Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors

Abstract

BackgroundBRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.MethodsAllele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib.Results245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27).ConclusionsQuantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

From chemotherapy to oncoviruses – modern methods of treatment in metastatic melanoma

“…Transfection with miR-301a/inhibitor allowed for significant inhibition of tumor growth. The study indicated that miR-301a may act as a potential target in treatment of malignant melanoma [21].…”

“…Transfekcja inhibitorem miR-301a pozwoliła na uzyskanie istotnego zahamowania progresji nowotworu. W badaniu stwierdzono, że rolę potencjalnego celu leczenia czerniaka może odgrywać miR-301a [21].…”

Liquid Biopsy: Value for Melanoma Therapy?

“…Of note, in this study, the well-established LDH had no impact on PFS. Other groups did not find a prognostic value of pre-treatment detection of BRAF-mutant ctDNA [33,[37][38][39]. Liquid biopsy studies on BRAF V600-mutant ctDNA without data on corresponding BRAF status in tumor tissue need to be interpreted with caution [28].…”

“…Liquid biopsy studies on BRAF V600-mutant ctDNA without data on corresponding BRAF status in tumor tissue need to be interpreted with caution [28]. Decrease, and disappearance of ctDNA have been shown to be associated with improved PFS [38] and prolonged OS [39]. An impact of decreasing ctDNA on response to treatment has been found in targeted but not in immunotherapies [35], and in adoptive T-cell transfer a complete clearance after an early peak was associated with better responses [39].…”

Clinical value of early detection of circulating tumour DNA-BRAFV600mut in patients with metastatic melanoma treated with a BRAF inhibitor

“…3 Furthermore, a significantly higher PFS was found for patients in whom ctBRAF V600mut became undetectable at some time point after initiation of targeted therapy. 4 From 2012 to 2014, 85 patients from the onco-dermatology department of the Saint-Louis Hospital (Paris, France) presenting unresectable stage III (n=12) or stage IV (n=73) melanoma with BRAF V600E mutated lesions at targeted therapy initiation (BRAF inhibitors, vemurafenib or dabrafenib) were included in this retrospective study after signed informed consent. The cohort included 52 (62%) patients presenting a stage IV m1c melanoma, and 23 (27%) had brain metastasis.…”