A scoping review of factors influencing the implementation of liquid biopsy for cancer care.
Abstract Background: Liquid biopsy (LB) offers a promising, minimally invasive alternative to traditional tissue biopsies in cancer care, enabling real-time monitoring and personalized treatment. Despite its potential, the routine implementation of LB in clinical practice faces significant challenges. This scoping review examines the barriers and facilitators influencing the implementation of liquid biopsies into standard cancer care. Methods: Four academic databases (PubMed, Scopus, Embase, and Web of Science) were systematically searched without language restrictions. We included peer-reviewed articles that were published between January 2019 and March 2024 that focused on the implementation of LB in cancer care or described barriers and facilitators [...]
Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance.
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Size matters: integrating tumour volume and immune activation signatures predicts immunotherapy response.
Abstract Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, providing significant benefit to patients across various tumour types, including melanoma. However, around 40% of melanoma patients do not benefit from ICI treatment, and accurately predicting ICI response remains challenging. We now describe a novel and simple approach that integrates immune-associated transcriptome signatures and tumour volume burden to better predict ICI response in melanoma patients. RNA sequencing was performed on pre-treatment (PRE) tumour specimens derived from 32 patients with advanced melanoma treated with combination PD1 and CTLA4 inhibitors. Of these 32 patients, 11 also had early during treatment (EDT, 5-15 [...]
1088P Molecular profiling and matched targeted therapy for patients with advanced melanoma: Results from part I of the MatchMEL study
Background While the molecular landscape of melanoma (Mel) has been defined, the clinicopathological associations of pts with BRAF/NRAS wild-type (WT) Mel and immune-checkpoint inhibitors (ICIs) treatment outcomes are less well understood. The MatchMEL study investigated the mutational profile of WT Mel and examined whether targeted treatments could be matched to specific molecular alterations with clinical efficacy. Methods In Part 1, consecutive pts with newly diagnosed advanced Mel presenting to two centres in Australia were enrolled. WT pts underwent FoundationOneCDx® (CDx) sequencing. Clinicopathologic features and ICI outcomes were examined. A molecular tumor board analysed CDx results to match targeted therapy [...]
Single-cell RNA sequencing reveals melanoma cell state-dependent heterogeneity of response to MAPK inhibitors.
Abstract Background: Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance. Methods: In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to ex vivo BRAF/MEK inhibitor treatment. Findings: We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to [...]
Circulating tumour DNA dynamics predict recurrence in stage III melanoma patients receiving neoadjuvant immunotherapy.
Abstract Background: Neoadjuvant therapy improves recurrence-free survival (RFS) in resectable stage III cutaneous melanoma. However, accurately predicting individual recurrence risk remains a significant challenge. We investigated circulating tumour DNA (ctDNA) as a biomarker for recurrence in measurable stage IIIB/C melanoma patients undergoing neoadjuvant immunotherapy. Methods: Plasma samples were collected pre-neoadjuvant treatment, pre-surgery and/or six weeks post-surgery from 40 patients enrolled in the OpACIN-neo and PRADO clinical trials. Patients received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before surgery. Cell free DNA (cfDNA) underwent unbiased pre-amplification followed by tumour-informed mutation detection using droplet digital polymerase chain reaction (ddPCR) with the Bio-Rad [...]
Use of early circulating tumour DNA dynamics in patients with stage III melanoma receiving neoadjuvant combination immunotherapy.
Abstract Background: Neoadjuvant therapy in resectable stage III cutaneous melanoma improves relapse-free survival compared to adjuvant therapy alone and is now a standard of care.While pathological response can help predict recurrence risk and the need for further treatment, more biomarkers are required. We investigated circulating tumour DNA (ctDNA) as a predictive biomarker for recurrence in stage IIIB/C melanoma patients following neoadjuvant immunotherapy and surgery. Methods: We retrospectively analysed plasma samples collected at baseline and six weeks post-surgery from 30 patients enrolled in the OpACIN-neo and PRADO clinical trials, who received two cycles of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) before [...]
Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma
Abstract Background: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. Patients and methods: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), [...]
Neoadjuvant Triplet Immune Checkpoint Blockade in Newly Diagnosed Glioblastoma.
Abstract Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront [...]
PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma.
Abstract Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant [...]