Bournet Barbara, Muscari Fabrice, Buscail Camille, Assenat Eric, Barthet Marc, Hammel Pascal, Selves Janick, Guimbaud Rosine, Cordelier Pierre, Buscail Louis
Department of Gastroenterology, CHU Toulouse Rangueil, University of Toulouse, Toulouse, France.
INSERM UMR 1037, Center for Cancer Research, Cancer Institute, University of Toulouse, Toulouse, France.
Clin Transl Gastroenterol. 2016 Mar 24;7(3):e157. doi: 10.1038/ctg.2016.18.
There is no molecular biomarker available in the clinical practice to assess the prognosis of advanced pancreatic carcinoma. This multicenter prospective study aimed to investigate the role of KRAS mutation subtypes within the primary tumor to determine the prognosis of advanced pancreatic cancer.
The exon-2 KRAS mutation status was tested on endoscopic ultrasound-guided fine-needle aspiration biopsy material (primary tumor; restriction fragment-length polymorphism plus sequencing and TaqMan allelic discrimination) of patients with proven locally advanced and/or metastatic pancreatic ductal carcinoma. We used the Kaplan-Meier method, log-rank test, and Cox's model to evaluate the impact of KRAS status on the overall survival (OS), adjusting for age, stage of disease, clinical performance status, CA 19-9 levels, and treatment.
A total of 219 patients (men: 116; mean age: 67±9.4 years) were included: 147 harbored a codon-12 KRAS mutation (G12D: 73; G12V: 53; G12R: 21) and 72 had a wild-type KRAS. There was no difference in the OS between patients with a mutant KRAS (8 months; 95% confidence interval (95% CI): 8.7-12.3) and the wild-type (9 months; 95% CI: 8.7-12.8; hazard ratio (HR): 1.03; P=0.82). However, the patients with a G12D mutation had a significantly shorter OS (6 months; 95% CI: 6.4-9.7) compared with the other patients (OS: 9 months; 95% CI: 10-13; HR: 1.47; P=0.003; i.e., wild type: 9 months, G12V: 9 months, G12R: 14 months). Similar results were observed in the subgroup of 162 patients who received chemotherapy (HR: 1.66; P=0.0013; G12D (n=49): 8 months, wild type (n=56): 10 months, G12V (n=38): 10 months, G12R (n=19): 14 months). Multivariate analyses identified KRAS G12D as an independent predictor for worse prognosis within the entire series (HR: 1.44; P=0.01) and in the subgroup of patients that received chemotherapy (HR: 1.84; P=0.02).
The KRAS G12D mutation subtype is an independent prognostic marker for advanced pancreatic ductal carcinoma. Codon and amino-acid-specific mutations of KRAS should be considered when evaluating the prognoses as well as in trials testing drugs that target RAS and downstream RAS pathways.
临床实践中尚无分子生物标志物可用于评估晚期胰腺癌的预后。这项多中心前瞻性研究旨在探讨原发性肿瘤内KRAS突变亚型在确定晚期胰腺癌预后方面的作用。
对经证实为局部晚期和/或转移性胰腺导管癌患者的内镜超声引导下细针穿刺活检材料（原发性肿瘤；限制性片段长度多态性加测序和TaqMan等位基因鉴别）进行第2外显子KRAS突变状态检测。我们使用Kaplan-Meier法、对数秩检验和Cox模型来评估KRAS状态对总生存期（OS）的影响，并对年龄、疾病分期、临床表现状态、CA 19-9水平和治疗进行校正。
共纳入219例患者（男性116例；平均年龄67±9.4岁）：147例携带密码子12 KRAS突变（G12D：73例；G12V：53例；G12R：21例），72例为野生型KRAS。KRAS突变患者的OS（8个月；95%置信区间（95%CI）：8.7-12.3）与野生型患者（9个月；95%CI：8.7-12.8；风险比（HR）：1.03；P=0.82）之间无差异。然而，与其他患者相比，G12D突变患者的OS显著缩短（6个月；95%CI：6.4-9.7）（OS：9个月；95%CI：10-13；HR：1.47；P=0.003；即野生型：9个月，G12V：9个月，G12R：14个月）。在接受化疗的162例患者亚组中观察到类似结果（HR：1.66；P=0.0013；G12D（n=49）：8个月，野生型（n=56）：10个月，G12V（n=38）：10个月，G12R（n=19）：14个月）。多因素分析确定KRAS G12D是整个系列中预后较差的独立预测因素（HR：1.44；P=0.01），在接受化疗的患者亚组中也是如此（HR：1.84；P=0.02）。
KRAS G12D突变亚型是晚期胰腺导管癌的独立预后标志物。在评估预后以及在测试靶向RAS和RAS下游通路药物的试验中，应考虑KRAS的密码子和氨基酸特异性突变。
