Sarcoid-like reaction in a BRAF V600E-mutated metastatic melanoma patient during treatment with BRAF/MEK-targeted therapy.

Treatment with combined BRAF and MEK inhibition is widely accepted as a first-line treatment option for patients with advanced BRAF V600E mutant melanoma. It is generally well-tolerated and has limited side-effects. However, we report a case of a sarcoid-like syndrome induced by treatment with dabrafenib/trametinib (D/T) in a patient with stage IV-M1d melanoma. Sarcoid-like syndrome is a known side-effect of immune checkpoint-inhibition therapy but has only rarely been described in BRAF/MEK inhibition. However, recognizing this side-effect is important because of potential misinterpretation as progressive disease and influence on treatment. We describe a 48-year-old female patient who initially presented with solitary brain metastasis and diffuse lung lesions. She was treated with D/T to which she had an initial response in all lesions. One year later, new hilar and mediastinal lymphadenopathies were detected. Imaging was suggestive of the sarcoid-like syndrome. An endoscopic biopsy of the enlarged lymph node showed no melanoma cells. Treatment was continued. Three months later, the patient experienced a drop in hemoglobin, which prompted further investigations into possible occult intestinal metastasis. Video capsule examination revealed a metastatic lesion in the small intestine. A treatment switch to the combination of checkpoint inhibitors nivolumab and ipilimumab successfully treated both lung and small intestine lesions. After the third dose of this combination therapy, she developed an immune-related pneumonitis. Treatment with corticosteroids resolved the pneumonitis and decreased metabolism in the sarcoid-like syndrome. The treatment was not restarted afterward. She remains free of the disease up to today, 2.5 years after diagnosis.

Psoriasis pustulosa asociada a inhibidores BRAF para el tratamiento del melanoma metastásico / Pustular psoriasis with BRAF inhibitors to treat metastatic melanoma

La inhibición dirigida de BRAF con vemurafenib y dabrafenib ha demostrado ser una opción de tratamiento del melanoma metastásico con mutación BRAF-V600E. Sin embargo, los eventos adversos cutáneos son frecuentes con los inhibidores de BRAF, siendo la psoriasis una complicación rara. Presentamos un caso de psoriasis pustulosa palmoplantar en un hombre adulto con melanoma metastásico tratado con ambos inhibidores de BRAF, de forma secuencial. Fue incluso necesario el tratamiento con corticoides sistémicos y apremilast para controlar la sintomatología. Hasta la fecha, sólo se ha descrito en la literatura un caso de psoriasis asociada a dabrafenib. Postulamos que la elevación del factor de necrosis tumoral alfa (TNF-a) y la activación paradójica de la vía de la proteína quinasa activada por mitógenos (MAPK) debido a la inhibición de BRAF pueden ser responsables de este caso. Se necesitan más estudios para dilucidar más a fondo los mecanismos inmunopatógenos detrás de este evento adverso

Targeted BRAF inhibition with vemurafenib and dabrafenib has proven to be a useful tool in the treatment of metastatic melanoma with BRAF-V600E mutation. While cutaneous adverse events are prevalent with BRAF inhibition, psoriasis is a rare complication. We report a case of palmoplantar pustular psoriasis in an adult man with metastatic melanoma treated with both BRAF inhibitors, sequentially. Systemic corticosteroids and apremilast were required to control symptomatology. To date, a case has been described in the literature of psoriasis associated with dabrafenib. We postulate that the elevation of tumor necrosis factor-alpha (TNF-a) and the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway due to BRAF inhibition may be responsible for this case. More studies are needed to further elucidate the immunopathogenic mechanisms behind this adverse event

Ação da proteína amiloide sérica A em melanomas / Activity of serum amyloid A protein in melanomas

Concentrações séricas basais da proteína amiloide sérica A (SAA) estão significativamente aumentadas em pacientes com câncer e alguns autores sugerem uma relação causal. Trabalho anterior do grupo mostrou que a SAA induz a proliferação de duas linhagens de glioblastoma humano e afeta os processos de invasividade in vitro, sustentando um papel pró-tumoral para esta proteína. Com base nesse trabalho, investigamos a abrangência dos efeitos de SAA para outro tipo de célula tumoral e para isso escolhemos um painel de linhagens de melanoma humano e uma linhagem primária obtida a partir de aspirado de linfonodo de paciente com melanoma, por nós isolada. Observamos que apesar da célula precursora de melanomas, isto é, melanócito, não produzir SAA, todas as linhagens de melanoma produziram a proteína e expressaram alguns dos seus receptores. Além disso, quando estas células foram estimuladas com SAA houve uma inibição da proliferação em tempos curtos de exposição (48 horas) e efeitos citotóxicos após um tempo maior (7 dias). A SAA também afetou processos de invasividade e a produção das citocinas IL-6, IL-8 e TNF-α. Aos avaliarmos o efeito da SAA na interação das células de melanoma com células do sistema imune, vimos que a SAA ativou uma resposta imune anti-tumoral aumentando a expressão de moléculas co-estumolatórias, como CD69 e HLA-DR, e sua função citotóxica. Ainda, vimos que a produção de TNF-α, IFN-γ, IL-10, IL-1ß e IL-8 estimuladas por SAA podem contribuir com os efeitos desta. De forma geral estes resultados nos levam a crer que a SAA tem atividade anti-tumoral em melanomas. Finalizando, com base na importância do desenvolvimento da resistência às terapias atuais para o melanoma, observamos que em células resistentes ao PLX4032, um inibidor de BRAF, os efeitos imunomodulatórios induzidos pela SAA estão abolidos, possivelmente identificando um novo componente da resistência

Basal serum concentrations of the protein serum amyloid A are significantly increased in cancer patients and some authors suggest a causal relationship. Previous work of our research group showed that SAA induces proliferation of two cell lines of human glioblastoma and affects invasiveness processes in vitro, supporting a pro-tumor role for this protein. Based on this work, we investigated the extent of SAA effects to another type of tumor cell and we chose a panel of human melanoma cell lines and primary line obtained from a patient with melanoma by lymph node aspirate. Melanoma cells were isolated by us. We observed that while the precursor cells of melanoma, melanocytes, do not produce SAA, all melanoma cell lines expressed the protein and produced some of their receptors. Moreover, when these cells were stimulated with SAA there was an inhibition of proliferation in short exposure times (48 hours) and cytotoxic effects after a longer period (7 days). SAA also affected invasive procedures and the production of the cytokines IL-6, IL-8 and TNF-α. To evaluate the SAA effect in the interaction of melanoma cells with immune system cells, we found that SAA activated an anti-tumor immune response by increasing the expression of co-estimulatory molecules such as CD69 and HLA-DR, and their cytotoxic function. Furthermore, we found that the production of TNF-α, IFN-γ, IL-10, IL-1ß and IL-8 stimulated by SAA can contribute to this effect. In general these results lead us to believe that the SAA has anti-tumor activity in melanomas. Finally, based on the importance of the resistance development to current therapies for melanoma we observed that in cells resistant to PLX4032, a BRAF inhibitor, the immunomodulatory effects induced by SAA are abolished, possibly identifying a new resistance component

Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma.

IMPORTANCE: Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported. OBSERVATIONS: Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy. CONCLUSIONS AND RELEVANCE: We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.