RESUMO
PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/secundário , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus. OBJECTIVES: To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas. MATERIALS AND METHODS: Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. RESULTS: The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma. CONCLUSIONS: To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus.
Assuntos
Genes Neoplásicos/genética , Melanoma/genética , Mutação/genética , Neoplasias Cutâneas/genética , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Dados de Sequência Molecular , Nevo Pigmentado/genética , Proteínas Nucleares/genética , Fosfoproteínas Fosfatases/genética , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas rac1 de Ligação ao GTP/genéticaRESUMO
BACKGROUND: The identification of BRAF mutations in melanoma led to the development and implementation of new and effective therapies. Few clinical and histological features have been associated with this mutational status. OBJECTIVES: The main objective of this study was to investigate clinical, histopathological and dermoscopic characteristics of primary melanomas according to BRAF or NRAS mutational status. METHODS: An observational retrospective study including melanoma dermoscopy images assessed for somatic mutations in BRAF and NRAS. RESULTS: Seventy-two patients were included, 30 women (42%) and 42 men (58%), mean age was 59 ± 15.51 years. BRAF-mutated melanomas were more frequently located on the trunk (n = 18, 64% for BRAF-mutated vs. n = 11, 29% for wild-type melanomas, P = 0.013). Histological ulceration was associated with the presence of BRAF mutations [odds ratio (OR) 3.141; 95% confidence interval (CI) 1.289-7.655; P = 0.002]. The Breslow index tended to be thicker in BRAF-mutated compared with wild-type (P = 0.086). BRAF mutations were present in 28 (39%) patients and only four cases were positive for NRAS mutations (6%), BRAF and NRAS mutations being mutually exclusive. The presence of dermoscopic peppering was associated with MAPK mutations (BRAF and NRAS) (OR 1.68; 95% CI 1.089-2.581; P = 0.015). Dermoscopic ulceration was also associated with BRAF mutations excluding acral and facial melanomas (OR 2.64; 95% CI 1.032-6.754). CONCLUSIONS: This study showed a correlation between BRAF and NRAS status and dermoscopic findings of 'peppering' as an expression of regression and melanophages in the dermis, suggesting a morphological consequence of immune behaviour in BRAF-mutated melanomas.