BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases

Abstract

OBJECTIVE Recent advancements in molecular biology have identified the BRAF mutation as a common mutation in melanoma. The wide use of BRAF kinase inhibitor ( BRAFi) in patients with metastatic melanoma has been established. The objective of this study was to examine the impact of BRAF mutation status and use of BRAFi in conjunction with stereotactic radiosurgery (SRS). METHODS This was a single-center retrospective study. Patient's charts and electronic records were reviewed for date of diagnosis of primary malignancy, BRAF mutation status, chemotherapies used, date of the diagnosis of CNS metastases, date of SRS, survival, local tumor control after SRS, and adverse events. Patients were divided into 3 groups: Group A, those with mutant BRAF without BRAFi treatment (13 patients); Group B, those with mutant BRAF with BRAFi treatment (17 patients); and Group C, those with wild-type BRAF (35 patients). Within a cohort of 65 patients with the known BRAF mutation status and treated with SRS between 2010 and 2014, 436 individual brain metastases (BMs) were identified. Kaplan-Meier methodology was then used to compare survival based on each binary parameter. RESULTS Median survival times after the diagnosis of melanoma BM and after SRS were favorable in patients with a BRAF mutation and treated with SRS in conjunction with BRAFi (Group B) compared with the patients with wild-type BRAF (Group C, 23 vs 8 months and 13 vs 5 months, respectively; p < 0.01, log-rank test). SRS provided a local tumor control rate of 89.4% in the entire cohort of patients. Furthermore, the local control rate was improved in the patients treated with SRS in conjunction with BRAFi (Group B) compared with patients with wild-type (Group C) or with BRAF mutation but no BRAFi (Group A) as an adjunct treatment for BMs. CONCLUSIONS BRAF mutation status appears to play an important role as a potent prognostic factor in patients harboring melanoma BM. BRAFi in conjunction with SRS may benefit this group of patients in terms of BM survival and SRS with an acceptable safety profile.

BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

“…Although initial studies of BRAFi alone in the setting of BM42,45 reported minimal intracranial toxicity, including hemorrhage, Lee et al67 noted the development of ICH in a patient treated with Cyberknife radiosurgery in combination with DAB and the MEKi TRA. Although Xu et al59 did note an increased rate of ICH in BRAF-mutated patients treated with BRAFi and radiation versus BRAF-mutated patients treated with radiotherapy alone (29.4% vs 8.6%), the results were not significant ( P =0.487). In contrast, Ly et al57 reported a significantly increased risk of hemorrhage in BRAF-mutated patients treated with BRAFi and radiation.…”

“…Gaudy-Marqueste et al55 and Patel et al60 reported 0% radiographic or symptomatic RN, while Narayana et al54 and Ahmed et al56 both reported very low rates of RN, 8.3% and 4.2%, respectively. Xu et al59 found no difference in the development of RN between BRAF-mutated patients treated with BRAFi and GKRS versus BRAF-mutated patients treated with GKRS alone (17.6% vs 8.6%, P =0.721). In contrast, Patel et al58 found a statistically significant difference in symptomatic RN between SRS and BRAFi and SRS alone cohorts (28.2% vs 11.1%, P <0.001).…”

“…At 1 year, the combined therapy cohort had a trend toward improved OS (64.3% vs 40.4%, P =0.205), LC (96.7% vs 90.4%, P =0.423), and distal intracranial control (36.1% vs 34.9%, P =0.450), though the results were not significant. Finally, Xu et al59 reported their institutional results on 65 patients with MBM treated with GKRS. The patients were stratified into 3 groups: Group A – BRAF-mutated without BRAFi (n=13), Group B – BRAF-mutated with BRAFi (n=17), and Group C – wild-type BRAF (n=35).…”

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…107 The multicenter, open-label, phase II BREAK-MB trial enrolled 172 patients with asymptomatic, untreated (cohort A) or progressive (cohort B) brain metastases in melanoma patients with V600E or V600K mutation for treatment with dabrafenib (class IIb). 108 Over 80% of patients in both cohorts with V600E mutations had intracranial disease control (CR+PR+SD), median PFS was longer than 16 weeks in both cohorts, and OS exceeded 31 weeks.The combination of BRAF inhibitors and SRS could improve survival, 109,110 but an increase of toxicities Table 3 Recommendations regarding treatment of newly diagnosed brain metastases…”

Radiation Therapy for Melanoma

“…Due to the minimum skin dose from SRS, several studies that evaluated BRAF inhibitor with SRS for patients with brain metastases reported favorable outcome (137)(138)(139). Studies that directly compared outcomes of patients treated with SRS alone and SRS with BRAF inhibitor suggest that there indeed may be a survival benefit of combination therapy (140)(141)(142). However, it seems that because of the radiosensitization effect, increased toxicity other than skin toxicity may also be induced, such as radionecrosis (141).…”