Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.     

BRAF和EGFR抑制剂联合用于BRAF突变型复发转移性结直肠癌PDXs模型的研究

背景与目的：结直肠癌患者中BRAF基因突变的概率为5%~15%,临床预后明显差于无突变者。该研究将BRAF与表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂联合用于BRAF V600E突变型复发转移性结直肠癌的患者来源异种移植(patient-derived xenografts,PDXs)模型,观察其安全性、可行性及疗效。方法：2016年1月—2016年12月,复旦大学附属肿瘤医院34例疑似结直肠癌术后复发或转移的患者利用CT引导下的穿刺活检方法获取组织标本,建立复发转移性结直肠癌的PDXs模型,筛选BRAF突变者传代培养至F2代进行药物实验,实验组分为BRAF抑制剂组(A组)、EGFR抑制剂组(B组)、BRAF和EGFR抑制剂联合组(C组)及安慰剂对照组(D组)。给药3周后处死实验动物,统计建模成功率及抑瘤率。结果：34例患者中共23例病理证实为结直肠癌复发或转移,成功建立16个PDX模型,建模成功率为69.6%(16/23)。共筛选出4例BRAF V600E基因突变者,成功建立4个BRAF突变型复发转移性结直肠癌的PDXs模型。实验组无明显药物毒性相关性死亡,实验组抑瘤率分别为21.57%、21.61%和66.81%,差异有统计学意义(P<0.05)。结论：CT引导下的穿刺活检建立复发转移性结直肠癌的PDXs模型成功率高,针对EGFR和BRAF的双重打击治疗安全、可行,能够明显提高BRAF突变型结直肠癌的疗效。     

169例国人结直肠癌患者BRAF基因的突变状态分析

目的 探讨国人结直肠癌患者鼠类肉瘤病毒癌基因同源物B1（BRAF）基因的突变状态,以期能为针对表皮生长因子受体（EGFR）的靶向治疗提供指导。方法 采用PCR测序法检测169例结直肠癌组织BRAF基因的突变情况。结果 在169例结直肠癌组织中,BRAF基因在第600位密码子（V600E）发生突变,突变频率为5.3％。BRAF基因在84例男性结直肠癌患者中的突变频率为7.1％,在85例女性患者中为3.5％,差异无统计学意义（P=0.329）。在17例结直肠癌年轻患者（25～44岁）中未检测到BRAF基因突变,在67例中年患者（45～59岁）中BRAF基因的突变频率为3.0％,在85例老年患者（60～90岁）中为8.2％,三者之间差异无统计学意义（P=0.211）。结论 BRAF基因的突变频率与结直肠癌患者的性别和年龄无关。     

BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics,clinical behavior,and response to targeted therapies

Despite new and more effective cytotoxic chemotherapy, limitations to conventional agents have been reached in a subset of patients with advanced colorectal cancer (CRC). The identification of novel prognostic and predictive biomarkers to guide individualized treatment plans is critical to overcoming therapeutic resistance. Mutation of the BRAF proto-oncogene is linked to a variety of cancers and is increasingly being used as a prognostic tool and therapeutic target. This paper is a comprehensive review of the literature that summarizes the clinical, pathologic, and molecular features of BRAF mutated CRC that support the hypothesis that BRAF mutant cancers represent a distinct subset of CRC with its own clinical implications with regard to prognosis, treatments and emerging therapeutic strategies.     

Anti-angiogenic agents in metastatic colorectal cancer

Colorectal cancer (CRC) is a major public health concern being the third leading cause of cancer mortality in the United States. The availability of better therapeutic options has led to a decline in cancer mortality in these patients. Surgical resection should be considered in all stages of the disease. The use of conversion therapy has made surgery a potentially curative option even in patients with initially unresectable metastatic disease. In this review we discuss the role of various anti-angiogenic agents in patients with metastatic CRC (mCRC). We describe the mechanism of action of these agents, and the rationale for their use in combination with chemotherapy. We also review important clinical studies that have evaluated the safety and efficacy of these agents in mCRC patients. Despite the discovery of several promising anti-angiogenic agents, mCRC remains an incurable disease with a median overall survival of just over 2 years in patients exposed to all available treatment regimens. Further insights into tumor biology and tumor microenvironment may help improve outcomes in these patients.     

Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer

Background:

In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.

Methods:

Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated.

Results:

In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2% specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy.

Conclusions:

Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.     

结直肠癌分子靶向治疗面临的若干问题

目前,结直肠癌的多学科综合治疗已经得到广泛的认同,但手术仍然是转移性结直肠癌的主要治疗手段.随着外科技术的进步以及临床医生对肝内、肝外转移病灶手术观念的变化,结直肠癌远处转移灶的可切除率显著提高,患者术后的5年生存率也提高到27%～41%[1].由于可切除的结直肠癌     

BRAF分子检测在结直肠癌中的研究进展

目的 结直肠癌经典化疗方案是以氟尿嘧啶为主的联合化疗.近年来,抗表皮生长因子受体(EGFR)的靶向治疗被广泛讨论,且在结直肠癌的治疗中取得一定疗效.目前,对抗EGFR靶向治疗的疗效研究已经涉及到相关基因的表达状态,如既往探讨较多的K-Ras基因表达,新近又发现BRAF基因的突变在结直肠癌的发展以及抗EGFR靶向药物的疗...     

Wild-type KRAS and BRAF could predict response to Cetuximab in Chinese colorectal cancer patients

Objective  

To analyze the relationship between KRAS, BRAF mutations and the response to Cetuximab in Chinese colorectal cancer patients.     

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer

BackgroundBRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4–6 months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding.Patients and methodsThis phase II trial was designed to detect an increase in 6 month-Progression Free Rate (6 m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618.ResultsTwo-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7 months, 6 m-PFR was 73%. Median PFS and OS were 9.2 and 24.1 months, respectively. In the pooled population, at a median follow up of 40.4 months, 6 m-PFR was 84%. Median PFS and OS were 11.8 and 24.1 months, respectively. Overall RR and disease control rate were 72% and 88%, respectively.ConclusionLacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.     

组蛋白去乙酰化酶及其抑制剂与结直肠癌的关系

组蛋白乙酰化、去乙酰化修饰影响到染色质重塑,在基因表达的表观遗传调控中扮演重要角色。结直肠癌是临床上最常见的恶性肿瘤之一,是我国第二高发的肿瘤,研究证实结直肠癌的发生发展与组蛋白去乙酰化酶（ｈｉｓｔｏｎｅ ｄｅａｃｅｔｙｌａｓｅｓ,ＨＤＡＣｓ）异常密切相关,ＨＤＡＣ抑制剂（ＨＤＡＣｉｎｈｉｂｉｔｏｒ,ＨＤＡＣｉ）靶向ＨＤＡＣｓ,大量研究已证实ＨＤＡＣｉ单用或联合其他药物对结直肠癌细胞具有诱导分化、促进凋亡等作用,并能提高结直肠癌细胞对化疗药物的敏感性,提示ＨＤＡＣ靶向治疗结直肠癌可能是今后又一个新的发展方向。     

Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer

BACKGROUND:

It is hypothesized that BRAF mutant cancers represent a discrete subset of metastatic colorectal cancer (CRC) defined by poorer survival. This study investigates whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread and explores the impact of BRAF mutation and microsatellite instability (MSI) on prognosis in metastatic CRC.

METHODS:

By using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center), patients with known BRAF mutation status were analyzed for clinical characteristics, survival, and metastatic sites.

RESULTS:

The authors identified 524 metastatic CRC patients where BRAF mutation status was known; 57 (11%) were BRAF mutant tumors. BRAF mutant tumors were significantly associated with right‐sided primary tumor, MSI, and poorer survival (median, 10.4 months vs 34.7 months, P < .001). A distinct pattern of metastatic spread was observed in BRAF mutant tumors, namely higher rates of peritoneal metastases (46% vs 24%, P = .001), distant lymph node metastases (53% vs 38%, P = .008), and lower rates of lung metastases (35% vs 49%, P = .049). In additional survival analyses, MSI tumors had significantly poorer survival compared with microsatellite stable tumors (22.1 months vs 11.1 months, P = .017), but this difference was not evident in the BRAF mutant population.

CONCLUSIONS:

The pattern of metastatic spread observed in this study further defines BRAF mutant CRC as a discrete disease subset. The authors demonstrated that, unlikely early stage disease, MSI is associated with poorer survival in metastatic CRC, although this is driven by its association with BRAF mutation. Cancer 2011;. © 2011 American Cancer Society.     

Third-line therapy for metastatic colorectal cancer

Background The past years’ therapy for colorectal cancer has evolved rapidly with the introduction of novel cytotoxic agents such as irinotecan, capecitabine and oxaliplatin. Further advances have been achieved with the integration of targeted agents such as bevacizumab, cetuximab and recently, panitumumab. As a result, third-line treatment is now a necessary step in the optimal treatment of patients with metastatic colorectal cancer (MCRC). Materials and methods We conducted a literature review of English language publications on third-line therapy for MCRC from January 2000 to April 2007. Data on median overall survival (mOS), median time to progression (mTTP) and response rate were recorded. Results We found 27 articles and 22 abstracts to fulfil the criteria. Patients who received regimens containing oxaliplatin and infusional 5-fluorouracil (5-FU) demonstrated mTTP up to 7 months and a mOS of 16 months. With irinotecan and 5-FU, mOS around 8 months were reported and with cetuximab combined with irinotecan, the highest mOS was 9.8 months. Conclusion Third-line therapy in advanced colorectal cancer may improve mOS for patients with MCRC. Therefore, randomized studies should be conducted in the future.     

Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance

Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.     

结直肠癌Ras、BRAF和PIK3CA基因突变分析及与临床病理特征的关系

目的 分析结直肠癌患者中Ras（K-Ras／N-Ras）、BRAF和PIK3CA基因突变情况及其与临床病理特征的关系。方法 回顾性分析2013年12月至2014年10月于北京大学肿瘤医院消化肿瘤内科接受诊治的200例结直肠癌患者的肿瘤组织标本,采用PCR扩增-直接测序法检测Ras,包括K-Ras（第2、3、4外显子）、N-Ras（第2、3、4外显子）、BRAF（第15外显子）及PIK3CA（第9、20外显子）基因的突变状态,分析其与结直肠癌临床病理特征的关系。结果 200例患者中存在Ras基因突变92例（46.0％）,其中K-Ras基因突变87例（43.5％）,主要发生在外显子2,N-Ras基因突变5例（2.5％）;其中1例患者存在K-Ras、N-Ras基因同时突变。存在BRAF基因突变15例（7.5％）,突变类型均为V600E,且与K-Ras突变存在排他性。存在PIK3CA基因突变9例（4.5％）,可与Ras或BRAF基因突变共存。Ras（K-Ras／N-Ras）基因在年龄≥65岁患者中的突变率明显高于＜65岁者（P＜0.05）,其表达与性别、原发部位、组织学类型、分化程度、TNM分期、区域淋巴结转移、远处转移、术后复发转移均无关（P均＞0.05）。BRAF、PIK3CA基因在原发部位为右半结肠患者中的突变率明显升高（P＜0.05）,但与年龄、性别、组织学类型、分化程度、TNM分期、区域淋巴结转移、远处转移、术后复发转移均无关（P＞0.05）。结论 N-Ras、PIK3CA基因在中国结直肠癌患者中的突变率较低。K-Ras、N-Ras基因突变与年龄相关,BRAF、PIK3CA基因与肿瘤原发部位相关;对结直肠癌患者进行Ras（K-Ras／N-Ras）、BRAF及PIK3CA基因的联合检测将会为提高临床靶向治疗的疗效提供更加可靠的依据。     

A systematic review of salvage therapy to patients with metastatic colorectal cancer previously treated with fluorouracil,oxaliplatin and irinotecan +/− targeted therapy

Oxaliplatin, irinotecan and 5-fluorouracil in combination with or without targeted therapies are well-documented treatment options for first- and second-line treatments of metastatic colorectal cancer. However, there are much less data on the beneficial effect on systemic therapy in the third-line setting. We therefore performed a systematic review of the current literature on third or later lines of treatment to patients with metastatic colorectal cancer after the use of approved drugs or combinations.     

非小细胞肺癌的BRAF基因突变及其临床意义

BRAF基因是一个驱动基因,可能是靶向治疗非小细胞肺癌的一个靶点。本文就BRAF基因的结构、表达、信号通路调节及研究热点、与肿瘤发生的关系尤其是与非小细胞肺癌的靶向治疗关系加以阐述。