Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma

Abstract

Simple Summary For patients with metastatic melanoma, a rapid BRAF mutation assessment is vital to reveal the treatment options per patient. Additionally, close monitoring of the disease during treatment is essential to allow for adjustments in the treatment strategy when needed. The aim of this prospective study was to confirm the clinical validity of circulating tumor DNA (ctDNA) for minimally invasive BRAF mutation testing and treatment monitoring of metastatic melanoma patients with elevated lactose dehydrogenase serum levels. We observed that ctDNA-based BRAF mutation testing was a reliable and minimally-invasive alternative to tissue-based testing in 98% of all patients and was 100% specific. The changes in ctDNA levels during therapy appeared helpful for disease monitoring and outperformed other blood-based biomarkers in predicting treatment response. Abstract For patients with newly diagnosed metastatic melanoma, rapid BRAF mutation (mBRAF) assessment is vital to promptly initiate systemic therapy. Additionally, blood-based biomarkers are desired to monitor and predict treatment response. Circulating tumor DNA (ctDNA) has shown great promise for minimally invasive mBRAF assessment and treatment monitoring, but validation studies are needed. This prospective study utilized longitudinal plasma samples at regular timepoints (0, 6, 12, 18 weeks) to address the clinical validity of ctDNA measurements in stage IV melanoma patients with elevated serum lactate dehydrogenase (LDH > 250U/L) starting first-line systemic treatment. Using droplet digital PCR, the plasma mBRAF abundance was assessed in 53 patients with a BRAFV600 tissue mutation. Plasma mBRAF was detected in 50/51 patients at baseline (98% sensitivity; median fraction abundance of 19.5%) and 0/17 controls (100% specificity). Patients in whom plasma mBRAF became undetectable during the first 12–18 weeks of treatment had a longer progression-free survival (30.2 vs. 4.0 months; p < 0.001) and cancer-specific survival (not reached vs. 10.2 months; p < 0.001) compared to patients with detectable mBRAF. The ctDNA dynamics outperformed LDH and S100 dynamics. These results confirm the clinical validity of ctDNA measurements as a minimally invasive biomarker for the diagnostic and monitoring trajectory of patients with LDH-high stage IV melanoma.