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

doi:10.3969/j.issn.1674-8115.2021.06.014

摘要/Abstract

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

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

中图分类号:

R657.3

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.

Sheng CHENG, Yi ZHAO, Yong-chen WANG, Ping HUANG. Meta-analysis of the effect of BRAF gene mutation on the prognosis of colorectal cancer patients with liver metastases after hepatectomy[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(6): 786-792.

图/表 7

参考文献 46

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Study	n	BRAF mutation / n(%)	OS or DFS			Source of genetic testing issue of BRAF mutation / %	Preoperative and/or postoperative chemotherapy
Study	n	BRAF mutation / n(%)	Index	BRAF-MT	BRAF- WT	Source of genetic testing issue of BRAF mutation / %	Preoperative chemotherapy only / %	Preoperative chemotherapy only / %	Preoperative and postoperative chemotherapy / %	Specific drugs and treatment
Teng ^[26], 2012	292	6 (2.1)	mOS	8.20 months	19.30 months	Liver / 100	22.60	83.90	11.30	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
			1-year OS	33.00%	94.70%
Umeda^[27], 2013	100	3 (3.0)	3-year OS	0	77.10%	Liver / 100	33.00	85.00	NA	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
			5-year OS	0	65.10%
Schirripa^[28], 2015	309	12 (3.9)	mOS	22.60 months	66.30 months	Liver / 16.5, colorectal/ 17.5, both / 66.0	50.00	21.00	36.00	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
Margonis^[29], 2018	849	43 (5.5)	3-year OS	12.10%	36.50%	Liver or colorectal / NA	67.70	62.40	NA	NA
			20-month OS	55.00%	85.00%
Lin ^[30], 2018	139	10 (7.2)	40-month OS	25.00%	60.00%	Colorectal / 100	23.00	100.00	23.00	5-FU, OXA, IRI, XEL
			60-month OS	0	55.00%
			20-month DFS	10.00%	55.00%
			40-month DFS	0	40.00%
Bachet^[31], 2019	249	66 (26.5)	3-year OS	54.00%	82.90%	Liver or colorectal / NA	82.70	NA	74.70	5-FU, OXA,targeted drugs, HAI
			mOS	52.70 months	>52.70 months
			1-year DFS	46.00%	55.40%
			3-year DFS	19.00%	27.80%
			5-year DFS	10.00%	13.00%
Ruzzenente^[32], 2019	784	17 (2.2)	5-year OS	0	47.60%	Liver or colorectal / NA	100.00	NA	NA	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)

Study	n	BRAF mutation / n(%)	OS or DFS			Source of genetic testing issue of BRAF mutation / %	Preoperative and/or postoperative chemotherapy
Study	n	BRAF mutation / n(%)	Index	BRAF-MT	BRAF- WT	Source of genetic testing issue of BRAF mutation / %	Preoperative chemotherapy only / %	Preoperative chemotherapy only / %	Preoperative and postoperative chemotherapy / %	Specific drugs and treatment
Teng ^[26], 2012	292	6 (2.1)	mOS	8.20 months	19.30 months	Liver / 100	22.60	83.90	11.30	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
			1-year OS	33.00%	94.70%
Umeda^[27], 2013	100	3 (3.0)	3-year OS	0	77.10%	Liver / 100	33.00	85.00	NA	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
			5-year OS	0	65.10%
Schirripa^[28], 2015	309	12 (3.9)	mOS	22.60 months	66.30 months	Liver / 16.5, colorectal/ 17.5, both / 66.0	50.00	21.00	36.00	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)
Margonis^[29], 2018	849	43 (5.5)	3-year OS	12.10%	36.50%	Liver or colorectal / NA	67.70	62.40	NA	NA
			20-month OS	55.00%	85.00%
Lin ^[30], 2018	139	10 (7.2)	40-month OS	25.00%	60.00%	Colorectal / 100	23.00	100.00	23.00	5-FU, OXA, IRI, XEL
			60-month OS	0	55.00%
			20-month DFS	10.00%	55.00%
			40-month DFS	0	40.00%
Bachet^[31], 2019	249	66 (26.5)	3-year OS	54.00%	82.90%	Liver or colorectal / NA	82.70	NA	74.70	5-FU, OXA,targeted drugs, HAI
			mOS	52.70 months	>52.70 months
			1-year DFS	46.00%	55.40%
			3-year DFS	19.00%	27.80%
			5-year DFS	10.00%	13.00%
Ruzzenente^[32], 2019	784	17 (2.2)	5-year OS	0	47.60%	Liver or colorectal / NA	100.00	NA	NA	5-FU, OXA, IRI, anti-EGFR (Beva, Cetu)

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