Molecular Profiling of Well-Differentiated Neuroendocrine Tumours: The role of ctDNA in Real World Practice

Background: The role of tumour genomic profiling for the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate of tumour tissue when this is insufficient for analysis. Methods: Patients diagnosed with WdNETs underwent ctDNA genomic profiling (FoundationLiquid®); non-WdNETs (paraganglioma, goblet cell or poorly-differentiated neuroendocrine carcinoma) were used for comparison. The aim was to determine the rate of; test failure (primary end-point), “pathological alterations” (PAs) (secondary end-point) and patients for whom ctDNA analysis impacted management (secondary end-point). Results: Forty-five patients were included; 15 patients with WdNET (18 ctDNA samples) were eligible: 8 female (53.3%), median age 63.2 years (range 23.5-86.8). Primary: small bowel (8;53.3%); pancreas (5;33.3%); gastric (1;6.7%) and unknown primary (1;6.7%); grade (G)1 (n=5;33.3%); G2 (9;60.0%) and G3 (1;6.7%); median Ki-67: 5% (range 1-30). Thirty patients with non-WdNETs (34 ctDNA samples) were included. Five WdNETs samples (27.78%) failed analysis (vs 17.65% in non-WdNETs; p-value 0.395). Of 13 WdNET samples with successful ctDNA, PAs were detected in 6 (46.15%) (vs 82.14% in non-WdNETs; p-value 0.018). In WdNETs, PA rate was independent of anti-cancer systemic therapy (2/7;28.57% vs 4/6;66.67%; p-value 0.286) at time of ctDNA: 4, 1 and 1 samples had 1, 2 and 3 PAs, respectively; these were: CDKN2A mutation (mut) (1 sample), CHEK2mut (1), TP53mut (2), FGFR2 amplification (1), IDH2mut (1), CTNNB1mut (1), NF1mut (1), PALB2mut (1); none were targetable (0%) or impacted clinical management (0%). There was a lower maximum mutant allele frequency (mMAF) in WdNETs (mean 0.33) vs non-WdNETs (mean 26.99); even though differences did not reach statistical significance (p-value 0.0584). Conclusions: Although feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rate of PAs and mMAF were higher in non-WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding likelihood of results impacting their treatment.

Keywords: Neuroendocrine; molecular profiling; targeted therapies; mutation; fusion; ctDNA