Metastatic Melanoma Treatment in Special Populations.

ABSTRACT: This review outlines the most up-to-date metastatic melanoma treatment recommendations and relevant risks for patients with solid organ transplants, patients with renal dysfunction, and patients with preexisting autoimmune conditions. These specific treatment populations were excluded from the original clinical trials, which studied immune checkpoint inhibitors and BRAF/MEK inhibitors in the advanced melanoma setting. We have synthesized the current body of literature, mainly case series and retrospective analyses, to reflect the evidence for the treatment of these special patient populations at present.

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

ABSTRACT: Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

The role of CRAF in cancer progression: from molecular mechanisms to precision therapies.

The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer.

Targeted therapeutic strategies for melanoma / 中华医学杂志(英文版)

Melanoma accounts for a small proportion of skin cancers diagnosed each year, but it has a high degree of malignancy and rapid progression, resulting in a short survival period for patients. The incidence of melanoma continues to rise, and now melanoma accounts for 1.7% of cancer diagnoses worldwide and is the fifth most common cancer in the United States. With the development of high-throughput sequencing technologies, the understanding of the pathophysiology of melanoma had also been improved. The most common activating mutations in melanoma cells are BRAF , NRAS , and KIT mutations, which disrupt cell signaling pathways related to tumor proliferation. The progress has led to the emergence of molecularly targeted drugs, which extends the survival of patients with advanced melanoma. A large number of clinical trials have been conducted to confirm that targeted therapy for patients with advanced melanoma can improve progression-free survival and overall survival, and for stage III patients after radical tumor resection targeted therapy can reduce the recurrence of melanoma. Patients who were originally stage III or IV inoperable have the opportunity to achieve tumor radical resection after targeted therapy. This article reviewed the clinical trial data and summarized the clinical benefits and limitations of these therapies.

Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant / 中华内科杂志

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.

Monitoramento do horizonte tecnológico: Medicamentos para tratamento de primeira linha do câncer colorretal metastático / Monitoring the technological horizon: Drugs for first-line treatment of metastatic colorectal cancer

A DOENÇA Os cânceres de cólon e reto, ou câncer colorretal, abrangem os tumores que acometem o intestino grosso (cólon) e o reto, sendo que cerca de 50% localizam-se no reto e sigmoide e 30% no ceco. Estima-se que, no mundo, no ano de 2020, o câncer colorretal (CCR) tenha sido, entre os tipos de neoplasias malignas, o terceiro mais diagnosticado e o segundo mais letal, com 1,9 milhões de casos novos e 935.000 óbitos. No Brasil, o CCR é considerado a segunda neoplasia maligna mais incidente entre homens e mulheres, desconsiderando os tumores de pele não melanoma. Para cada ano do triênio de 2020-2022, são estimados 20.520 casos em homens e 20.470 em mulheres. O risco estimado de novos casos é de 19,63 para cada 100 mil homens e 19,03 para cada 100 mil mulheres. Em 2019, foram registradas aproximadamente 20 mil mortes por câncer colorretal no Brasil. TRATAMENTOS SISTÊMICOS DE PRIMEIRA LINHA DISPONÍVEIS: Na Agência Nacional de Vigilância Sanitária (Anvisa) estão registrados dez medicamentos com indicação em bula para o CCRm, que podem compor diferentes esquemas terapêuticos. São eles: aflibercepte, bevacizumabe, capecitabina, cetuximabe, fluorouracil (5- FU), irinotecano, oxaliplatina, panitumumabe, pembrolizumabe, regorafenibe e trifluridina + tipiracila. As Diretrizes Diagnósticas e Terapêuticas (DDT) do Câncer de Cólon e Reto, publicada em 2014, estão em processo de atualização no momento22,23 . O CCRm irressecável não é alvo da versão atual em curso da diretriz supracitada, sendo seu tratamento apresentado de forma geral. Para os doentes com metástases hepáticas irressecáveis e ausência ou mínima invasão extra-hepática é recomendada a quimioterapia paliativa sistêmica baseada em fluoropirimidina contendo ou não oxaliplatina ou irinotecano, com o objetivo de reduzir o volume tumoral e permitir, assim, a ressecção cirúrgica. De acordo com a DDT, existe evidência de que o uso de esquema terapêutico associado ao cetuximabe ou bevacizumabe promove uma taxa de ressecabilidade maior que controles históricos, entretanto, na época da sua elaboração (busca realizada em 2012) ainda existia incerteza quanto ao significado clínico em termos de benefícios clínicos duradouros ou ganho de sobrevida. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de desenvolvimento para o tratamento de primeira linha de pacientes com CCRm foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 01 de julho de 2021 e atualizado em 15 de outubro de 2021, com filtro para estudo de intervenção, na fase 3 de ensaio clínico e em andamento (situação do recrutamento: ativo, não recrutando ainda, ativo sem recrutamento, inscrição por convite). TECNOLOGIAS EM DESENVOLVIMENTO: A busca inicial no Clinicaltrials.gov retornou 52 registros de ensaios clínicos, dentre os quais onze ensaios foram selecionados a partir dos critérios de elegibilidade definidos. A partir desses ensaios clínicos foram identificados oito medicamentos potenciais em desenvolvimento nas classes: inibidores checkpoint imunológico PD-1, inibidor do receptor do fator de crescimento epidérmico, inibidor multi-tirosina quinase e inibidor da proteína quinase BRAF. CONSIDERAÇÕES FINAIS: Em 2020, o câncer colorretal (CCR) foi o terceiro tipo de câncer mais incidente e a segunda causa mais comum de mortes relacionadas ao câncer no mundo2 . Quando detectado precocemente e sem a presença de metástase em outros órgãos o CCR pode ser tratado e curado. Entretanto, quando há a presença de metástases não ressecáveis, o quadro clínico é de pior prognóstico. Nas últimas duas décadas, o tratamento de câncer colorretal metastático (CCRm) teve avanços com a aprovação de novos medicamentos citotóxicos e de terapia-alvo. As classes de inibidores do receptor do fator de crescimento endotelial vascular (cetuximabe e panitumumabe) e do receptor do fator de crescimento epidérmico (bevacizumabe) representaram um aumento na sobrevida dos pacientes com CCR. Apesar dos ganhos em sobrevida global e sobrevida livre de progressão da doença com as diferentes combinações de esquemas terapêuticos entre quimioterápicos e biológicos, o componente genético característico do CCR tem importante influência sobre o desempenho dos tratamentos entre os pacientes. Este informe de Monitoramento do Horizonte Tecnológico identificou oito tecnologias que se encontram em fase 3 de ensaio clínico para o tratamento de primeira linha do CCRm, inclusive pela via oral para maior comodidade posológica dos pacientes. Entre as classes dos medicamentos estão os inibidores de pontos de verificação imunológico PD-1 (checkpoint), inibidores do receptor do fator de crescimento epidérmico, inibidores multi-tirosina quinase e inibidores da proteína quinase BRAF. Na classe de inibidores checkpoint imunológico PD-1 foram identificadas cinco tecnologias (atezolizumabe, nivolumabe, serplulimabe, sintilimabe e imunoterapia com células autólogas). O atezolizumabe, nivolumabe, serplulimabe e o sintilimabe são anticorpos monoclonais humanizados direcionados ao receptor de morte programada. O nivolumabe é registrado no FDA e EMA para pacientes com CCRm com a presença confirmada de instabilidade de microssatélites elevada (MSI-H ­ microsatellite instability-high) ou deficiência de reparação por incompatibilidade (dMMR ­ mismatch repair deficient). O atezolizumabe também está sendo estudado para os pacientes com CCRm e presença de MSI-H e dMMR. O serplulimabe e sintilimabe iniciaram seus ensaios clínicos de fase 3 recentemente, em 2020 e 2021, respectivamente e não apresentam resultados parciais publicados. Os resultados da fase anterior (fase 2) em outras linhas de tratamento demostraram que o serplulimabe apresentou uma taxa de resposta objetiva em torno de 38% para os tumores com MSI-H e dMMR, incluindo o CCR. A imunoterapia de células autólogas é uma terapia avançada na qual os linfócitos T autólogos são retirados e ativados para ter como alvo o receptor de morte programada-1 e assim retornam ao mesmo paciente para desempenhar melhor seu papel imunológico de modo direcionado ao tumor. Os resultados de fase 3 também não foram publicados até o momento da busca. Após a expiração da patente do medicamento cetuximabe de referência, algumas empresas começaram a desenvolver biossimilares. Atualmente, existem alguns ensaios clínicos em andamento em diversas fases com o cetuximabe biossimilar para a indicação de CCR metastático. Não foram identificados resultados publicados para a fase 3 em andamento para o tratamento de primeira linha, entretanto resultados para a segunda linha de tratamento de CCR metastático indicaram que o CMAB009 (um dos códigos de biossimilares sendo estudado) aumentou a taxa de resposta global em relação ao irinotecano em monoterapia. Outro medicamento, o anlotinibe foi identificado na classe de inibidores multitirosina quinase, que possui ação em vários receptores que implicam no crescimento tumoral, na angiogênese e na progressão metastática do câncer. Os ensaios clínicos de fase 3 ainda estão em andamento com previsão de finalização em 2024. Resultados preliminares de fase 2 com o anlotinibe indicaram melhora em alguns desfechos. Por fim, foi identificado o medicamento encorafenibe, pertencente à classe de inibidor da proteína quinase BRAF, que possui resultados promissores em estudos de fase 2, tendo sido registrado, recentemente, nas agências EMA e FDA para os pacientes com CCR metastático com gene BRAF V600E mutado que apresentaram progressão com tratamentos anteriores. Motivados por esses resultados promissores em linhas posteriores de tratamento o esquema terapêutico com o encorafenibe associado a outros medicamentos vem sendo testado na população de pacientes com CCRm BRAF V600 mutado sem tratamento prévio. Os ensaios clínicos de todos os medicamentos identificados específicos para tratamento de primeira linha estão em andamento com previsão de finalização até 2025. De modo que é preciso continuar seu monitoramento a fim de observar os resultados e os impactos que as tecnologias estudadas possam apresentar no tratamento inicial dos pacientes com CCR metastático.

An extremely rare case of concurrent BRAF V600E mutation driven hairy cell leukemia and melanoma: case report and review of literature

BRAF protein is a serine/threonine kinase with 766 amino acids. Approximately 15% of human cancers harbor BRAF mutations as well as other BRAF anomalies (amplifications, fusions). Somatic mutations mainly occur in the catalytic kinase domain (CR3), and the predominant mutation is p.V600E which is the substitution of glutamic acid (E) for valine (V) as result of a mutation at codon 600 of the kinase domain. To our knowledge, the vast majority of the cancers have non-germline BRAF mutations. Here we describe a case of a 60-year-old female with a history of hairy cell leukemia (HCL) who presented with aphasia and forgetfulness. A follow-up Brain CT scan showed three distinct brain lesions which were found to be diagnostic of melanoma (confirmed by immunohistochemistry) with no evidence of a concurrent brain involvement by a B-cell neoplasm. Molecular studies confirmed the same BRAF p.V600E mutation in both malignancies (hairy cell leukemia and melanoma). Thereafter the patient was started on BRAF inhibitor treatment and is now symptom-free after one year of follow up. Having two concurrent malignancies with a shared BRAF mutation is extremely rare and makes this an excellent example of a genomic marker-driven treatment in two histologically and immunophenotypically distinct tumors.