Case reportBRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib
Introduction
Targeted therapy in treatment of molecularly selected populations with non-small-cell lung cancer (NSCLC) is remarkably effective as measured by response rates, progression-free survival (PFS), and quality of life [1], [2], [3]. EGFR-mutant and ALK-rearranged lung adenocarcinoma patients show improved PFS with targeted therapies compared to cytotoxic chemotherapy. As new oncogene targets in NSCLC are identified, more novel targeted therapies are leading to patient benefit.
One of the newer driver mutations discovered in NSCLC is in the BRAF gene, which encodes for a serine/threonine kinase downstream from KRAS in the mitogen-activated protein kinase signaling cascade [4]. BRAF mutations recently have been shown to be important in melanoma, with a glutamine for a valine at residue 600 (V600E) being the most common variant [5]. More recently, lung adenocarcinomas were genotyped and found to have BRAF missense mutations in 3–4.9% of patient cases [6], [7], [8]. These mutations seem to be mutually exclusive of KRAS and EGFR mutations. Initial reports suggested that up to 50% of the BRAF mutations were the V600E alteration and were observed in patients who never-smoked [7]. This latter finding was not replicated in a subsequent study where increased prevalence of BRAF mutations in prior smokers, both V600E and non-V600E, was described [9]. In 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18). Fourteen patients within the BRAF cohort were eligible for response assessment after platinum-based chemotherapy. V600E mutation patients (n = 7) had lower response rates and shorter median PFS (4.1 vs 8.9 months) than non-V600E mutation patients [9]. Median PFS of patients with advanced NSCLC treated with platinum-based chemotherapy was shorter (5.2 vs 6.7 months) for BRAF-mutant versus wild-type patients, respectively. This is consistent with a previous report of less favorable outcomes among patients with BRAF V600E mutations compared to BRAF-wild type [7]. Therefore, interim results of a phase II trial investigating use of the BRAF inhibitor, dabrafenib, for treatment of BRAF V600E-mutant metastatic NSCLC were timely. Treatment of patients with dabrafenib demonstrated early anti-tumor activity with overall response rates of 50% and a median progression free survival of 5.1 months; however, patients with brain metastases were excluded [10]. Herein we report off-label use of another BRAF inhibitor, vemurafenib, for a patient with BRAF V600E-mutant NSCLC with metastases to the brain.
Section snippets
Methods
TTF-1 immunohistochemistry was performed using the BenchMarch System (Ventana Medical Systems, Inc., Tucson, AZ) using a TTF-1 clone (Dako North America, Inc., Carpenteria, CA; 8g7g3/1; lot#10078105 exp 05/2015) at a 1:100 dilution.
Genomic profiling was performed in a CLIA-certified, CAP-accredited laboratory (Foundation Medicine, Inc., Cambridge, MA) using validated methods [11].
Case
A 51-year-old never-smoker woman with a history of locally advanced, inflammatory, invasive ductal carcinoma of right breast in 1999 presented to her oncologist 13 years later in 2013 complaining of shortness of breath and cough. Prior treatment for her inflammatory, ER/PR negative, HER2/neu positive breast cancer included preoperative chemotherapy and trastuzumab followed by a right mastectomy and then right chest wall and regional lymphatic irradiation.
At presentation in 2013, CT scan
Discussion
The BRAF inhibitors, vemurafenib and dabrafenib, have shown potent selective activity against V600 BRAF mutant advanced melanoma in randomized phase 3 trials and have garnered FDA approval for this indication. Whether these inhibitors will provide the same benefit in NSCLC with the BRAF V600E mutation is currently being evaluated. While BRAF-mutated melanoma harbors a V600E amino acid substitution in more than 80% of cases, in NSCLC, the V600E mutation is only seen in half of BRAF positive
Conflicts of interest
SDR, JAO, and KK have no conflicts of interest to disclose. CLC serves as a consultant and is a member of the speaker's bureau for Genetech.
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2022, Lung CancerCitation Excerpt :Vemurafenib has shown intracranial activity in BRAF V600E-positive lung cancer, even in the setting of meningeal carcinomatosis in a few case reports. Prospective studies are needed to validate these findings [48,49]. The described safety profile of vemurafenib was similar to previous observations in patients with melanoma, with acneiform dermatitis (35–65%), fatigue (30–60%, anorexia (30–45%), arthralgia (30%) and nausea and diarrhoea (35–40%) the most common adverse events (AE).
Cancer driver gene and non-coding RNA alterations as biomarkers of brain metastasis in lung cancer: A review of the literature
2021, Biomedicine and PharmacotherapyCitation Excerpt :Dagogo-Jack and colleagues (2019) have shown that NSCLC patients harboring class II or III BRAF mutations are more likely to have BM than those with class I mutations [139]. Treatment of a never-smoker woman with BRAF V600E LCBM with vemurafenib, a BRAF inhibitor, was efficacious in treating BM [140]. Thus, BRAF mutations might also be considered as a predictive marker in patients with LCBM.
Management of Brain Metastasis in Non-Small Cell Lung Cancer (NSCLC)
2021, Encyclopedia of Respiratory Medicine, Second EditionDiagnostic value of <sup>18</sup>F-fluordesoxyglucose positron emission tomography for patients with brain metastasis from unknown primary site
2018, European Journal of CancerCitation Excerpt :The first four criteria are used to determine the graded prognostic assessment (GPA) score [3,4]. Targeted therapies and immunotherapy may improve overall survival in subgroups of patients with BM selected for molecular characteristics of the primary tumours [5–8]. Therefore, identifying the primary lesion and further extracranial metastases are a major clinical need in patients with BM-CUPS to define prognosis and treatment [4,9].