Background There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov NCT01071655.

中文翻译：

---

基于基因型的晚期大肠癌（SETICC）患者的治疗选择：一项基于药物遗传学的随机II期临床试验。

背景技术针对转移性结直肠癌（mCRC）患者的个性化治疗进展甚微。先前已报道了TYMS-3'非翻译区（UTR）6 bp ins / del和ERCC1-118C / T多态性，以利于选择接受氟嘧啶为基础的治疗并结合奥沙利铂作为一线治疗的患者。我们评估了这些标志物在选择mCRC患者治疗中的效用。患者和方法这项随机开放标签的II期临床试验比较了贝伐单抗加XELOX（对照）与根据TYMS-3'UTR 6 bp ins / del和ERCC1-118C / T多态性量身定制的治疗。随机分配至实验治疗的患者接受贝伐单抗加FUOX，FUIRI，XELIRI或XELOX的治疗，具体取决于他们对FUOX治疗有利的多态性的组合（TYMS-3' UTR ins / del或del / del；ERCC1-118T / T）。无进展生存期（PFS）是主要终点。结果总共195例患者被随机分组​​（对照组n = 65；实验组n = 130）。主要目标未达到：对照组中位PFS为9.4个月，实验组中位PFS为10.1个月（P = 0.745）。两组中位总生存期相似（分别为16.5个月和19.1个月； P = 0.797）。实验组患者的总缓解率（ORR；对照组为65％，而对照组为47％； P = 0.042）和R0切除率（分别为86％和44％； P = 0.018）显着更高。神经病，手足综合征，血小板减少症和感觉异常在实验组中明显较少见。结论本研究未显示基于mCRC多态性的个性化治疗后的生存获益。然而，提高的ORR和R0切除率以及更少的致死性毒性表明，通过TYMS-3'UTR和ERCC1-118多态性进行的定制治疗值得对mCRC患者进行进一步的研究。ClinicalTrials.gov NCT01071655。