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Sci Rep. 2019 Nov 25;9(1):17471. doi: 10.1038/s41598-019-53917-5.

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

Author information

1
Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway.
2
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
3
Department of Biosciences, University of Bergen, Bergen, Norway.
4
Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
5
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
6
Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
7
Norwegian Cancer Genomics Consortium, Institute for Cancer Research, The Norwegian Radium Hospital/Oslo University Hospital, Oslo, Norway.
8
Genomics Core Facility, Department of Core Facilities, Oslo University Hospital, Oslo, Norway.
9
K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
10
Centre of Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway. oddbjorn.straume@helse-bergen.no.
11
Department of Oncology, Haukeland University Hospital, Bergen, Norway. oddbjorn.straume@helse-bergen.no.

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.

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