上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2021 , Vol. 41 >Issue 6: 786 - 792

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.06.014

论著 · 循证医学

BRAF基因突变对肝切除后的结直肠癌肝转移患者预后影响的meta分析

  • 程盛 ,
  • 赵益 ,
  • 王永琛 ,
  • 黄平
展开
  • 重庆医科大学附属第一医院肝胆外科，重庆 400016
程 盛（1994—），男，硕士生；电子信箱：1617404396@qq.com。

网络出版日期: 2021-06-29

收起

Meta-analysis of the effect of BRAF gene mutation on the prognosis of colorectal cancer patients with liver metastases after hepatectomy

  • Sheng CHENG ,
  • Yi ZHAO ,
  • Yong-chen WANG ,
  • Ping HUANG
Expand
  • Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

Online published: 2021-06-29

Fold

摘要

目的·评估BRAF基因突变对肝切除后的结直肠癌肝转移（colorectal cancer liver metastasis，CRLM）患者预后的影响。方法·计算机检索PubMed上10年间的临床研究，起止时间为2010年1月—2020年6月。检索方式为"BRAF" and （"colon" or "colorectal" or "rectal" or "rectum"） and （"metastasis" or "metastatic" or "metastases" or "mets" or "metastasectomy"） and （"hepatic" or "liver"）。根据纳入及排除标准筛选文献，并进行质量评价和数据提取。应用RevMan 5.4软件进行数据分析，主要结局指标为总生存期（overall survival，OS），次要结局指标为无病生存率（disease-free survival，DFS）。结果·最终7篇文献被纳入meta分析，共包含2 722例患者，BRAF突变率为5.77%。7篇文献报道了CRLM患者行肝切除后，按BRAF基因状态进行分层分析的OS。meta分析结果显示，合并效应量危险比（hazard ratio，HR）=3.04，95％CI 2.30~4.01，P=0.000，有统计学意义，说明有BRAF突变的CRLM患者，行肝切除后OS缩短。OS的HR漏斗图基本对称，未发现明显的发表偏倚。3篇文献报道了CRLM患者行肝切除后，按BRAF基因状态进行分层分析的DFS，共1 237例患者，BRAF的突变率为9.62%。meta分析结果显示，合并效应量HR=2.07，95％CI 1.06~4.03，P=0.03，有统计学意义，说明有BRAF突变的CRLM患者，行肝切除术后DFS缩短。DFS的HR漏斗图不对称，不能确定是否存在发表偏倚，可能与纳入研究的样本量较少有关。结论·BRAF突变是肝切除后的CRLM患者预后不良的生物标志物，与较差的OS相关，而与较差的DFS是否有关仍需更多研究来证实。

关键词： BRAF基因; 突变; 结直肠癌; 肝转移; 预后

本文引用格式

程盛 , 赵益 , 王永琛 , 黄平 . BRAF基因突变对肝切除后的结直肠癌肝转移患者预后影响的meta分析[J]. 上海交通大学学报（医学版）, 2021 , 41(6) : 786 -792 . DOI: 10.3969/j.issn.1674-8115.2021.06.014

Abstract

Objective

·To assess the impact of BRAF gene mutation on the prognosis of colorectal cancer liver metastasis (CRLM) patients after hepatectomy.

Methods

·The clinical research was obtained from PubMed from January 2010 to June 2020. Retrieval method was as follows: "BRAF" and ("colon" or "colorectal" or "rectal" or "rectum") and ("metastasis" or "metastatic" or "metastases" or "mets" or "metastasectomy") and ("hepatic" or "liver"). The articles were screened according to inclusion and exclusion criterias, and the quality evaluation and data extraction were carried out. The RevMan 5.4 software was used for meta-analysis. The main outcome index was overall survival (OS), and the secondary outcome index was disease-free survival (DFS).

Results

·Finally, seven studies containing 2 722 patients were included in the meta-analysis. The mutation rate of BRAF was 5.77%. Seven studies reported CRLM patients' OS after hepatic resection through stratified analysis by BRAF gene status. The result of meta-analysis showed that hazard ratio (HR)=3.04, 95% CI 2.30－4.01, P=0.000. That was statistically significant. It indicated that the OS of CRLM patients with BRAF mutation was shortened after hepatectomy. HR funnel plot of OS was basically symmetrical, and no obvious publication bias was found. Three studies reported 1 237 CRLM patients'DFS after hepatectomy through stratified analysis by BRAF gene status. The mutation rate of BRAF was 9.62%. The result of meta-analysis showed that HR=2.07, 95%CI (1.06－4.03), P=0.03. That was statistically significant. It indicated that the DFS of CRLM patients with BRAF mutation was shortened after hepatectomy. HR funnel plot of DFS was asymmetric, and it was uncertain whether there was publication bias, which may be related to the small sample size included in the study.

Conclusion

·BRAF mutation is a biomarker of poor prognosis in CRLM patients after hepatectomy. It is related to poor OS, and more studies are needed to confirm the relationship with poor DFS.

Key words： BRAF gene; mutation; colorectal cancer; liver metastasis; prognosis

参考文献

1 Bahrami A, Amerizadeh F, ShahidSales S, et al. Therapeutic potential of targeting wnt/β-catenin pathway in treatment of colorectal cancer: rational and progress[J]. J Cell Biochem, 2017, 118(8): 1979-1983.
2 Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132.
3 王锡山. 中美结直肠癌流行病学特征及防诊治策略的对比分析[J]. 中华结直肠疾病电子杂志, 2017, 6(6): 447-453.
4 van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2014, 25(): iii1-iii9.
5 Bouviez N, Lakkis Z, Lubrano J, et al. Liver resection for colorectal metastases: results and prognostic factors with 10-year follow-up[J]. Langenbeck's Arch Surg, 2014, 399(8): 1031-1038.
6 Primrose JN. Surgery for colorectal liver metastases[J]. Br J Cancer, 2010, 102(9): 1313-1318.
7 Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy[J]. J Clin Oncol, 2009, 27(22): 3677-3683.
8 Hayashi M, Inoue Y, Komeda K, et al. Clinicopathological analysis of recurrence patterns and prognostic factors for survival after hepatectomy for colorectal liver metastasis[J]. BMC Surg, 2010, 10: 27.
9 Kayhanian H, Goode E, Sclafani F, et al. Treatment and survival outcome of BRAF-mutated metastatic colorectal cancer: a retrospective matched case-control study[J]. Clin Colorectal Cancer, 2018, 17(1): e69-e76.
10 Schmoll HJ, van Cutsem E, Stein A, et al. ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making[J]. Ann Oncol, 2012, 23(10): 2479-2516.
11 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer[J]. Nature, 2012, 487(7407): 330-337.
12 Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial[J]. J Clin Oncol, 2009, 27(35): 5931-5937.
13 Kadowaki S, Kakuta M, Takahashi S, et al. Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer[J]. World J Gastroenterol, 2015, 21(4): 1275-1283.
14 Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer[J]. Cancer, 2011, 117(20): 4623-4632.
15 Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer[J]. Br J Cancer, 2011, 104(5): 856-862.
16 Cremolini C, di Bartolomeo M, Amatu A, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis[J]. Ann Oncol, 2015, 26(10): 2092-2097.
17 Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases[J]. Cancer, 2013, 119(23): 4137-4144.
18 Price TJ, Beeke C, Townsend AR, et al. BRAF mutation testing and metastatic colorectal cancer in the community setting: is there an urgent need for more education?[J]. Mol Diagn Ther, 2016, 20(1): 75-82.
19 Huang CJ, Teng HW, Chien CC, et al. Prognostic significance of C-reactive protein polymorphism and KRAS/BRAF in synchronous liver metastasis from colorectal cancer[J]. PLoS One, 2014, 8(6): e65117.
20 Deshwar A, Margonis GA, Andreatos N, et al. Double KRAS and BRAF mutations in surgically treated colorectal cancer liver metastases: an international, multi-institutional case series[J]. Anticancer Res, 2018, 38(5): 2891-2895.
21 Lang H, Baumgart J, Heinrich S, et al. Extended molecular profiling improves stratification and prediction of survival after resection of colorectal liver metastases[J]. Ann Surg, 2019, 270(5): 799-805.
22 Brunsell TH, Sveen A, Bj?rnbeth BA, et al. High concordance and negative prognostic impact of RAS/BRAF/PIK3CA mutations in multiple resected colorectal liver metastases[J]. Clin Colorectal Cancer, 2020, 19(1): e26-e47.
23 Lin Q, Ye QH, Zhu DX, et al. Determinants of long-term outcome in patients undergoing simultaneous resection of synchronous colorectal liver metastases[J]. PLoS One, 2014, 9(8): e105747.
24 Margonis GA, Buettner S, Andreatos N, et al. Prognostic factors change over time after hepatectomy for colorectal liver metastases: a multi-institutional, international analysis of 1 099 patients[J]. Ann Surg, 2019, 269(6): 1129-1137.
25 L?es IM, Immervoll H, Sorbye H, et al. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases[J]. Int J Cancer, 2016, 139(3): 647-656.
26 Teng HW, Huang YC, Lin JK, et al. BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy[J]. J Surg Oncol, 2012, 106(2): 123-129.
27 Umeda Y, Nagasaka T, Mori Y, et al. Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability[J]. J Hepatobiliary Pancreat Sci, 2013, 20(2): 223-233.
28 Schirripa M, Bergamo F, Cremolini C, et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection[J]. Br J Cancer, 2015, 112(12): 1921-1928.
29 Margonis GA, Buettner S, Andreatos N, et al. Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer[J]. JAMA Surg, 2018, 153(7): e180996.
30 Lin Q, Jian M, Niu ZC, et al. Prognostic impact of KRAS and BRAF mutations in patients who underwent simultaneous resection for initially resectable colorectal liver metastases[J]. Int J Clin Exp Pathol, 2018, 11(12): 5981-5991.
31 Bachet JB, Moreno-Lopez N, Vigano L, et al. BRAF mutation is not associated with an increased risk of recurrence in patients undergoing resection of colorectal liver metastases[J]. Br J Surg, 2019, 106(9): 1237-1247.
32 Ruzzenente A, Bagante F, Ratti F, et al. Response to preoperative chemotherapy: impact of change in total burden score and mutational tumor status on prognosis of patients undergoing resection for colorectal liver metastases[J]. HPB (Oxford), 2019, 21(9): 1230-1239.
33 Garcia-Carbonero N, Martinez-Useros J, Li WY, et al. KRAS and BRAF mutations as prognostic and predictive biomarkers for standard chemotherapy response in metastatic colorectal cancer: a single institutional study[J]. Cells, 2020, 9(1): 219.
34 Sterne JA, Sutton AJ, Ioannidis JP, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials[J]. BMJ, 2011, 343: d4002.
35 Tosi F, Magni E, Amatu A, et al. Effect of KRAS and BRAF mutations on survival of metastatic colorectal cancer after liver resection: a systematic review and meta-analysis[J]. Clin Colorectal Cancer, 2017, 16(3): e153-e163.
36 Passiglia F, Bronte G, Bazan V, et al. Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis[J]. Crit Rev Oncol Hematol, 2016, 99: 150-157.
37 Kopetz S, Vauthey JN. Perioperative chemotherapy for resectable hepatic metastases[J]. Lancet, 2008, 371(9617): 963-965.
38 Blazer DG, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases[J]. J Clin Oncol, 2008, 26(33): 5344-5351.
39 Chun YS, Vauthey JN, Boonsirikamchai P, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases[J]. JAMA, 2009, 302(21): 2338-2344.
40 Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases[J]. J Clin Oncol, 2012, 30(36): 4566-4572.
41 Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1 568 patients. Association Fran?aise de Chirurgie[J]. Cancer, 1996, 77(7): 1254-1262.
42 Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1 001 consecutive cases[J]. Ann Surg, 1999, 230(3): 309-318.
43 Rees M, Tekkis PP, Welsh FK, et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients[J]. Ann Surg, 2008, 247(1): 125-135.
44 Kopetz S, Overman MJ, Chen K, et al. Mutation and copy number discordance in primary versus metastatic colorectal cancer (mCRC)[J]. J Clin Oncol, 2014, 32(): 3509.
45 Artale S, Sartore-Bianchi A, Veronese SM, et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer[J]. J Clin Oncol, 2008, 26(25): 4217-4219.
46 Sartore-Bianchi A, Loupakis F, Argilés G, et al. Challenging chemoresistant metastatic colorectal cancer: therapeutic strategies from the clinic and from the laboratory[J]. Ann Oncol, 2016, 27(8): 1456-1466.
Options
文章导航

/

〈 〉