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Abstract：
BACKGROUND: RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS: We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS: Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS: In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
METHODS: We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS: Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS: In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
摘要：
背景：RAS突变影响转移性结直肠癌（mCRC）患者的预后，并已被确定为抗表皮生长因子受体单克隆抗体（抗EGFRmAb）治疗的强阴性预测标志物，但是许多含有野生型RAS基因的肿瘤仍然对这些疗法没有反应。一些额外的生物标志物可能具有预后或预测作用，但结论仍有争议。
方法：我们对比较抗EGFRmAb治疗与替代疗法的随机对照试验进行了荟萃分析和系统评价，研究了其他生物标志物在RAS野生型(wt)mCRC患者中的预后和预测影响。计算无进展生存期（PFS）和总生存期（OS）的危险比（HR）和95％置信区间（CIs）以及客观缓解率（ORR）的比值比（ORs）。通过单独合并个体研究中不同治疗组的HR和OR来研究生物标志物的预后价值。通过汇集治疗效果和生物标志物亚组之间的研究相互作用来评估预测值。
结果：选择了30篇报告18项试验的出版物，包括13,507名患者。在预后分析中，在实验和对照组中，BRAF突变与较差的PFS[HR=3.76（2.47-5.73）和2.69（1.82-3.98）]和OS[HR=2.66（1.95-3.65）和2.45（1.55-3.88）]相关；低miR-31-3p表达似乎具有较长的PFS和OS。就预测效果而言，在BRAF突变型肿瘤患者中观察到对抗EGFR治疗缺乏应答(PFS的P交互作用<0.01).与所有野生型肿瘤相比，具有KRAS/NRAS/BRAF/PIK3CA基因中任何突变的肿瘤患者也显示出相似的结果（PFS的P相互作用，操作系统,和ORR分别为<0.01、<0.01和0.01)。而低miR-31-3p表达可以预测PFS(P相互作用=0.01)和OS(P相互作用=0.04)的益处。PIK3CA突变的预后和预测价值，PTEN突变或缺失，EGFR,EREG/AREG,HER2、HER3和HER4的表达仍不确定。
结论：在接受EGFR靶向治疗的RASwtmCRC患者中，BRAF突变是一种强大的预后和治疗预测生物标志物，没有发现PIK3CA突变的影响，PTEN突变或缺失,但联合生物标志物KRAS/NRAS/BRAF/PIK3CA突变预测抗EGFR治疗耐药.低miR-31-3p表达可能具有积极的预后和治疗预测作用。关于EGFR及其配体的预后和预测作用的证据，HER2/3/4是不够的。
方法：我们对比较抗EGFRmAb治疗与替代疗法的随机对照试验进行了荟萃分析和系统评价，研究了其他生物标志物在RAS野生型(wt)mCRC患者中的预后和预测影响。计算无进展生存期（PFS）和总生存期（OS）的危险比（HR）和95％置信区间（CIs）以及客观缓解率（ORR）的比值比（ORs）。通过单独合并个体研究中不同治疗组的HR和OR来研究生物标志物的预后价值。通过汇集治疗效果和生物标志物亚组之间的研究相互作用来评估预测值。
结果：选择了30篇报告18项试验的出版物，包括13,507名患者。在预后分析中，在实验和对照组中，BRAF突变与较差的PFS[HR=3.76（2.47-5.73）和2.69（1.82-3.98）]和OS[HR=2.66（1.95-3.65）和2.45（1.55-3.88）]相关；低miR-31-3p表达似乎具有较长的PFS和OS。就预测效果而言，在BRAF突变型肿瘤患者中观察到对抗EGFR治疗缺乏应答(PFS的P交互作用<0.01).与所有野生型肿瘤相比，具有KRAS/NRAS/BRAF/PIK3CA基因中任何突变的肿瘤患者也显示出相似的结果（PFS的P相互作用，操作系统,和ORR分别为<0.01、<0.01和0.01)。而低miR-31-3p表达可以预测PFS(P相互作用=0.01)和OS(P相互作用=0.04)的益处。PIK3CA突变的预后和预测价值，PTEN突变或缺失，EGFR,EREG/AREG,HER2、HER3和HER4的表达仍不确定。
结论：在接受EGFR靶向治疗的RASwtmCRC患者中，BRAF突变是一种强大的预后和治疗预测生物标志物，没有发现PIK3CA突变的影响，PTEN突变或缺失,但联合生物标志物KRAS/NRAS/BRAF/PIK3CA突变预测抗EGFR治疗耐药.低miR-31-3p表达可能具有积极的预后和治疗预测作用。关于EGFR及其配体的预后和预测作用的证据，HER2/3/4是不够的。
