Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma

Abstract

BACKGROUND: Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations. METHODS: Retrospective clinical and pathologic data were collected for patients with advanced melanoma with BRAF or NRAS mutations. The demographics, tumor characteristics, and clinical outcomes of the patients were compared to identify significant mutation-specific associations. RESULTS: Among 302 patients with activating BRAF mutations, 76% had BRAF V600E and 24% had V600K substitutions. Compared with V600E, the presence of a V600K mutation was significantly associated with older age (median, 60.0 years vs 44.7 years; P <.001), male sex (80% vs 59%; P 5.001), head=neck primary tumor location (30% vs 15%; P 5.0026), shorter interval to stage IV disease (0.98 years vs 2.8 years; P 5.015), and a shorter overall survival from the time of diagnosis of stage IV disease (median, 2.44 years vs 1.25 years; hazards ratio, 1.68 [P 5.014]). Comparison of 136 patients with NRAS exon 1 (18%) and exon 2 (82%) mutations found an association with primary tumor histology (P 5.0096) only. CONCLUSIONS: The presence of different substitutions at BRAF V600 correlates with patient demographics, tumor characteristics, and prognosis. These findings demonstrate the presence of mutation-specific clinical differences between different BRAF genotypes in patients with melanoma, and support the incorporation of this information in patient evaluation and clinical trial design. Cancer 2013;119:3821-9.

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

“…The data about BRAF V600 mutation which was accumulated following the discovery of this mutation in cancer by Davies et al (3) revealed that at least half of malignant melanomas (50 to 70%) may exhibit mutations in the BRAF V600 gene (1,2,7,10, 13-16) The BRAF V600E mutation constitutes more than 80% of BRAF mutations, and other BRAF mutations include V600K (1798 1799 GT > AA; 5% to 6%; valine to lysine), V600R (1798 1799 GT > AG; 1%; valine to arginine), V600E2 (1799 1800 AG > AA; 0.7%) and V600D (1799 1800 AG > AT) (1,4,6). Although it is said that the BRAF V600K mutation is rare, a few recent papers report higher rates of this mutation (20 to 44%) in some populations (6)(7)(8)15).…”

“…Other BRAF mutations include V600K (1798 1799 GT > AA; 5% to 6%; valine to lysine), V600R (1798 1799 GT > AG; 1%; valine to arginine), V600E2 (1799 1800 AG > AA; 0.7%) and V600D (1799 1800 AG > AT). Other rare mutations affecting various codons of the BRAF gene have also been described (1,4,6). Although the BRAF V600K mutation is said to be rare, a few recent papers have reported an occurrence rate of this mutation as high as 20% in some populations (6)(7)(8).…”

“…Melanoma has a poor prognosis (1,2). Davies et al introduced the idea of molecular alterations as an alternative to ultraviolet (UV) signature, particularly with BRAF (v-raf murine sarcoma viral oncogene B) V600 mutations (3), marking a milestone in the treatment of previously-incurable melanoma patients.…”

“…However, one of the BRAF inhibitors has been used for both BRAF V600E and BRAF V600K, with reported overall V600K response lower than that of V600E (11,12). Shorter survival and shorter intervals between initial diagnosis and metastasis have been reported for V600K as compared to V600E as well (1,6). Some studies investigating the differences between the V600K and V600E mutations reveal that age, gender and primary tumour site may differ according to the mutation subtype and changing amino acids (1,6).…”

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…Melanoma is relatively more common in Caucasian populations and hence analyses of characteristics of patients with BRAF mutations in detail have been restricted to these patients 5, 6. Studies involving China, Korea and Japan revealed that there may be some differences in incidence of melanoma compared with the findings in Caucasians, including frequency and an age association with BRAF mutation 7, 8, 9, 10.…”