Mohamed Amr, Twardy Brandon, AbdAllah Nadine, Akhras Alaa, Ismail Hibah, Zordok Magdi, Schrapp Kelly, Attumi Taraq, Tesfaye Anteneh, El-Rayes Bassel
Department of Medical Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Department of Medicine, Wayne State University, Detroit, MI, USA.
J Gastrointest Cancer. 2019 Jun;50(2):269-275. doi: 10.1007/s12029-018-0062-y.
Understanding the molecular mechanisms of colorectal cancer has evolved during the last decade ushering the era of personalized medicine. Alteration of BRAF and PI3K is common in colorectal cancer, and can affect several signaling pathways including EGFR (epidermal growth factor receptor). The aim of this meta-analysis is to evaluate the clinical role of PI3K and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer (MCRC) receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor as first-line therapy.
A literature search was performed to identify studies exploring the association between PI3K/BRAF mutations and clinical outcomes of KRAS wild-type mCRC patients treated with anti-EGFR as a first-line therapy. The primary clinical outcome was overall response rate (ORR). The secondary outcomes included progression-free survival (PFS) and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effect model or random effect model according to heterogeneity between studies.
Ten studies with 1470 mCRC patients (357 for PI3K studies and 1113 from BRAF studies) met selection criteria. We observed a trend towards lower ORR in patients with PI3K mutations (3 studies, 357 patients; ORR = 14.3% in mutant-type PI3K vs. 52.4% in wild-type PIK3CA [95% CI - 0.12-0.02]; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3 studies, 357 patients, 3.8 vs. 4.15 months, HR = 1.36; [95% CI 1.04-1.77]; P = 0.02]), and OS (3 studies, 357 patients, 14.17 vs. 16.3 months, HR = 1.50; [95% CI 1.14-1.97]; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significantly lower ORR (7 studies, 1113 patients; ORR = 33% vs. 39%; [95% CI - 0.16-0.01]; P = 0.03), shorter PFS (5 studies, 814 patients, 3.9 vs. 5.7 months, HR = 1.72; [95% CI 1.47-2.01]; P = 0.00001), and shorter OS (4 studies, 766 pts., 9.1 vs. 18.9 months, HR = 1.22; [95% CI 1.04-1.44]; P = 0.01) compared to those with wild-type.
This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K.
在过去十年中，对结直肠癌分子机制的理解不断发展，迎来了个性化医疗时代。BRAF和PI3K的改变在结直肠癌中很常见，并且可以影响包括表皮生长因子受体（EGFR）在内的多种信号通路。本荟萃分析的目的是评估PI3K和BRAF突变在接受EGFR单克隆抗体（抗EGFR）抑制剂作为一线治疗的KRAS野生型转移性结直肠癌（MCRC）患者中的临床作用。
进行文献检索，以确定探索PI3K/BRAF突变与接受抗EGFR作为一线治疗的KRAS野生型mCRC患者临床结局之间关联的研究。主要临床结局是总缓解率（ORR）。次要结局包括无进展生存期（PFS）和总生存期（OS）。根据研究之间的异质性，使用固定效应模型或随机效应模型估计合并相对风险（RR）或风险比（HR）。
10项研究纳入了1470例mCRC患者（PI3K研究357例，BRAF研究1113例），符合入选标准。我们观察到PI3K突变患者的ORR有降低趋势（3项研究，357例患者；PI3K突变型的ORR为14.3%，野生型PIK3CA为52.4%[95%CI -0.12 - 0.02]；P = 0.13）。与野生型PI3K患者相比，PI3K突变型患者的PFS显著缩短（3项研究，357例患者，3.8个月对4.15个月，HR = 1.36；[95%CI 1.04 - 1.77]；P = 0.02），OS也显著缩短（3项研究，357例患者，14.17个月对16.3个月，HR = 1.50；[95%CI 1.14 - 1.97]；P = 0.004）。对于BRAF，与野生型相比，突变型患者的ORR显著降低（7项研究，1113例患者；ORR = 33%对39%；[95%CI -0.16 - 0.01]；P = 0.03），PFS显著缩短（5项研究，814例患者，3.9个月对5.7个月，HR = 1.72；[95%CI 1.47 - 2.01]；P = 0.00001），OS也显著缩短（4项研究，766例患者，9.1个月对18.9个月，HR = 1.22；[95%CI 1.04 - 1.44]；P = 0.01）。
该分析表明，mCRC且伴有PI3K或BRAF突变的患者一线接受抗EGFR治疗时可能反应较低且结局较差。鉴于其较差的结局，应考虑对BRAF和PI3K突变状态进行常规检测。对于BRAF或PI3K突变的患者，需要新的治疗方法。
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