Endocrine Abstracts

Introduction: There is a clinical need to develop novel and better biomarkers to monitor patients with neuroendocrine neoplasms (NENs). Our aim was to identify and track plasma circulating cell free tumour derived DNA (ctDNA) in a cohort of patients using a personalised, patient specific approach.

Materials and methods: 35 serial plasma samples were collected from 9 patients with metastatic NENs (6 small intestinal and 1 each of lung, ovarian, and pelvic; range 2-5 plasma samples per patient) over the space of 2-25 months from a single centre. For each patient, NEN specific somatic mutations (single nucleotide variants and insertions/deletions) were identified through whole exome sequencing of paired tumour-leucocyte DNA and were used to design a bespoke multi-variant Ampliseq™ HD ctDNA panel (5-20 variants per patient) for targeted next generation sequencing. Imaging and treatment were provided as per usual clinical care.

Results: ctDNA was detectable in 6/9 patients and in 19/35 plasma samples. A rise in the number of ctDNA target variants and/or variant allele frequency was seen in 4/6 patients who experienced disease progression. Two of these patients received peptide receptor radionuclide therapy after which ctDNA disappeared in 1 patient and substantially reduced in the other, which correlated with treatment response. The 3 patients who did not have detectable ctDNA at any time point all had grade 1 small intestinal NETs with stable disease during the observation period.

Discussion: Our data provide exciting evidence for the feasibility of utilising ctDNA as a biomarker in NENs. Using a personalised panel assay, we have demonstrated that ctDNA can track changes in disease burden and can monitor response to treatment. Of equal importance, ctDNA was not detectable in patients with quiescent disease. This could be helpful in identifying patients who do not need intensive monitoring. Targeting bespoke, multiple variants per patient is a novel and powerful approach for NENs, as targeting single variants through techniques such as droplet digital PCR may risk missing the dominant tumour variant(s) circulating in plasma. This study provides important early evidence that ctDNA may be a clinically useful biomarker for surveillance in NENs.