BRAFV600E protein expression and outcome from BRAF inhibitor treatment in BRAFV600E metastatic melanoma

Background:

To examine the association between level and patterns of baseline intra-tumoural BRAF^V600E protein expression and clinical outcome of BRAF^V600E melanoma patients treated with selective BRAF inhibitors.

Methods:

Fifty-eight BRAF^V600E metastatic melanoma patients treated with dabrafenib or vemurafenib on clinical trials had pre-treatment tumour BRAF^V600E protein expression immunohistochemically (IHC) assessed using the BRAF V600E mutant-specific antibody VE1. Sections were examined for staining intensity (score 1–3) and percentage of immunoreactive tumour cells, and from this an immunoreactive score (IRS) was derived (intensity × per cent positive/10). The presence of intra-tumoural heterogeneity for BRAF^V600E protein expression was also assessed. BRAF^V600E expression was correlated with RECIST response, time to best response (TTBR), progression-free survival (PFS) and overall survival (OS).

Results:

Expression was generally high (median IRS 28 (range 5–30)) and homogeneous (78%). Expression of mutated protein BRAF^V600E as measured by intensity, per cent immunoreactive cells, or IRS did not correlate with RECIST response, TTBR, PFS or OS, including on multivariate analysis. Heterogeneity of staining was seen in 22% of cases and did not correlate with outcome.

Conclusion:

In the current study population, IHC-measured pre-treatment BRAF^V600E protein expression does not predict response or outcome to BRAF inhibitor therapy in BRAF^V600E metastatic melanoma patients.     

The safety and efficacy of cobimetinib for the treatment of BRAF V600E or V600K melanoma

Introduction: In the recent years, melanoma patients’ outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting.

Areas covered: This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib. We searched the PubMed for published papers related to safety and efficacy of cobimetinib, and resistance mechanisms to BRAF inhibition. The abstract databases of the American Society of Clinical Oncology and European Society for Medical Oncology were also searched for updates on the mentioned clinical trials.

Expert commentary: Patients treated with targeted therapy experience a rapid tumor response. However, virtually all patients will develop resistance to treatment. Therapeutic combinations to overcome resistance mechanisms are currently addressed. In the future, targeted therapy strategy will include three or more drugs, probably from different therapeutic classes.     

甲状腺乳头状癌BRAFV600E突变分析

  目的  检测BRAFV600E突变在甲状腺乳头状癌(PTC)中的发生情况, 分析BRAFV600E突变与临床各病理参数以及与合并桥本氏甲状腺炎(HT)和结节性甲状腺肿的关系。  方法  天津医科大学附属肿瘤医院2011年3月至2011年8月所收治的临床考虑甲状腺癌患者112例, 术中取部分新鲜肿瘤组织, 送基因诊断室检测BRAFV600E突变情况, 其中30例患者同时取部分正常甲状腺组织进行检测对照。  结果  112例患者病理结果显示110例为PTC, 2例为结节性甲状腺肿。其中BRAFV600E突变在110例PTC的突变率为62.7%, 不存在于结节性甲状腺肿及正常甲状腺组织。年龄≤30岁PTC患者8例, 突变率为25.0%;30~60岁患者86例, 突变率为62.8%;≥60岁患者16例, 突变率为81.2%, 差异有统计学意义(P=0.027)。、BRAFV600E突变与其他临床病理参数间的差异无统计学意义。合并HT的PTC患者40例, 突变率42.5%;未合并HT的PTC患者70例, 突变率74.3%, 差异有统计学意义(P=0.001)。合并结节性甲状腺肿的PTC患者61例, 突变率72.1%;未合并结节性甲状腺肿的PTC患者49例, 突变率51.0%, 差异有统计学意义(P=0.023)。  结论  PTC的BRAFV600E突变率可能与种族差异有关。BRAFV600E突变率可能与患者年龄构成比有一定的相关性。合并HT的PTC BRAFV600E突变率低, 而合并结节性甲状腺肿的PTC BRAFV600E突变率高。      

BRAFV600E突变与甲状腺乳头状癌

BRAF基因属于RAF基因家族,其编码的蛋白在RAS-RAF-MEK-ERK信号转导调节途径中起重要作用。最近国外研究发现,BRAF^V600E突变与甲状腺乳头状癌（PTC）的发生、发展密切相关,为未来PTC的诊断和治疗提供了新的突破口。现综述BRAF^V600E突变与PTC的研究进展。     

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review

BackgroundDetailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development.MethodsOur systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response.ResultsBased on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45–89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48–64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23–54%], ganglioglioma (GG): 40% [33–46%], and anaplastic ganglioglioma (aGG): 46% [18–76%]. Prevalence in astroblastoma was 24% [8–43%], desmoplastic infantile astrocytoma (DIA): 16% [0–57%], subependymal giant cell astrocytoma (SEGA): 8% [0–37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0–11%], diffuse astrocytoma (DA): 3% [0–9%], and pilocytic astrocytoma (PA): 3% [2–5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively.Conclusions BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.     

BRAF inhibitor activity in V600R metastatic melanoma

Activating mutations in the BRAF gene occur in approximately 50% of melanomas. More than 70% of BRAF mutations are V600E and 10–30% are V600K. Potent and selective BRAF inhibitors have demonstrated significant clinical benefits in patients with V600E and V600K BRAF-mutated melanoma. V600R mutations constitute approximately 3–7% of all BRAF mutations and the activity of BRAF inhibitors in patients with this mutation is unknown. We have treated 45 patients with V600 mutated melanoma including patients with V600R mutation between July 2011 and October 2012 with the selective BRAF inhibitor dabrafenib (n = 43) or vemurafenib (n = 2) via a compassionate access programme. The overall response rate was 50% for the whole population with a progression-free survival of 5.5 months. Five objective responses were seen in six assessable patients with V600R BRAF mutation (n = 9). Our experience suggests that patients with V600R BRAF mutations can be treated successfully with oral BRAF inhibitors, and molecular diagnostic assays should include detection of this type of mutation.     

原发性腹膜后肿瘤600例临床研究

[目的]总结原发性腹膜后肿瘤(PRPT)临床治疗经验,分析影响PRPT术后效果的因素。[方法]回顾性分析解放军总医院600例PRPT的临床资料。[结果]600例PRPT中546例行手术,病理结果恶性369例,良性177例。366例获随访,随访时间1个月～15年。PRPT完全切除者的1、3、5年生存率分别为:90.5%、73.2%、53.6%,恶性PRPT部分切除者的1、3、5年生存率分别为:70.6%、32.0%、5.7%(P<0.01)。Cox多因素回归分析显示:PRPT的局部复发、生存期与肿瘤是否完全切除、肿瘤大小、肿瘤细胞的分化程度明显相关。[结论]充分做好PRPT手术前准备,提高肿瘤完全切除率,是降低PRPT肿瘤复发,提高生存率的关键。     

BRAFV600E基因突变与甲状腺乳头状癌

 BRAF^V600E基因突变是甲状腺乳头状癌中最常见的遗传学事件,是浸润性肿瘤临床表型和预后不佳的指标,BRAF^V600E因突变检测对甲状腺恶性结节的术前鉴别诊断及指导甲状腺癌的手术切除范围、判断患者预后、指导术后后继治疗均有重要的指导意义。     

BRAF^V600E基因突变与甲状腺乳头状癌

BRAF^V600E基因突变是甲状腺乳头状癌中最常见的遗传学事件,是浸润性肿瘤临床表型和预后不佳的指标。BRAF^V600E因突变检测对甲状腺恶性结节的术前鉴别诊断及指导甲状腺癌的手术切除范围、判断患者预后、指导术后后继治疗均有重要的指导意义。     

Insight on BRAFV600E mutated colorectal cancer immune microenvironment

Colorectal cancer (CRC) is the second deadliest malignancy for both sexes. The BRAF^V600E mutation, one of the most common driver mutations in CRC, is known for its poor prognosis due to the increased risk of metastasis. The effect of the BRAF^V600E mutation on the tumor microenvironment was the topic of the study reported in World Journal of Gastrointestinal Oncology, with special focus on immune status. The authors presented insightful findings that were exclusively based on macrophage polarity and cytokine levels, without investigating other relevant immune elements. A more comprehensive look into the dynamic immune activity of cancer environments will warrant more meaningful practical findings. In this letter, we discuss other significant immune factors and their possible implications on the tumor microenvironment of BRAF-mutated CRC.     

Somatic BRAF-V600E mutations in familial colorectal cancer.

The BRAF gene is mutated in 4% to 12% of unselected colorectal cancers, particularly those with high microsatellite instability and in premalignant lesions, such as serrated adenomas and hyperplastic polyps. However, it has been shown that activating BRAF mutations are almost never found in tumors from hereditary nonpolyposis colorectal cancer patients. To evaluate the role of oncogenic BRAF mutations in non-hereditary nonpolyposis colorectal cancer/non-familial adenomatous polyposis familial colorectal cancer, we did a mutation screening of the most common BRAF mutation, the V600E mutation, in 194 colorectal tumors from patients with a positive family history of the disease. The BRAF-V600E mutation was identified in 100% (8 of 8) of microsatellite-unstable tumors and in 9.7% (18 of 186) of microsatellite-stable tumors. Interestingly, families with extracolonic tumors showed a much higher mutation frequency (17.5%) compared with families with colonic cancer only (3.5%; P = 0.009). In addition, we studied colonoscopic results from 448 family members who had been under colonoscopic surveillance for several years. Subjects from families where the V600E mutation was identified had less adenomas compared with those from families where no BRAF mutation had been found (odds ratio, 8.5; 95% confidence interval, 1.1-64.6). These findings indicate that adenomas might be less important in the cancer development in the group of families with BRAF-V600E mutations and indirectly support a previous hypothesis that tumors might develop through the hyperplastic polyp-serrated adenoma pathway. In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal cancer families characterized by an increased risk of other common malignancies.