Analysis of Molecular Markers by Anatomic Tumor Site in Stage III Colon Carcinomas from Adjuvant Chemotherapy Trial NCCTG N0147 (Alliance)
Analysis of Molecular Markers by Anatomic Tumor Site in Stage III Colon Carcinomas from Adjuvant Chemotherapy Trial NCCTG N0147 (Alliance)
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DOI：
10.1158/1078-0432.ccr-15-0527
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发表时间：
2015-12-01
影响因子：
11.5
通讯作者：
Alberts, Steven R.
中科院分区：
文献类型：
--
作者：
Sinicrope, Frank A.;Mahoney, Michelle R.;Alberts, Steven R.
目的：为了确定III期结肠癌患者解剖肿瘤部位分子标志物的频率和预后相关性，实验设计：在辅助FOL-FOX +/-西妥昔单抗的随机试验中，分析了肿瘤（N = 3，018）中BRAF（V600 E）和KRAS（外显子2）突变和DNA错配修复（MMR）蛋白与肿瘤部位（包括亚部位）的关系。结果：KRAS基因第12位密码子突变发生在脾曲和盲肠，第13位密码子突变分布均匀。BRAF突变频率从横结肠到盲肠急剧增加，与缺陷（d）MMR平行。未突变的BRAF和KRAS肿瘤从乙状结肠到横结肠逐渐减少（所有P < 0.0001）。值得注意的是，突变KRAS在远端癌中的OS较差[HR，1.98; 95%置信区间（CI），1.49-2.63; P < 0.0001-相对于近端癌（1.25; 95% CI，0.97-1.60; P = 0.079）。BRAF状态和结果与肿瘤部位无显著相关性。近端与远端dMMR肿瘤的结局明显更好。通过KRAS进行的相互作用检验对肿瘤部位具有显著性（P调整= 0.043）和MMR FOLFOX组中不同肿瘤部位的生物标志物的预后差异显著。肿瘤部位是独立的预后因素，从盲肠到乙状结肠逐步改善结论：BRAF或KRAS密码子12的突变在近端肿瘤中富集，而未突变的BRAF/KRAS在远端肿瘤中增加。不同肿瘤部位的KRAS突变和dMMR结果存在显著差异，表明其解释应在肿瘤位置的背景下进行。(C)2015年AACR。
Purpose: To determine the frequency and prognostic association of molecular markers by anatomic tumor site in patients with stage III colon carcinomas.Experimental Design: In a randomized trial of adjuvant FOL-FOX +/- cetuximab, BRAF(V600E) and KRAS (exon 2) mutations and DNA mismatch repair (MMR) proteins were analyzed in tumors (N = 3,018) in relationship to tumor location, including subsite. Cox models were used to assess clinical outcome, including overall survival (OS).Results: KRAS codon 12 mutations were most frequent at the splenic flexure and cecum; codon 13 mutations were evenly distributed. BRAF mutation frequency sharply increased from transverse colon to cecum in parallel with deficient (d) MMR. Nonmutated BRAF and KRAS tumors progressively decreased from sigmoid to transverse (all P < 0.0001). Significantly, poorer OS was found for mutant KRAS in distal [HR, 1.98; 95% confidence interval (CI), 1.49-2.63; P < 0.0001-versus proximal (1.25; 95% CI, 0.97-1.60; P = 0.079) cancers. BRAF status and outcome were not significantly associated with tumor site. Proximal versus distal dMMR tumors had significantly better outcome. An interaction test was significant for tumor site by KRAS (P-adjusted = 0.043) and MMR (P-adjusted = 0.010) for OS. Significant prognostic differences for biomarkers by tumor site were maintained in the FOLFOX arm. Tumor site was independently prognostic with a stepwise improvement from cecum to sigmoid (OS: P-adjusted = 0.001).Conclusions: Mutation in BRAF or KRAS codon 12 was enriched in proximal cancers whereas nonmutated BRAF/KRAS was increased in distal tumors. Significant differences in outcome for KRAS mutations and dMMR were found by tumor site, indicating that their interpretation should occur in the context of tumor location. (C) 2015 AACR.