ABSTRACT Introduction: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterised by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. Methods: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA were sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction (MAF). Results: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n=21), RB1 (n=2), KRAS (n=4), BRAF (n=3). Ten (42%) had a “adenocarcinoma-like” profile. Five of six patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA-mutation/immunohistochemistry-profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR=3.60, 95%CI [1.06-12.04]) and BRAF (HR=4.25, 95%CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the two patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR=0.37, 95%CI [0.15; 0.91]). Conclusion: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).


中文翻译：

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胃肠胰腺来源或原发性未知的神经内分泌癌中的 ctDNA：CIRCAN-NEC 初步研究

摘要 简介：胃肠胰腺神经内分泌癌（GEPNEC）的特点是分子结构异质性和预后不良。循环肿瘤 DNA (ctDNA) 分析可能对 NEC 管理有用。本研究旨在描述 ctDNA 突变，评估它们对化疗反应的预测价值，以及它们根据疾病进展而发生的变化。方法：CIRCAN-NEC 研究包括 GEPNEC 或来自未知原发灶的 NEC 患者，计划开始一线或二线化疗。在化疗开始前、首次评估时和疾病进展期间收集血样。ctDNA 通过二代测序 (NGS) 进行测序。分子反应被定义为突变等位基因部分 (MAF) 减少至少 30%。结果：所有 24 名患者均接受了铂-依托泊苷一线化疗；19 人接受了基于 FOLFIRI 的一线治疗后方案。22 名患者至少有一个驱动突变：TP53 (n=21)、RB1 (n=2)、KRAS (n=4)、BRAF (n=3)。十个（42%）具有“腺癌样”特征。在 ctDNA/组织 NGS 匹配的 6 名患者中，有 5 名至少有一个一致的突变（基因水平的一致率为 44%）。TP53/p53+ 和 RB1/pRb- 的 ctDNA 突变/免疫组织化学谱之间的一致率为 64% (7/11) 和 14% (1/7)。在这项包括少数亚组患者的初步研究中，具有 KRAS (HR=3.60, 95%CI [1.06-12.04]) 和 BRAF (HR=4.25, 95%CI [1.11-16.40]) 突变的患者的无进展生存期较短（PFS）铂依托泊苷，而两名具有 RB1 突变的患者在基于 FOLFIRI 的化疗下 PFS 较短。评估了 28 个治疗期：10 名患者有分子反应（7/10 有形态学反应），这与更长的 PFS 相关（HR=0.37, 95%CI [0.15; 0.91]）。结论：这项初步研究显示了 ctDNA 评估的高灵敏度，这对于 GEPNEC 的未来管理（肿瘤分子诊断和疾病进展评估）是令人鼓舞的。