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Case 3.15
Published in Monica Fawzy, Plastic Surgery Vivas for the FRCS(Plast), 2023
You have mentioned requesting the BRAF status for this patient: how does that affect clinical management?V600E is the most common mutation of the BRAF gene and is involved in the MAP kinase cell signalling pathway that keeps the cell in the mitotic phase.Patients with this mutation will respond to targeted therapy with BRAF and MEK inhibitors, which can be used to convert unresectable intransit disease to resectable disease.
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
BRAF gene mutation testing can assist with determining diagnosis, prognosis, and selection of treatment for patients with certain cancers [13]. For example, BRAF mutations assist with differentiating papillary thyroid cancer from other types of thyroid cancer and benign thyroid nodules; sporadic colorectal cancer with microsatellite instability-high (MSI-H) from hereditary nonpolyposis colorectal carcinoma (HNPCC) or Lynch syndrome; and HCL from other B-cell lymphomas with similar clinical and morphologic features. BRAF V600E mutations are associated with poorer outcomes in patients with papillary thyroid carcinoma and colorectal carcinoma. Most importantly, BRAF mutation testing determines treatment for patients with cancer. For patients with melanoma, NSCLC testing for BRAF V600E and BRAF V600K should be done before initiating treatment with a BRAF inhibitor. For patients with CRC, testing for BRAF mutations should be done at time of diagnosis of metastatic disease and can be used to guide treatment decisions. BRAF V600E mutations denotes low response to panitumumab and cetuximab among patients with CRC and wildtype KRAS but may be responsive to the combination of EGFR antibody with BRAF and MEK inhibitors [33].
Malignant Melanoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The frequency of BRAF and NRAS mutations in cutaneous melanoma is 40–50% and 20%, respectively. Approximately 75% of BRAF mutations comprise a single amino acid substitution from valine to glutamic acid at codon 600 (V600E). This leads to a constitutively active BRAF protein which is responsible for the continuous downstream activation of the MAPK pathway with consequent abnormal cell growth and survival. Less frequent mutations include V600K (valine substitution to lysine), seen in approximately 10–30% of cases. The V600E mutation is more frequent in younger patients. In contrast, the V600K mutation is associated with increased age, chronic UV exposure, and cutaneous head and neck melanomas. The presence of a BRAF mutation within melanocytes is not solely responsible for the malignant transformation of a cell, rather it serves to facilitate the oncogenic process in association with other factors.
BRAF testing in a South African cohort of MLH1 deficient endometrial carcinomas: lessons learnt
Published in Southern African Journal of Gynaecological Oncology, 2021
Tumour DNA was extracted from archived tissue blocks. Tissue sections were cut, deparaffinised, washed with ethanol, dried and placed in Protein K buffer solutions. PCR using primers targeting the BRAF V600E mutation site was undertaken according to the manufacturer’s instructions.10 Four mutation assays were performed for V600E/V600Ec, V600D, V600K and V600R. Both V600E and V600Ec mutations were assessed, but the V600E/Ec assay did not allow for differentiation between the two.10 PCR was run on a Rotor-Gene Q 5plex HRM instrument with fluorescence channels for Cycling Green and Cycling Yellow and analysis used Rotor-Gene Q Software version 2.1.10 A cycle threshold value (Ct) between 20.95 and 33 was required in order for DNA of sufficient quantity to be present for assessment according to the manufacturer’s instructions. Ct values between 35 and 45 implied that only a few amplifiable copies were detected and that mutations were identified if these were present on most copies. A Ct value of > 33 suggested that low quantities of mutations were present. Mutations were identified by calculating the difference in Ct values between the test sample and the control sample, which was provided with the purchased kit: ΔCt = (Ct value of mutation)—(Ct value of control tissue).
Developments in therapy for brain metastases in melanoma patients
Published in Expert Opinion on Pharmacotherapy, 2021
Justin G. Wilkes, Ayushi Patel, Erin McClure, Yolanda Pina, Jonathan S. Zager
A multicenter phase 2 trial published by Long et al., in 2012, described the treatment of BRAF mutant MBM with the BRAF inhibitor dabrafenib (150 mg, twice daily, until progression, death, or unacceptable AE). Patients were stratified based on prior treatment and BRAF mutation subtype. Of the 172 patients enrolled, 83 patients had treatment naive MBM (cohort A), and 89 patients had received previous treatment (cohort B). In total, 139 patients had V600E mutations and 33 patients had V600K mutations. This study demonstrated similar intracranial response regardless of previous treatment, but dramatically poorer intracranial response among patients with V600K mutations when compared to V600E mutations. In patients with V600E mutations, overall intracranial response rate was 39% in cohort A and 31% in cohort B. Only two patients had a complete response; however, 42% (cohort A) and 58% (cohort B) had stable disease, resulting in 81% and 89% intracranial disease control, respectively. Median PFS was approximately 16 weeks in both cohorts A and B, while median OS was 33 weeks in cohort A and 31 weeks in cohort B. Patients with V600K mutations had lower overall intracranial response (7% [1/15] in cohort A; 22% [4/18] in cohort B). Treatment-related, grade 3 or higher, AEs occurred in 22% (38/172) of patients. The most frequent serious AE included pyrexia, intracranial hemorrhage, and squamous cell carcinoma [58].
Safety and efficacy evaluation of encorafenib plus binimetinib for the treatment of advanced BRAF-mutant melanoma patients
Published in Expert Opinion on Drug Safety, 2020
Almost half of cutaneous melanomas harbor hotspot mutations in the B-Raf proto-oncogene kinase (BRAF), which constitutively activate the mitogen-activated extracellular signal regulated kinase (MEK). The RAS/RAF/MEK/ERK (i.e. the mitogen-activated protein kinase [MAPK] pathway) has a major role in many cellular processes, and is involved in tumor cell proliferation, survival, differentiation [1] and an immunosuppressive modulation of the tumor microenvironment [2]. BRAF mutant melanomas most frequently show a BRAF V600 mutation (74–90%), the most common being V600E mutation (accounting for nearly 90% of the identified mutations), while others (e.g. V600K, V600D/R) account for the remaining 10% observed mutations. Approximately 15% of melanomas harbor loss or mutations in the NF1 gene, playing an inhibitory role on the MAPK signaling; the remaining 15%-30% harbor an activating mutation of neuroblastoma RAS (NRAS), which is always exclusive to BRAF mutation [3].