Circulating MicroRNAs: functional biomarkers for melanoma prognosis and treatment.
Abstract MicroRNAs (miRNAs) hold significant promise as circulating cancer biomarkers and unlike many other molecular markers, they can provide valuable insights that extend beyond tumour biology. The expression of circulating miRNAs may parallel the cellular composition and dynamic activity within the tumour microenvironment and reveal systemic immune responses. The functional complexity of miRNAs-where a single miRNA can regulate multiple messenger RNAs (mRNAs) to fine tune fundamental processes, and a single mRNA can be targeted by multiple miRNAs-underscores their broad significance and impact. However, this complexity poses significant challenges for translating miRNA research into clinical practice. In melanoma, specific miRNA [...]
Prognostic and predictive value of gastric acid suppressants in the EORTC 1325/KEYNOTE-054 randomized phase III trial of pembrolizumab vs placebo in resected stage III melanoma.
Abstract Background The gut microbiome plays a pivotal role in regulating immunity. Gastric acid suppressants (GAS) are known to alter the gut microbiome and might therefore modify response to immunotherapy in cancer patients. We estimated associations of GAS with recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in the EORTC 1325/KEYNOTE-054 trial. Methods Patients with resected stage III melanoma were randomized to receive 200 mg of pembrolizumab or placebo. Pembrolizumab prolonged RFS and DMFS (reported elsewhere). We used Cox models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between GAS at baseline, and RFS and [...]
ASO Author Reflections: A Cost-Effectiveness Decision About Groin Lymphadenectomy: Reflections from the EAGLE FM Randomized Trial.
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Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Long-term follow-up, crossover, and rechallenge with pembrolizumab in the phase III KEYNOTE-716 study.
Abstract Background: Adjuvant pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB/IIC melanoma in KEYNOTE-716. Results of a post hoc 4-year analysis are reported, including progression/recurrence-free survival 2 (PRFS2). Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks (part 1). RFS was the primary end point; DMFS was secondary. Patients with recurrence following placebo or 17 cycles of pembrolizumab could cross over to or be rechallenged with pembrolizumab (part 2). Results: Median follow-up (n = 976) was 52.8 months (range, 39.4-64.8). RFS (HR, 0.62 [95 % CI, 0.50-0.78]) [...]
Reduction in surgical interventions in melanoma.
Abstract Melanoma surgery has evolved from elective lymph node dissection (ELND) to sentinel lymph node biopsy (SLNB) and wide local excision (WLE) margins have come down from 5 cm to nowadays 1 - 2 cm. Recent studies have illustrated the low frequency of residual tumour cells in WLE specimen, particularly for pT2 or lower tumours, where 97 % of patients cannot benefit from WLE. Moreover, a cohort of completely excised primary melanomas did not seem to have inferior clinical outcomes to those who did undergo WLE. Biomarkers, such as clinicopathological gene expression profilers (CP-GEP), can stratify high- and low-risk [...]
Transforming Clinical Trials in Skin Cancer Research: Exploring the Potential of Flexible and Innovative Designs.
Abstract Over the past 2 decades, innovations in trial design have significantly advanced the field of clinical research. Methodological developments, such as adaptive designs, basket trials, umbrella trials, and platform trials, along with technological advancements such as virtual studies have proven effective in tackling complex research questions and managing resource constraints. These approaches enable prospectively planned modifications to trial designs and facilitate addressing multiple research questions within a single infrastructure, with technological advancements such as virtual studies enhancing accessibility, efficiency, and patient engagement. These designs can also integrate biomarker information or risk-prediction scores to enhance the efficacy of future [...]
Characterizing Chronic Cutaneous Immune-Related Adverse Events Following Immune Checkpoint Inhibitors.
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Association of inherited genetic variants with multiple primary melanoma.
Abstract Background: Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear. Methods: We investigated the associations of 69 single nucleotide polymorphisms (SNPs) in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma (SPM) in the international, population-based Genes, Environment, and Melanoma (GEM) study. Per-minor allele odds ratios (ORs) and 95% confidence intervals (CIs) for individuals with MPM 'cases' (n=1,205) relative to SPM 'controls' (n=2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis [...]
Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K mutated melanoma (EBIN): an international randomized phase II study.
Abstract Background: Current first-line treatment for patients with metastatic melanoma with BRAFV600E or BRAFV600K mutations includes immunotherapy with immune checkpoint inhibitors and targeted therapy; however, the optimal sequencing of these treatments is unclear. We aimed to investigate the use of a targeted-therapy induction regimen before treatment with immune checkpoint inhibitors. Methods: This open-label, randomised, controlled, phase 2 trial (EBIN) was conducted at 37 centres in eight European countries. Eligible patients were 18 years or older and had previously untreated, unresectable, stage III or IV melanoma with BRAFV600E or BRAFV600K mutations and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly [...]