Neoplastic leptomeningitis presenting in a melanoma patient treated with dabrafenib (a V600EBRAF inhibitor): a case report

Abstract

IntroductionLeptomeningeal metastases are occurring at higher frequency in cancer patients. The prognosis of leptomeningeal metastases is poor and standard treatment, which includes radiotherapy and chemotherapy, is mostly ineffective. Melanoma represents one of the tumors with the highest incidence of leptomeningeal metastases. For such a disease, the BRAF inhibitors have recently been demonstrated to be effective on melanoma brain metastases harboring the V600EBRAF mutation.Case presentationWe report a case of a 39-year-old Italian woman with advanced melanoma with brain, lung and peritoneum metastases harboring the V600EBRAF mutation. In August 2010 she was enrolled into the BRIM3 trial and after the randomization process she received dacarbazine. After two cycles, there was evidence of disease progression in her peritoneum and lung. For this reason, she was enrolled into another clinical trial with the GSK2118436 BRAF inhibitor, dabrafenib, as a second line of therapy. She had a partial response that was maintained until 13 weeks of treatment. In January 2011 she developed symptoms typical for brain metastases and received a diagnosis of leptomeningeal involvement of melanoma cells after an examination of her cerebral spinal fluid; magnetic resonance imaging was negative for meningitis or brain metastases. Analysis of her cerebral spinal fluid sample confirmed that the melanoma cells still carried the V600EBRAF mutation. After a few days, our patient went into a coma and died.ConclusionStarting with a clinical case, we discuss the pathogenesis of leptomeningeal metastases and whether the leptomeninges may represent a sanctuary where melanoma cells may generate resistance and/or BRAF inhibitors cannot reach an adequate concentration for significant activity. We assess whether treatment with BRAF inhibitors in melanoma patients should be interrupted as soon as disease progression appears or continued beyond progression, through the administration of additional compounds.

Incidence and characteristics of melanoma brain metastases developing during treatment with vemurafenib

“…To our knowledge, no study has been published about the prognosis of melanoma patients with brain metastases since the introduction of targeted therapies and BRAF mutational status analysis. Four published clinical cases reported the clinical course of BRAF inhibitor-treated patients who developed brain metastases: two cases with fatal outcome two weeks after diagnosis of brain metastases under vemurafenib [9,10], one death a few days after diagnosis of carcinomatous meningitis under dabrafenib while the BRAF V600E mutation was still present in the cerebrospinal fluid [11] and one well-controlled case with leptomeningeal metastases with an 18-month followup after vemurafenib continuation and addition of wholebrain radiotherapy [12].…”

“…Under vemurafenib, secondary resistance is most often associated with a reactivation of the MAPK pathway, mediated by specific BRAF aberrations [13,14], switches between RAF isoforms [15], neomutations in NRAS and MEK [16] and the increased expression of a ''partner'' kinase, COT [5,17]. In rarer cases, BRAF-independent signaling pathways such as insulin growth factor 1 receptor (IGF1R)-phosphatidylinositol-3 kinase (PI3K) [18,19] or platelet-derived growth factor b (PDGFRb) pathways are activated [11,20]. Brain-specific phenomena have also been shown from tumor samples of melanoma patients with overactivation of the AKT survival pathway and loss of PTEN expression, induced by the brain environment, contributing to melanoma cell survival in the brain parenchyma [21].…”

Therapy of leptomeningeal metastasis in solid tumors

“…Shortterm stabilization in melanoma patients with nitrosoureas [21] or a response to the BRAF inhibitors vemurafenib [54] or dabrafenib [55] have been described. However, vemurafenib and dabrafenib may hardly penetrate the blood-CSF barrier.…”

Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

“…In a subsequent phase II study of patients with metastatic melanoma treated with both rucaparib and temozolomide, the combination was safe and was associated with an improvement in progression-free survival when compared to historical controls (13). Clinical trials in patients with metastatic breast and advanced ovarian cancer are currently evaluating rucaparib, both as a single agent and in combination with platinum-based chemotherapy (14-19). In anticipation of developing a clinical trial for patients with GBM, we performed a pre-clinical evaluation of rucaparib in combination with TMZ in GBM xenograft models.…”