Elsevier

Lung Cancer

Volume 85, Issue 2, August 2014, Pages 326-330
Lung Cancer

Case report
BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib

https://doi.org/10.1016/j.lungcan.2014.05.009Get rights and content

Highlights

  • Somatic BRAF mutations have been reported in 1–4% of non-small cell lung cancers.

  • Our patient had NSCLC with metastases to her brain with the BRAF (V600E) mutation.

  • Vemurafenib, a BRAF inhibitor approved for use in metastatic melanoma, was used.

  • Vemurafenib was active against intracranial metastases from this patient's NSCLC.

Abstract

Somatic BRAF mutations have been reported in 1–4% of non-small cell lung cancer (NSCLC), primarily in adenocarcinomas with the BRAF (V600E) mutation in about 50% of the cases. The role of BRAF mutation in NSCLC and the treatment for tumors with such mutations is still evolving. Our patient had metastatic NSCLC with metastases to her brain. Due to the BRAF (V600E) mutation in her tumor and her poor functional status, we offered her off-label treatment with vemurafenib, a BRAF inhibitor approved for use in metastatic melanoma. Our patient's visceral disease improved supporting vemurafenib's efficacy in the treatment of metastatic BRAF-mutated NSCLC. The regression of intracranial disease indicated vemurafenib was able to cross the blood–brain barrier and was efficacious in treating brain metastases in this patient with lung cancer.

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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