Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
BMC Cancer. 2023 Nov 16;23(1):1117. doi: 10.1186/s12885-023-11600-z.
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.
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.
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 (P < 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 (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 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.
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.
RAS 基因突变影响转移性结直肠癌（mCRC）患者的预后，已被确定为抗表皮生长因子受体单克隆抗体（抗 EGFR mAb）治疗的强负预测标志物，但许多含有野生型 RAS 基因的肿瘤仍对这些治疗无反应。一些额外的生物标志物可能具有预后或预测作用，但结论仍存在争议。
我们对比较抗 EGFR mAb 治疗与替代治疗的随机对照试验进行了荟萃分析和系统评价，这些试验研究了 RAS 野生型（wt）mCRC 患者中额外生物标志物的预后和预测影响。无进展生存期（PFS）和总生存期（OS）的风险比（HRs）和 95%置信区间（CIs）以及客观缓解率（ORR）的比值比（ORs）均进行了计算。通过分别在单独的研究中为不同的治疗组汇总 HR 和 OR，研究了生物标志物的预后价值。通过评估治疗效果与生物标志物亚组之间的研究相互作用，评估了预测价值。
共选择了 30 篇报告 18 项试验的出版物，共纳入 13507 名患者。在预后分析中，BRAF 突变与较差的 PFS [HRs=3.76（2.47-5.73）和 2.69（1.82-3.98）]和 OS [HRs=2.66（1.95-3.65）和 2.45（1.55-3.88）]有关，在实验组和对照组中均如此；低 miR-31-3p 表达似乎与更长的 PFS 和 OS 有关。在预测效果方面，BRAF 突变的肿瘤患者对 EGFR 治疗无反应（P<0.01，用于 PFS）。与所有野生型肿瘤相比，KRAS/NRAS/BRAF/PIK3CA 基因突变的肿瘤患者也显示出类似的结果（PFS、OS 和 ORR 的 P 值分别为<0.01、<0.01 和 0.01）。而低 miR-31-3p 表达可预测 PFS（P=0.01）和 OS（P=0.04）获益。PIK3CA 突变、PTEN 突变或缺失、EGFR、EREG/AREG、HER2、HER3 和 HER4 表达的预后和预测价值仍不确定。
在接受 EGFR 靶向治疗的 RAS wt mCRC 患者中，BRAF 突变是一种强大的预后和治疗预测生物标志物，未发现 PIK3CA 突变、PTEN 突变或缺失的影响，但联合生物标志物 KRAS/NRAS/BRAF/PIK3CA 突变预测对 EGFR 治疗的耐药性。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 及其配体和 HER2/3/4 的预后和预测作用的证据不足。
