Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
Department of Ultrasound, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
Eur J Surg Oncol. 2024 Sep;50(9):108474. doi: 10.1016/j.ejso.2024.108474. Epub 2024 Jun 5.
Colorectal cancer (CRC) patients with peritoneal metastasis (CRC-PM) have a worse prognosis than those with liver and lung metastases. Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective locoregional treatment for CRC-PM. To date, the prognostic analysis of CRS/HIPEC mostly focuses on clinical and pathological characteristics; however, genetic characteristics, such as RAS/BRAF mutation status, are not sufficient. This study aimed to systematically assess the correlation between RAS/BRAF status and PM risk, as well as the prognostic efficacy of CRS/HIPEC for CRC.
This study was written in accordance with the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We searched PubMed, EMBASE, and the Cochrane library with the following keywords: "Peritoneal Neoplasms," "raf Kinases" and "ras Proteins". The fixed-effects model and inverse variance method were used for analysis. Odds ratios (OR) and 95 % confidence intervals (CI) were used to reflect the risk of PM associated with RAS/BRAF mutations. Hazard ratios (HR) and 95 % CI were used to evaluate the effects of RAS/BRAF mutations on the prognosis of CRS/HIPEC.
Eighteen articles included 5567 patients. In the risk analysis of PM, patients with BRAF mutation were more likely to have PM than those with wild-type BRAF (OR = 2.28, 95 % CI = 1.73-3.01, P < 0.001, I = 0 %). In contrast, there was no significant difference in the effect of RAS mutation and wild-type on PM of CRC (OR = 1.28, 95 % CI = 0.99-1.66, P = .06, I = 0 %). In a prognostic analysis of CRS/HIPEC, RAS mutation predicted poor overall survival (HR = 1.68, 95 % CI = 1.39-2.02, P < 0.001, I = 1 %) and disease-free survival (HR = 1.61, 95 % CI = 1.34-1.94, P < 0.001, I = 42 %). The results for BRAF mutation was consistent with the prognostic impact of RAS mutation's overall survival (HR = 2.57, 95 % CI = 1.93-3.44, P < 0.001, I = 0 %) and disease-free survival (HR = 1.90, 95 % CI = 1.40-2.56, P < 0.001, I = 82 %).
BRAF mutation, rather than RAS mutation, was a high-risk factor for CRC-PM. And both BRAF and RAS mutations negatively affected the prognosis of CRS/HIPEC in CRC-PM patients. Our results could provide suggestions for the selection of comprehensive treatment for CRC-PM with RAS/BRAF mutations.
结直肠癌（CRC）伴腹膜转移（CRC-PM）患者的预后比肝肺转移患者更差。细胞减灭术（CRS）联合腹腔热灌注化疗（HIPEC）是 CRC-PM 的有效局部治疗方法。迄今为止，CRS/HIPEC 的预后分析主要集中在临床和病理特征上；然而，遗传特征，如 RAS/BRAF 突变状态，并不充分。本研究旨在系统评估 RAS/BRAF 状态与 PM 风险的相关性，以及 CRS/HIPEC 对 CRC 的预后疗效。
本研究按照 2020 年系统评价和荟萃分析报告指南编写。我们使用以下关键词在 PubMed、EMBASE 和 Cochrane 图书馆中进行了搜索：“腹膜肿瘤”、“raf 激酶”和“ras 蛋白”。使用固定效应模型和逆方差法进行分析。比值比（OR）和 95%置信区间（CI）用于反映 RAS/BRAF 突变与 PM 相关的风险。风险比（HR）和 95%CI 用于评估 RAS/BRAF 突变对 CRS/HIPEC 预后的影响。
纳入了 18 篇文章，共 5567 名患者。在 PM 的风险分析中，BRAF 突变患者发生 PM 的可能性高于野生型 BRAF 患者（OR=2.28，95%CI=1.73-3.01，P<0.001，I=0%）。相比之下，RAS 突变和野生型对 CRC 的 PM 影响没有显著差异（OR=1.28，95%CI=0.99-1.66，P=0.06，I=0%）。在 CRS/HIPEC 的预后分析中，RAS 突变预测总生存期不良（HR=1.68，95%CI=1.39-2.02，P<0.001，I=1%）和无病生存期不良（HR=1.61，95%CI=1.34-1.94，P<0.001，I=42%）。BRAF 突变的结果与 RAS 突变的总生存期预后影响一致（HR=2.57，95%CI=1.93-3.44，P<0.001，I=0%）和无病生存期（HR=1.90，95%CI=1.40-2.56，P<0.001，I=82%）。
BRAF 突变而非 RAS 突变是 CRC-PM 的高危因素。BRAF 和 RAS 突变均对 CRC-PM 患者的 CRS/HIPEC 预后产生负面影响。我们的研究结果可为 CRC-PM 患者的 RAS/BRAF 突变综合治疗选择提供建议。
