Dados do Resumo

Título

Evaluation of tumor genomic profiling and ctDNA dynamics in metastatic melanoma to correlate with predictive response

Introdução

Metastatic melanoma at diagnosis is associated with high mortality with a 5-year survival rate of around 5-10%. Despite the great advances with immune checkpoint inhibitor (ICIs) therapy, disease progression is observed in 30 to 40% of patients. With that, it is crucial identify better and combined predictive biomarkers to help to elucidate gaps to more accurately select ICIs responders and patients at risk for developing severe immune toxicity.

Objetivo

This study aims to characterize tumor genomic profiling and access the dynamics of circulating tumor DNA (ctDNA) to identify predictive biomarkers for immune checkpoint inhibitor response in metastatic melanoma patients.

Métodos

Patients with metastatic melanoma are being enrolled both retrospectively and prospectively (ethical approval: 3215/22), with therapies including anti-PD1 antibody alone or in combination with anti-CTLA4. Tumor genomic profiling is being evaluated using an expanded panel with more than 500 cancer genes and performing next generation sequencing using Ion GeneStudio S5 (ThermoFisher) platform. To annotate and prioritize the variants, VarSeq (Golden Helix) tool is being used. TMB is categorized as high (≥10 mutations/Mb) or low (<10 mutations/Mb). Somatic variants are being screened in plasma cfDNA (cell-free DNA) from prospective samples collected at six distinct time points: days 0 (baseline, before treatment initiation), 30, 60, 90, 180, and 365. ctDNA analysis is being conducted using deep amplicon sequencing. Statistical analysis is being performed using Fisher Exact Test, comparing variables such as TMB, complete response, disease progression, mutated genes and ctDNA status in distinct moments.

Resultados

Preliminary data includes GP from 42 tumors. The most frequently mutated genes were BRAF (42.9%), NRAS (26.2%), TP53 (23.8%), and NF1 (23.8%). Acquired alterations in less common genes, such as CSMD3, APC, ZFHX3, KMT2C and others, were also identified. TMB-high was observed in 69% of cases, with no current association with complete response, progression, or specific mutations in BRAF, NRAS, KIT, and NF1. From 21 prospective cases included, 15 have results of ctDNA analysis, in which baseline ctDNA (BS ctDNA) was positive in 67% of cases. Among TMB data, 56% (5/9) of BS ctDNA positive samples and 100% (5/5) of BS ctDNA negative samples were TMB-high, although without statistical significance. The BS ctDNA status was independent of each gene mutations, but a tendency of BS ctDNA positivity was observed in cases with NRAS mutations (5/5, 100%; p = .08). Regarding other collection time points, the number of cases is still small to explore data.

Conclusões

Current data provide a genomic profiling of metastatic melanoma in a series of patients, confirming the high frequency of BRAF and NRAS activating mutations, in addition to somatic mutation in TP53 and NF1. Although without statistical significance, TMB-high was observed in all cases with BS ctDNA negative and in a half of ctDNA positive cases. Additionally, in cases with NRAS alterations, a tendency of ctDNA positive was observed. Patient recruitment and additional analyses are ongoing.

Financiador do resumo

Oncomine Clinical Research Grant (ThermoFisher Scientific)

Palavras Chave

Metastatic melanoma; Predictive biomarkers; Circulating tumor DNA