Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer
Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer
复制标题
DOI：
10.1093/jnci/djw272
复制
发表时间：
2017-05-01
影响因子：
10.3
通讯作者：
Sinicrope, Frank A.
中科院分区：
文献类型：
--
作者：
Taieb, Julien;Le Malicot, Karine;Sinicrope, Frank A.
背景资料：BRAF和KRAS突变在微卫星不稳定（MSI）和微卫星稳定（MSS）亚组结肠癌切除患者中的预后价值仍存在争议。我们在前瞻性收集的III期结肠癌生物标本中研究了这个问题，并对接受辅助FOLFOX +/-cetuximab的患者在两项辅助治疗试验中的MSI和MSS肿瘤进行了单独分析：定义了三组：BRAF突变体，KRAS突变体和双野生型。分析策略包括估计研究特异性效应、评估结果的同质性，然后分析汇总数据，因为在两项试验的治疗组之间未发现患者结局的差异。突变与患者的结果进行了分析，多变量模型进行了调整治疗和相关factors.Results：四千四百一十一肿瘤可评估BRAF和KRAS突变和错配修复状态，3934 MSS和477 MSI。在MSS患者中，所有BRAF V600E突变（风险比[HR]= 1.54，95%置信区间[CI]= 1.23至1.92，P <0.001），KRAS密码子12变异和p.G13D突变（HR = 1.60，95%CI = 1.40 - 1.83，P <.001）与复发时间（TTR）和复发后生存期较短相关（SAR; HR = 3.02，95%CI = 2.32至3.93，P <0.001; HR = 1.20，95%CI = 1.01至1.44，P = 0.04）。与野生型相比，BRAF突变型患者（HR = 2.01，95% CI = 1.56 - 2.57，P <0.001）和KRAS突变型患者（HR = 1.62，95% CI = 1.38 - 1.91，P <0.001）的MSS患者的总生存期（OS）较差。在MSI患者中未观察到KRAS或BRAF突变的预后作用。此外，没有发现治疗臂（有或没有西妥昔单抗）和KRAS和BRAF突变之间的相互作用TTR或OS在MSS patient.Conclusions：在一个汇总分析切除III期结肠癌患者接受辅助FOLFOX，BRAF或KRAS突变是独立相关的较短的TTR，SAR和OS的MSS患者，但不MSI，肿瘤。未来的辅助治疗临床试验应将这些突变作为重要的分层因素。
Background: The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials.Methods: Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors.Results: Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02, 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P < .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm(with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients.Conclusions: In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.