The role of BRAF V600 mutation in melanoma

Abstract

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.

Can detection of Braf p.V600E mutation be improved? Comparison of allele specific multiplex sequencing to present tests

“…The clinical significance of the Braf p.V600E/K mutations in metastatic melanoma, including use of inhibitors, are reported. [17][18][19][20][21][22][23] Hence, low level detection of Braf p.V600E/K plays a pivotal role in the use of Braf kinase inhibitors. False negative Braf p.V600E/K results will prevent some patients from receiving treatment with kinase inhibitors, while at the same time allow for continuation of Braf p.V600E/V60K mediated intrinsic signal transduction in mutated cancer cells, potentially resulting in further proliferation of the tumor mass.…”

Malignant melanoma of the female urethra

“…It is well known that BRAF mutations are often noted in MM, and BRAF (V600E) immunohistochemistry can help to detect the BRAF mutations. [9,10] Therefore, future works will include BRAF mutational profiling of MM.…”

Dabrafenib Resistance Overridden by Switch to Vemurafenib and Trametinib in 53-year Old Patient with Metastatic Lung Carcinoma: Clinical Case Report

“…Both inhibitors bind to forms of the oncogenic B-Raf protein with mutations at position V600E in the BRAF gene, leading to inactivation of the MAP Kinase pathway and potential apoptosis of tumor cells [13]. Rudin et al [14] reported the case of a 63-yearold never smoker with lung Adenocarcinoma whose mutational profile indicated an aberration in BRAF V600E.…”