In advanced pancreatic neuroendocrine neoplasms (PanNEN), there are little data detailing the frequency of genetic alterations identified in cell free DNA (cfDNA), plasma–tissue concordance of detected alterations, and clinical utility of cfDNA. Patients with metastatic PanNENs underwent cfDNA collection in routine practice. Next-generation sequencing (NGS) of cfDNA and matched tissue when available was performed. Clinical actionability of variants was annotated by OncoKB. Thirty-two cfDNA samples were analyzed from 25 patients, the majority who had well-differentiated intermediate grade disease (13/25; 52%). Genomic alterations were detected in 68% of patients and in 66% of all cfDNA samples. The most frequently altered genes were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%), and ATRX (12%). Twenty-three out of 25 (92%) patients underwent tumor tissue NGS. Tissue–plasma concordance for select genes was as follows:DAXX (95.7%), ARID1A (91.1%), ATRX (87%), TSC2 (82.6%), MEN1 (69.6%). Potentially actionable alterations were identified in cfDNA of 8 patients, including TSC2 (4; level 3b), ATM (1; level 3b), ARID1A (2; level 4), and KRAS (1; level 4). An ETV6:NTRK fusion detected in tumor tissue was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second-generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN-associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.

在晚期胰腺神经内分泌肿瘤 (PanNEN) 中，几乎没有数据详细说明无细胞 DNA (cfDNA) 中发现的遗传改变的频率、检测到的改变的血浆组织一致性以及 cfDNA 的临床用途。转移性 PanNEN 患者在常规实践中接受了 cfDNA 采集。对 cfDNA 和匹配的组织（如果有）进行了下一代测序 (NGS)。OncoKB 注释了变体的临床可操作性。对 25 名患者的 32 份 cfDNA 样本进行了分析，其中大多数患有分化良好的中度疾病（13/25；52%）。68% 的患者和 66% 的 cfDNA 样本中检测到基因组改变。最常改变的基因是DAXX (28%)、TSC2 (24%)、MEN1 (24%)、ARID1B (20%)、ARID1A (12%) 和ATRX (12%)。25 名患者中有 23 名 (92%) 接受了肿瘤组织 NGS。选定基因的组织-血浆一致性如下：DAXX (95.7%)、ARID1A (91.1%)、ATRX (87%)、TSC2 (82.6%)、MEN1 (69.6%)。在 8 名患者的 cfDNA 中发现了潜在的可操作的改变，包括TSC2（4；3b 级）、ATM（1；3b 级）、ARID1A（2；4 级）和KRAS（1；4 级）。在肿瘤组织中检测到 ETV6 : NTRK融合，并用 larotrectinib 进行治疗；在进展过程中，cfDNA 测序发现NTRK3 G623R 改变是获得性耐药机制；该患者参加了第二代 TRK 抑制剂的临床试验，具有临床益处。在转移性 PanNEN 中，基于 cfDNA 的 NGS 在 66% 的血浆样本中鉴定出肿瘤相关突变，并且 PanNEN 相关基因的血浆组织一致性较高。通过循环 cfDNA 基因分型检测克隆进化、可操作的改变和耐药机制。