BRAF和KRAS突变在微卫星高度不稳定和稳定的III期结肠癌中的预后价值
Prognostic Value of BRAF and KRAS Mutations in MSI and MSS Stage III Colon Cancer.
作者信息
Taieb Julien, Le Malicot Karine, Shi Qian, Penault-Llorca Frédérique, Bouché Olivier, Tabernero Josep, Mini Enrico, Goldberg Richard M, Folprecht Gunnar, Luc Van Laethem Jean, Sargent Daniel J, Alberts Steven R, Emile Jean Francois, Laurent Puig Pierre, Sinicrope Frank A
机构信息
Affiliations of authors: Department of Gastroenterology and GI Oncology, Université Paris Descartes, Hopital Européen Georges Pompidou, Paris, France (JTai); Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France (KLM); Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN (QS, DJS); Department of Pathology, Centre Jean Perrin, EA ERTICa, Université d'Auvergne, Clermont-Ferrand, France (FPL); Centre Hospitalier Universitaire Robert Debré, Reims, France (OB); Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain (JTab); Spanish Gastrointestinal Tumors TTD Group, Universitat Autònoma de Barcelona, Barcelona, Spain (JTab); Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy (EM); Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH (RMG); First Medical Department, University Hospital Carl Gustav Carus, Dresden, Germany (GF); Department of Gastroenterology, Hôpital Universitaire Erasme, Brussels, Belgium (JLVL); Department of Oncology, Mayo Clinic and Mayo Cancer Center, Rochester, MN (SRA, FAS); Pathology Department, Ambroise Paré Hospital, Boulogne, France (JFE); Université Paris Descartes, Sorbonne Paris Cité, France (PLP); Assistance Publique Hôpitaux de Paris, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France (PLP); INSERM UMR-S1147, Paris, France (PLP).
出版信息
J Natl Cancer Inst. 2016 Dec 31;109(5). doi: 10.1093/jnci/djw272. Print 2017 May.
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.
背景
在接受手术切除的结肠癌患者的微卫星不稳定（MSI）和微卫星稳定（MSS）亚组中，BRAF和KRAS突变的预后价值仍存在争议。我们在两项辅助治疗试验中，对前瞻性收集的III期结肠癌生物标本进行了研究，分别分析了接受辅助性FOLFOX±西妥昔单抗治疗患者的MSI和MSS肿瘤。
方法
定义了三组：BRAF突变型、KRAS突变型和双野生型。分析策略包括估计研究特异性效应、评估结果的同质性，然后对汇总数据进行分析，因为在两项试验的治疗组之间未发现患者预后存在差异。分析了突变与患者预后的关联，并对治疗和相关因素进行了多变量模型调整。
结果
4411个肿瘤可评估BRAF和KRAS突变及错配修复状态；3934个为MSS，477个为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<.001）、KRAS密码子12改变和p.G13D突变（HR=1.60，95%CI=1.40至1.83，P<.001）均与较短的复发时间（TTR）和复发后较短的生存期（SAR；HR=3.02，95%CI=2.32至3.93，P<.001，以及HR=1.20，95%CI=1.01至1.44，P=.04）相关。BRAF突变患者（HR=2.01，95%CI=1.56至2.57，P<.001）和KRAS突变患者（HR=1.62，95%CI=1.38至1.91，P<.001）的MSS患者总生存期（OS）较野生型患者差。在MSI患者中未发现KRAS或BRAF突变具有预后作用。此外，在MSS患者中，治疗组（使用或不使用西妥昔单抗）与KRAS和BRAF突变之间在TTR或OS方面未发现相互作用。
结论
在对接受辅助性FOLFOX治疗的手术切除III期结肠癌患者的汇总分析中，BRAF或KRAS突变与MSS肿瘤患者（而非MSI肿瘤患者）较短的TTR、SAR和OS独立相关。未来在辅助治疗环境中的临床试验应将这些突变视为重要的分层因素。
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