B-Raf proteins are intermediate to Ras and MAPK in the cellular proliferative pathway.
A serine threonine kinase and important component of the Ras/Raf/MEK signaling cascade.
Most common mutation results in a substitution of valine residue at amino acid position 600 to glutamic acid in the BRAF protein.
Typically activated by Ras by phosphorylation.
Activated Raf activates MAPK by phoshorylation.
The BRAF gene activates the mitogen activated protein kinase (MPPK) pathway.
The BRAF protein is a member of the serine-threonine kinase RAF family, and is part of the RAS-RAF-MAPK signaling pathway, which plays a major role in regulating cell survival, cell proliferation, and cell differentiation.
BRAF mutations, with V600E being the most common, activates the MAPK-ERK pathway, leading to enhanced cell proliferation, survival and neoplastic transformation.
Activating BRAF V600E mutations has been successfully targeted with dual molecular therapy in melanoma, non-small cell lung cancer, colorectal cancer and thyroid cancer.
BRAF V600E mutations have been identified in a subset of patients with pediatric and adult brain tumors.
BRAF V600E mutations present in 1 to 3% of high-grade gliomas, 3% of colorectal cancers, 3% of non-small cell lung cancers, 0.5% of ovarian cancers,, and 1.4-3% in squamous cell carcinomas of the head and neck.
BRAF V600E Mutations represent 5-10% of patients with metastatic colon rectal cancer and it is a subgroup with aggressive disease biology, poor responses to standard of care chemotherapy, and shorter survivals.
BRAF variants in colorectal cancer are associated with poor prognosis, are more common in women, older patients, right sided lesions, poorly differentiated tumors and those with sessile serrated polyp precursors.
BRAF metastatic colorectal cancers have a higher rate of micro satellite instability and epigenetic modifications such as hyper methylation.
BRAF V600 mutations are seen in xanthoastrocytomas at 50-65%, gangliogliomas 20-70%, pilocytic astrocytoma 9 to 10%, low grade gliomas 5-15%, and adult glioblastoma 1-5%.
Patients with BRAF positive disease in Colon cancers have improved outcome if EGFR targeted therapy is used in the frontline setting.
Right-sided colorectal cancer patients with stage III and high-risk stage II cancers have a worse disease free survival than patients with left-sided tumors (Saunders M).
Right-sided colon tumors more frequently harbor BRAF mutations, have a higher tumor/node/metastases stage a presentation, and have a worse prognosis compared with left-sided colorectal tumors.
8-10% of patients with colorectal cancer have a BRAF mutationsn and 80% of those are BRAF V600E mutations.
BRAF mutations are more common in women and elderly patients with colorectal cancer.
BRAF lesions are predominantly right sided and large primaries.
BRAF lesions are associated with mismatch repair deficiency, tend to have a higher grade, a greater rate of peritoneal disease, and more expensive lymph node metastasis.
Valine to glutamine replacement at position 600 determines BRAF activation.
BRAF mutation rate in melanoma declines with age-more than 80% of those aged 20-40 years to 50% of those aged 41-70 years, and to less than 25% of those older than 70 years.
BRAF V600E mutations in melanoma occur in 86% of younger patients aged 20-30 years, and V600K mutation emerge in older patients.
BRAF positive melanoma occurs in approximately 50% of cases that arise in the skin, 10 to 20% of cases that arise on mucosal surfaces, such as the mouth, sinuses, genitals, and rectum, 20 to 25% of cases of ocular melanoma affecting the conjunctiva, and no cases of ocular melanomas affecting the choroid.
This mutation when introduced into normal cells confer malignant properties.
BRAF-T1799A encodes for BRAF-V600E, a constitutively active protein serine kinase that activates the BRAF-MEK1/2-ERK1/2MAP kinase pathway.
BRAF is an enzyme that utilizes adenosine triphosphate (ATP) as an energy source.
Melanomas associated with BRAF mutations include younger age, a few of markers of chronic sun damage in this skin, higher total body nevus counts, histopathologic findings of large epithelioid cells, heavy melanization, and prominent scatter of melanocytes.
Encorafenib and binimetinib are now approved in combination for the treatment of unresectable or metastatic melanomas with a BRAF V600E or V600K mutation.
Encorafenib and binimetinib approval is based on the randomized, active-controlled, open-label, multicenter COLOMBUS trial in which 577 patients with BRAF V600E or V600K mutations-positive unresectable or metastatic melanoma were randomized (1:1:1) to receive binimetinib (45 mg) twice daily plus encorafenib (450 mg) once daily, encorafenib (300 mg) once daily, or vemurafenib (960 mg) twice daily.
The median progression-free survival was 14.9 months for patients receiving binimentinib plus encorafenib compared with 7.3 months for patients in the vemurafenib monotherapy arm.
Overall response rated were 63% and 40%, respectively.
In the above study median duration of response was 16.6 months and 12.3 months, respectively.
The most common adverse effects in patients receiving the encorafenib and binimetinib combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.
BRAF mutations may be a negative prognostic marker for survival in metastatic melanoma.
The BRAF V600E mutation is associated with highly aggressive behavior and colorectal cancer, and is associated with resistance to chemotherapy and epidermal growth factor receptor directed therapies, leading to shorter survival outcomes than with wild type BRAF.
The composition of a BRAF inhibitor and EGFR blockade creates a synergistic effect in colon cancer with a BRAF V600E mutation.
The BRAF V600E mutation is invariably associated with Hairy cell leukemia.
BRAF Mutation with of malignant diseases including Langerhans cell histiocytosis, papillary thyroid cancer, and colorectal cancer.
BRAF mutations Have been identified in a subset of patients with pediatric and adult brain tumors.
The BRAF V600E is present in the entire spectrum of patients, including those with leukocytosis or without splenomegaly and those evaluated after treatment, and it is present in the entire tumor cell clone in virtually all patients with hairy cell leukemia.
The BRAF V600E mutation is implicated in the pathogenesis of hairy cell leukemia.
The BRAF V600E seen in approximately 40% of patients with papillary thyroid carcinomas, and 57% of patients with Langerhans’ cell histiocytsis.
For patients with BRAF V600E–mutant NSCLC who have progressed on platinum based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may be beneficial.