A pilot study of individualised monitoring of patients with metastatic melanoma using plasma and urine DNA.

Abstract:

e21032 Background: Circulating tumour DNA (ctDNA) is released by cancer cells into the bloodstream and can be analysed via liquid biopsy, providing a real-time snapshot of tumour burden. After treatment, ctDNA concentrations may be low, making detection challenging, and collecting larger sample volumes may be impractical. Our study aims to achieve high-sensitivity monitoring of melanoma patients melanoma on therapy, maximising the number of mutations targeted per patient by individualised sequencing. Methods: 72 patients with stage 3 or 4 melanoma have so far been recruited to MelResist, a translational research study. 235 plasma, urine, tumour and buffy coat samples have been analysed for 10 BRAF mutant metastatic melanoma patients receiving systemic therapies, and 30 matched CT scans were analysed for RECIST response. Exome or targeted sequencing were carried out on tumour samples and plasma at baseline and progression and mutations identified were used to design individualised amplicon and hybrid-capture sequencing panels targeting hundreds to thousands of mutations per patient. Results: Baseline ctDNA allele fraction predicted for overall survival ( r = -0.56, p < 0.05). Longitudinal analysis of ctDNA showed that mutant allele fractions significantly correlated with tumour burden from CT imaging ( r = 0.79, p < 0.0001) and ctDNA changes were concordant with 20/22 (90%) of RECIST response events. ctDNA allele fractions increased with a lead time of 70 days relative to serum lactate dehydrogenase, a standard measure of disease burden (IQR = 42-142 days). Targeting multiple mutations per patient enabled detection of less than one mutant genome copy per sample and allowed comprehensive monitoring of clonal evolution on therapy, even using limited sample volumes. Conclusions: Analysis of an initial cohort of BRAF mutant metastatic melanoma patients has confirmed feasibility to apply an individualised targeted sequencing panel on both plasma and urine DNA. For a given sample volume, monitoring multiple mutations improves detection sensitivity compared to targeting individual loci, has predictive value and can be applied to all melanoma patients, irrespective of BRAF mutation status.

Authors:

J Wan, S Murphy, DG Gale, JA Morris, F Mouliere, A Gill, F Marass, K Heider, C Parkinson, FA Gallagher, AJ Durrani, U McDermott, C Massie, P Corrie, N Rosenfeld

Journal:

Journal of Clinical Oncology

Citation info:

35(15_suppl):e21032-e21032

Publication date:

20th May 2017

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