ctDNA detected by ddPCR reveals changes in tumour load in metastatic malignant melanoma treated with bevacizumab

Abstract

Bevacizumab is included in an increasing number of clinical trials. To find biomarkers to predict and monitor treatment response, cancer and angiogenesis relevant mutations in tumour and circulating tumour DNA (ctDNA) were investigated in 26 metastatic melanoma patients treated with bevacizumab. Patients with >1% BRAF/NRAS ctDNA at treatment start had significantly decreased progression free survival (PFS) and overall survival (OS) (PFS: p = 0.019, median 54 vs 774 days, OS: p = 0.026, median 209 vs 1064 days). Patients with >1% BRAF/NRAS ctDNA during treatment showed similar results (PFS: p = 0.002, OS: p = 0.003). ≤1% BRAF/NRAS ctDNA and normal lactate dehydrogenase (LDH) levels both significantly predicted increased response to treatment, but BRAF/NRAS ctDNA was better at predicting response compared to LDH at treatment start (OR 16.94, p = 0.032 vs OR 4.57, p = 0.190), and at predicting PFS (HR 6.76, p = 0.002) and OS (HR 6.78, p = 0.002) during therapy. ctDNA BRAF p.V600D/E/K and NRAS p.G12V/p.Q61K/L/R were better biomarkers for response prediction than TERT promoter mutations (OR 1.50, p = 0.657). Next generation sequencing showed that all patients with ≥2 mutations in angiogenesis-relevant genes had progressive disease, but did not reveal other biomarkers identifying responders. To conclude, ctDNA and LDH are useful biomarkers for both monitoring and predicting response to bevacizumab.

The prognostic value of circulating tumor DNA in patients with melanoma: A systematic review and meta-analysis

“…For PFS, 5 studies reported adjusted HR by multivariable analysis [ 11 , 13 , 14 , 16 , 17 ] and 2 studies reported unadjusted HR for univariate analysis [ 15 , 18 ] was performed and a significant prognostic effect was confirmed in the analysis of studies that collected ctDNA at baseline (multivariable: HR = 2.68, 95% CI 1.77–4.06, p < 0.001; univarible: HR = 3.27, 95% CI 1.54–6.96, p = 0.002). Obvious heterogeneity was not observed in multivariate PFS ( I 2 = 21.4%, p = 0.278) or univariate OS ( I 2 = 0%, p = 0.363) ( Fig.…”

“…BRAF mutations account for the vast majority of melanomas, followed by NRAS, TERT promoter and other specific gene mutations [ 13 , 15 , 33 , 34 ]. There are also references in the literature that gene mutations in melanoma patients are related to drug resistance, such as BRAFV600E and NRASQ61K mutations [11] . Majority of studies regard great clinical significance of BRAF V600 specific mutation in ctDNA of melanoma.…”

“…Risk of bias findings are presented in Table 1 . Overall risk of bias in the studies was judged to be low for 6 studies [ [10] , [11] , [12] , [13] , [14] , [15] ] and moderate for 3 studies [ 16 – 18 ]. Study participation and prognostic factor measurement were typically low.…”

“…Study participation and prognostic factor measurement were typically low. The domains most commonly at high risk of bias were study attrition (n= 3) [ 11 , 14 , 15 ] and statistical analysis and reporting ( n = 2) [ 16 , 18 ].…”

Blood-Based Detection of BRAF V600E in Gliomas and Brain Tumor Metastasis

“…While the detection of central nervous system (CNS) tumor hotspot mutations and molecular markers within the cerebrospinal fluid (CSF) of patients has been accomplished with high sensitivity and specificity [ 9 , 10 , 11 , 12 ], the detection of these targets in plasma has been difficult due to lower levels of circulating tumor nucleic acids, including cell-free DNA (cfDNA) and tumor-associated EV RNA (exRNA) [ 13 ]. In patients with primary cancers outside the CNS, liquid biopsy assays have been developed for the diagnosis and monitoring of several cancers, including malignant melanoma, colorectal cancer and prostate cancer [ 8 , 14 , 15 , 16 ].…”