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ctDNA informs treatment in BRAF-mutated melanoma

Researchers find that cell-free circulating tumour DNA (ctDNA) analyses before and during treatment could help guide selection of therapy for patients with BRAF V600-mutant melanoma.

ctDNA and melanoma

In recent years, attention has shifted to the use of non-invasive methods with increased accuracy to help predict clinical outcomes. Currently, no validated blood-based biomarkers for monitoring and predicting treatment efficacy for melanoma exist.

Lactate dehydrogenase is an established prognostic biomarker. However, it lacks sufficient specificity and sensitivity to routinely inform on-treatment decision making. CtDNA has emerged as a promising biomarker in many types of cancers. The detection and quantification of ctDNA has been associated with tumour burden, minimal residual disease, treatment response and clonal evolution. However, studies showing the clinical utility of these methods are limited.

In melanoma, BRAFV600 or NRASQ61 hotspot mutations are found in ~ two-thirds of metastatic tumours. Patients with BRAFV600 mutant tumours can be treated with highly efficacious MEK-targeted therapies.

Several studies have shown that ctDNA concentrations can inform tumour burden, early detection of disease, resistance to targeted therapies and survival. However, nearly all studies have involved small, mostly retrospectively collected data. Additionally, no large studies have examined the association between serial changes in ctDNA and survival after therapy.

Clinical validation study

In this clinical validation study, published in The Lancet Oncology, researchers used analytically validated droplet digital PCR assays to measure BRAFV600 mutant ctDNA in preteament and on-treatment plasma samples. The samples were collected from patients enrolled in two clinical trials – COMBI-d and COMBI-MB. The first was a double-blind, randomised, phase 3 trial evaluating dabrafenib plus trametinib vs. dabrafenib plus placebo for previously untreated BRAF V600-mutant melanoma. The latter was an open-label, phase 2 trial evaluating the dabrafenib-trametinib combination among patients with BRAF V600-mutant metastatic melanoma and brain metastases. In this current study, researchers obtained pretreatment plasma samples of 345 patients and on-treatment samples of 224 patients in the COMBI-d trial, and pretreatment and on-treatment samples of 38 patients in the COMBI-MB trial.

The team found that elevated baseline BRAFV600 mutation-positive ctDNA concentration was associated with worse overall survival outcomes. This was independent of treatment group and baseline lactate dehydrogenase concentrations. A ctDNA cut-off point of 64 copies per mL of plasma stratified patients enrolled in COMBI-d as high risk or low risk with respect to survival outcomes. The team validated these findings in the COMBI-MB cohort. In COMBI-d, undetectable ctDNA at week 4 was significantly associated with extended progression-free and overall survival. This was particularly the case among those with high lactate dehydrogenase levels.

These results provide evidence that ctDNA might serve as a biomarker to identify patients who could gain from targeted therapy. It also provides a foundation for investigating the clinical utility of ctDNA to guide the management of patients with melanoma.

Image credit: By kjpargeter – freepik

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Cancer / Cancer Research / ctDNA