新的EPOC3期研究中，将KRAS野生型（WT），可经手术切除治疗或可考虑手术治疗的结直肠癌肝转移（CRLM）患者在肝切除前后按1:1的比例随机分配接受化疗联合或不联合西妥昔单抗治疗。主要终点指标是无进展生存期（PFS）。该试验表明化疗加西妥昔单抗使患者PFS不佳，PFS从20.5个月降至14.1个月。 在12、13及61密码子使用焦磷酸测序确定KRAS基因（HR 1.48 95％CI为1.04-2.12，P = 0.03）。随后，将研究对象限定至所有RAS野生型晚期患者人群，表皮生长因子抑制剂的获益明显改善（Douillard NEJM 2013）。我们在全野生型新EPOC人群中进一步分析了PFS。
研究方法
获取原发结直肠癌和肝癌切除肿瘤样本。使用KRAS （12，13，61，117和146密码子），BRAF（V600E），NRAS（12，13，61，117和146），PIK3CA（547和1047）MiSeq进一步分析。那些没有任何突变者列为“全野生型”。对MET，AREG，EREG，EGFR，HER2-4，PTEN和NT5E进行定量PCR检测。采用Kaplan-Meier法和log-rank检验完成生存分析。
研究结果
迄今为止，共对106份原发肿瘤样本和103份CRLM样本进行了分析，涉及236例 KRAS野生型患者中的155例。KRAS野生型组发现22例进一步的基因突变（KRAS16例，NRAS 12例，PIK3CA 3例和BRAF 6例）。47例进行原发肿瘤和CRLM肿瘤配对样本分析。原发和相应的CRLM之间有3种突变匹配，其余13种突变（原发肿瘤6种，CRLM7种）在配对样本中没有发现。以前初步分析中包括的全野生型患者（单独化疗组48例，化疗加西妥昔单抗组 54例）的PFS分析显示类似趋势，即PFS从20.5个月降至16.4个月（HR 1.34 95％CI（0.76-2.36），P=0.32）。
结论
在可手术治疗CRLM的KRAS野生型患者的化疗及手术中加入西妥昔单抗治疗的PFS较差。更严格的选择全WT队列不会显著改变KRAS野生型人群中观察到的结果。
医脉通整理报道，转载请注明出处。
会议专题》》》2014年ASCO年会专题报道
阅读英文摘要
Analysis of progression-free survival in the new EPOC study in an “all wild-type” population.（Abstract No:3566）
Authors: John A. Bridgewater, Sian Alexandra Pugh, Karwan Moutasim,et al.
Session Type: General Poster Session
Background: The phase 3 new EPOC study, randomised KRAS wild-type (WT) patients with resectable or suboptimally resectable colorectal cancer liver metastases (CRLM) 1:1 to receive chemotherapy with or without cetuximab before and after liver resection. The primary end point was progression free survival (PFS). The trial demonstrated a detriment in PFS following the addition of cetuximab to chemotherapy from 20.5 to 14.1 months. KRAS was determined using pyrosequencing in codons 12, 13, and 61 (HR 1·48 95% CI 1·04-2·12 p=0.03). Subsequently, benefit from epidermal growth factor inhibition was shown to be improved following restriction to an all RAS WT population in patients with advanced disease (Douillard NEJM 2013). We describe a further analysis of PFS in an all WT new EPOC population.
Methods: Samples of tumor from the primary colorectal and liver resections were obtained. Patients were further analysed using MiSeq for KRAS (codon 12, 13, 61, 117 and 146), BRAF (V600E), NRAS (12, 13, 61, 117 and 146), PIK3CA (547 and 1047). Those without any mutation were classed as “all WT”. Additional qPCR was performed for MET, AREG, EREG, EGFR, HER2-4, PTEN and NT5E. Survival analyses were completed using the Kaplan-Meier method and the log-rank test.
Results: To date 106 samples of primary tumor and 103 samples of CRLM have been analysed corresponding to 155 of the 236 KRAS WT patients. Further mutations were found in samples from 22 patients in the KRAS WT group (16 KRAS, 12 NRAS, 3 PIK3CA, and 6 BRAF mutations). Paired samples of primary tumour and CRLM were analysed for 47 patients. Three mutations were matched between the primary and corresponding CRLM, with the remaining 13 mutations (six in the primary tumor, seven in CRLM) not found in the paired sample. Analysis of PFS in the all WT population of patients previously included in the primary analysis (chemo alone arm n=48, chemo plus cetuximab arm n=54) demonstrated a similar trend in detriment in median PFS of 20.5 months to 16.4 months respectively (HR 1.34 95% CI (0.76-2.36) p = 0.32).
Conclusions: The addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients results in an inferior PFS. More stringent selection of an all WT cohort does not significantly alter the detriment observed in the KRAS WT population.Clinical trial information: 22944367.
