Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.
Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value.
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DOI：
10.1158/1078-0432.ccr-12-0605
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发表时间：
2012-12-01
期刊：
影响因子：
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通讯作者：
Pogue-Geile KL
中科院分区：
文献类型：
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作者：
Gavin PG;Colangelo LH;Fumagalli D;Tanaka N;Remillard MY;Yothers G;Kim C;Taniyama Y;Kim SI;Choi HJ;Blackmon NL;Lipchik C;Petrelli NJ;O'Connell MJ;Wolmark N;Paik S;Pogue-Geile KL
本研究的目的是检查错配修复（MMR）状态和常见热点突变的预后和奥沙利铂预测价值，我们以前在II期和III期结肠癌中发现了这些突变。在来自国家外科辅助乳腺和肠道项目（NSABP）临床试验C-07（n = 1，836）和C-08（n = 463）的2，299例II期和III期结肠肿瘤中，使用化学和质谱分析了BRAF、KRAS、NRAS、MET和PIK 3CA的突变。C-07测试了在5-氟尿嘧啶加亚叶酸的基础上加用奥沙利铂的价值，C-08测试了在FOLFOX基础上加用贝伐珠单抗的价值。使用考克斯比例风险模型评估突变对肿瘤复发、总生存期（OS）和复发后生存期（SAR）的预后或奥沙利铂预测价值。BRAF突变与MMR缺陷型肿瘤（P < 0.0001）、较差OS [HR，1.46; 95%置信区间（CI），1.20-1.79; P <0.0002]和较差SAR（HR，2.31; 95% CI，1.83-2.95; P < 0.0001）相关。KRAS、NRAS、MET和PIK 3CA突变与复发、OS或SAR无关。MMR缺陷型肿瘤与基于复发的预后改善相关（HR，0.48; 95%CI，0.33-0.70; P < 0.0001）。突变和MMR状态不能预测奥沙利铂获益。这项研究表明，从II期和III期结肠癌肿瘤中分析的BRAF突变与SAR差相关，并至少部分验证和解释了先前的观察结果，将其与OS差相关。所有这些突变的分析对于未来测试阻断相关信号通路的新靶向治疗的临床试验是必要的。NSABP正在开展此类临床试验。
The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer. Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P S: 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP.