Abstract
Simple SummaryThe analysis of circulating tumour DNA (ctDNA) can help to identify genetic alterations present in cancer cells without the need to access tumour tissue, which can be an invasive approach. This study explored the feasibility of analysing ctDNA in patients with advanced well-differentiated neuroendocrine tumours (WdNETs). A total of 45 patients (15 with WdNETs) were included. Although feasible (with a non-evaluable sample rate of 27.8%), mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. While patients with WdNETs could still be offered genomic profiling (if available and reimbursed), it is important to manage patients’ expectations regarding the likelihood of the results impacting their treatment.Background: The role of tumour genomic profiling in the clinical management of well-differentiated neuroendocrine tumours (WdNETs) is unclear. Circulating tumour DNA (ctDNA) may be a useful surrogate for tumour tissue when the latter 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. A total of 15 patients with WdNETs (18 ctDNA samples) were eligible: 8 females (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). A total of 30 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 the 13 WdNET samples with successful ctDNA analyses, PAs were detected in 6 (46.15%) (vs. 82.14% in non-WdNETs; p-value 0.018). In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs. 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. These were: CDKN2A mutation (mut) (one sample), CHEK2mut (one), TP53mut (one), FGFR2 amplification (one), IDH2mut (one), CTNNB1mut (one), NF1mut (one) and PALB2mut (one). 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 rates of PAs and mMAFs 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 the likelihood of the results impacting their treatment.
Highlights
Neuroendocrine neoplasms (NENs) are broadly classified according to their morphological differentiation and proliferative rate in well-differentiated neuroendocrine tumours (WdNETs) (grade (G)1–2 (Ki-67 < 20%) or G3 (Ki-67 ≥ 20%, usually ≤50%)) and in poorly differentiated neuroendocrine carcinomas (PdNECs) [1]
In relation to the use of next-generation sequencing (NGS) technologies in neuroendocrine neoplasms (NENs), the current recommendation from the European Society for Medical Oncology (ESMO) is to assess the tumour mutational burden (TMB), an estimate of the rate of somatic mutations within a tumour genome, in welldifferentiated neuroendocrine tumours (WdNETs) [2], as this may predict the tumour’s response to immunotherapy. This recommendation is based on the results of a prospective exploratory analysis of the multi-cohort phase II KEYNOTE-158 trial, which assessed the activity of the programmed death-1 inhibitor Pembrolizumab in previously treated patients with 10 different cancer types, including NETs
This study showed that 17% of pancreatic NETs (PanNETs) harbour germline mutations affecting DNA repair genes (e.g., MUTYH, CHEK2 and BRCA2), or the genes MEN1 and Von Hippel–Lindau disease (VHL)
Summary
Neuroendocrine neoplasms (NENs) are broadly classified according to their morphological differentiation and proliferative rate in well-differentiated neuroendocrine tumours (WdNETs) (grade (G) (Ki-67 < 20%) or G3 (Ki-67 ≥ 20%, usually ≤50%)) and in poorly differentiated neuroendocrine carcinomas (PdNECs) (always G3, Ki-67 ≥ 20%) [1]. In relation to the use of next-generation sequencing (NGS) technologies in neuroendocrine neoplasms (NENs), the current recommendation from the European Society for Medical Oncology (ESMO) is to assess the tumour mutational burden (TMB), an estimate of the rate of somatic mutations within a tumour genome, in WdNETs [2], as this may predict the tumour’s response to immunotherapy. In WdNETs, the PA rate was independent of concomitant administration anti-cancer systemic therapies (2/7; 28.57% vs 4/6; 66.67%; p-value 0.286) at the time of the ctDNA analysis: four, one and one samples had one, two and three PAs, respectively. Conclusions: feasible, mutation-based ctDNA analysis was of limited clinical utility for patients with advanced WdNETs. The rates of PAs and mMAFs 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 the likelihood of the results impacting their treatment
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