Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review.

BACKGROUND: The incidence of brain metastases (BM) in melanoma patients is common and associated with poor prognosis. MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients; however, patients with BM are under-represented or excluded from the majority of clinical trials and the impact of new drugs on their survival is less clear. With the present systematic review, we aimed to analyze outcomes of patients with melanoma BM treated with the new drugs, both in the setting of phase I-II-III clinical trials and in the "real world". METHODS: An electronic search was performed to identify studies reporting survival outcomes of patients with melanoma BM treated with MAP-kinase inhibitors and/or immunologic checkpoint blockade antibodies, regardless of study design. RESULTS: Twenty-two studies were included for a total of 2153 patients. Median OS was 7.9 months in phase I-II-III trials and 7.7 months in "real world" studies. In clinical trials, median OS was 7.0 months for patients treated with immunotherapy and 7.9 months for patients treated with BRAF inhibitors. In "real world" studies, median OS was 4.3 months and 7.7 months for patients treated with immunotherapy and BRAF inhibitors, respectively. Evidence of clinical activity exists for both immunotherapy and MAP-kinase inhibitors. CONCLUSIONS: MAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM. These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma.

BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies.

BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. More recently, the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown improved progression-free survival, compared to dabrafenib monotherapy, in a Phase II study and has received approval by the US Food and Drug Administration. However, even when treated with the combination, most patients develop mechanisms of acquired resistance, and some of them do not achieve tumor regression at all, because of intrinsic resistance to therapy. Along with the development of BRAF inhibitors, immunotherapy made an important step forward: ipilimumab, an anti-CTLA-4 monoclonal antibody, was approved for the treatment of metastatic melanoma; anti-PD-1 agents achieved promising results in Phase I/II trials, and data from Phase III studies will be ready soon. The availability of such drugs, which are effective regardless of BRAF status, has made the therapeutic approach more complex, as first-line treatment with BRAF inhibitors may not be the best choice for all BRAF-mutated patients. The aim of this paper is to review the systemic therapeutic options available today for patients affected by BRAF V600-mutated metastatic melanoma, as well as to summarize the mechanisms of resistance to BRAF inhibitors and discuss the possible strategies to overcome them. Moreover, since the molecular analysis of tumor specimens is now a pivotal and decisional factor in the treatment strategy of metastatic melanoma patients, the advances in the molecular detection techniques for the BRAF V600 mutation will be reported.

A novel multiplex pyrosequencing assay for genotyping functionally relevant CTLA-4 polymorphisms: potential applications in autoimmunity and cancer.

CTLA-4 expression/function can be affected by single nucleotide polymorphisms (SNPs) of CTLA-4 gene, which have been widely associated with susceptibility or progression to autoimmune diseases and cancer development. In this study, we analyzed six CTLA-4 SNPs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, CT60G>A) in 197 DNA samples from 43 B-lymphoblastoid cell lines (B-LCLs), 40 systemic sclerosis (SSc) patients, 14 pre-analyzed melanoma patients and 100 Italian healthy subjects. Genotyping of -1661A>G, -1577G>A, -658C>T and CT60G>A was performed by newly developed multiplex pyrosequencing (PSQ) assays, whereas -319C>T and +49A>G by T-ARMS PCR and direct sequencing. Genotype/allele frequency were analyzed using χ(2) or Fisher exact test. Our study provides the first multiplex PSQ method that allows simultaneous genotyping of two CTLA-4 SNP pairs (i.e. -1661A>G/-658C>T and -1577G>A/CT60G>A) by two multiplex PSQ reactions. Herein, we show the CTLA-4 genotype distribution in the B-LCLs providing the first and best characterized cell line panel typed for functionally relevant CTLA-4 SNPs. We also report the significant association of the -1661A/G genotype, -1661 & -319 AC-GT diplotype and -319 & CT60 TG haplotype with susceptibility to SSc without Hashimoto's thyroiditis occurrence. Furthermore, we confirmed previous genotyping data referred to melanoma patients and provided new genotyping data for Italian healthy subjects.