC队列中，APC突变状态和CHFR甲基化状态均与疗效无关。在来自SBA患者的异种移植物中的紫杉醇的体内测试验证了这种疾病类型中紫杉烷类的活性。结论尽管临床前研究表明紫杉烷敏感性与染色体稳定性和野生型APC有关，但我们发现nab-紫杉醇对CIMP高转移性CRC无效。纳布紫杉醇可能代表SBA的一种新的治疗选择。我们发现nab-紫杉醇在CIMP高转移性CRC中无效。纳布紫杉醇可能代表SBA的一种新的治疗选择。我们发现nab-紫杉醇在CIMP高转移性CRC中无效。纳布紫杉醇可能代表SBA的一种新的治疗选择。