Mutation frequency in <i>BRAF</i> and <i>NRAS</i> genes among primary tumors and different types of metastasis from melanoma patients.

Colombino, Maria; Capone, Mariaelena; Maio, M.; Giorgi, Vincenzo De; Cossu, Alessia Maria; Lissia, Amelia; Rubino, Corrado; Massidda, B.; Staibano, S.; Nappi, Oscar; Botti, Gerardo; Caracò, Corrado; Mozzillo, N; Manca, Antonella; Sini, Maria Cristina; Ascierto, P.A.; Palmieri, Giuseppe

doi:10.1200/jco.2011.29.15_suppl.8574

Cited by 5 publications

(6 citation statements)

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“…Although both seem to act on melanoma brain metastases [ 4 , 7 ], the BRAFi (vemurafenib, GSK2118436, dabrafenib) seem to be particularly effective on melanoma brain metastases harboring the V600E BRAF mutation - which represents the most prevalent oncogenic variant in such a gene [ 7 - 9 ]. Moreover, a high concordance for V600E BRAF mutation frequency between primary melanomas and correspondent brain metastases from the same patients has been recently reported by our group [ 10 ]. To date, two important studies are focusing on the treatment of melanoma brain metastases with BRAFi [ 11 , 12 ].…”

Section: Introductionsupporting

confidence: 75%

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

et al. 2012

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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.

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Section: Introductionsupporting

confidence: 75%

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

et al. 2012

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“…Most vemurafenib clinical studies, however, excluded patients with untreated CNS disease, and relatively little is known about the effectiveness of this agent in patients with melanoma brain metastases. If the premise is that melanoma cells do not change their BRAF mutation status on forming brain metastases, 9,10 then BRAFi could represent an important therapeutic approach for these patients. A clinical trial evaluating the efficacy and safety of vemurafenib in patients with metastatic melanoma and treated or untreated brain lesions is currently under way (clinicaltrials.gov Identifier: NTC01378975).…”

Section: Discussionmentioning

confidence: 99%

Melanoma Brain Metastases and Vemurafenib: Need for Further Investigation

Rochet

Dronca

Kottschade

et al. 2012

Mayo Clinic Proceedings

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Brain metastases are a major cause of morbidity and mortality in patients with advanced melanoma. With the development of targeted agents for the treatment of metastatic melanoma, a great deal of interest has focused on whether selective BRAF inhibitors may play a role in the treatment of brain metastases in lieu of or in addition to surgery and/or radiation therapy. However, relatively little is known about the intracranial effectiveness of vemurafenib, the only US Food and Drug Administration-approved selective BRAF V600E inhibitor, because patients with brain metastases have historically been excluded from vemurafenib clinical trials. We describe 3 patients with BRAF V600E mutation metastatic melanoma in whom treatment with vemurafenib resulted in prompt extracranial disease response but progression of metastatic disease in the brain. Further, we discuss possible mechanisms responsible for the suboptimal central nervous system response observed in these patients and alternative therapies for patients with melanoma metastatic to the brain.

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“…An estimated 40-50% of melanomas harbour activating mutations in the BRAF oncogene, most commonly the substitution of valine to glutamic acid (V600E) or lysine (V600 K) at codon 600. In addition, mutations in NRAS have been identified in approximately 15-20% of melanomas [26,27]. The RAS and BRAF proteins regulate cellular proliferation and survival, mainly through activation of the mitogen-activated protein kinase (MAPK) pathway [28].…”

Section: Targeted Therapymentioning

confidence: 99%

Gaining momentum: New options and opportunities for the treatment of advanced melanoma

Michielin

Höeller

2015

Cancer Treatment Reviews

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Mutation frequency in BRAF and NRAS genes among primary tumors and different types of metastasis from melanoma patients.

Cited by 5 publications

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

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

Melanoma Brain Metastases and Vemurafenib: Need for Further Investigation

Gaining momentum: New options and opportunities for the treatment of advanced melanoma

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