Despite ongoing oncological advances, pancreatic ductal adenocarcinoma (PDAC) continues to have an extremely poor prognosis with limited targeted and immunotherapeutic options. Its genomic background has not been fully characterized yet in large-scale populations all over the world. Methods: Replicating a recent study from China, we collected tissue samples from consecutive Greek patients with pathologically-confirmed metastatic/unresectable PDAC and retrospectively investigated their genomic landscape using next generation sequencing (NGS). Findings: From a cohort of 409 patients, NGS analysis was successfully achieved in 400 cases (56.50% males, median age: 61.8 years). Consistent with a previous study,KRASwas the most frequently mutated gene in 81.50% of tested samples, followed byTP53(50.75%),CDKN2(8%), andSMAD4(7.50%).BRCA1/2variants with on-label indications were detected in 2%, and 87.50% carried a variant associated with off-label treatment (KRAS,ERBB2,STK11, or HRR-genes), while 3.5% of the alterations had unknown/preliminary-studied actionability (TP53/CDKN2A). Most of HRR-alterations were in intermediate- and low-risk genes (CHEK2,RAD50,RAD51,ATM,FANCA,FANCL,FANCC,BAP1), with controversial actionability: 8% harbored a somatic non-BRCA1/2alteration, 6 cases had a high-risk alteration (PALB2,RAD51C), and one co-presented aPALB2/BRCA2alteration. Elevated LOH was associated with HRR-mutated status andTP53mutations while lowered LOH was associated withKRASalterations. Including TMB/MSI data, the potential benefit from an NGS-oriented treatment was increased from 1.91% to 13.74% (high-MSI: 0.3%, TMB > 10 muts/MB: 12.78%). TMB was slightly increased in females (4.75 vs. 4.46 muts/MB) and in individuals with age > 60 (4.77 vs. 4.40 muts/MB). About 28.41% showed PD-L1 > 1% either in tumor or immune cells, 15.75% expressed PD-L1 ≥ 10%, and only 1.18% had PD-L1 ≥ 50%. This is the largest depiction of real-world genomic characteristics of European patients with PDAC, which offers some useful clinical and research insights.
尽管肿瘤学领域不断取得进展，胰腺导管腺癌（PDAC）的预后仍然极差，靶向治疗和免疫治疗方案有限。其基因组背景在全球大规模人群中尚未得到充分表征。方法：参照中国近期的一项研究，我们收集了经病理确诊的转移性/不可切除PDAC希腊连续患者的组织样本，并采用新一代测序技术（NGS）对其基因组特征进行回顾性研究。结果：在409例患者队列中，成功完成400例NGS分析（男性占56.50%，中位年龄61.8岁）。与既往研究一致，KRAS是突变频率最高的基因（81.50%），其次为TP53（50.75%）、CDKN2（8%）和SMAD4（7.50%）。2%的样本检测到具有标签适应症的BRCA1/2变异，87.50%携带与超适应症治疗相关的变异（KRAS、ERBB2、STK11或HRR基因），而3.5%的变异具有未知/初步研究的可操作性（TP53/CDKN2A）。大多数HRR变异发生在中低风险基因（CHEK2、RAD50、RAD51、ATM、FANCA、FANCL、FANCC、BAP1），其可操作性存在争议：8%存在体细胞非BRCA1/2变异，6例携带高风险变异（PALB2、RAD51C），1例同时存在PALB2/BRCA2变异。LOH升高与HRR突变状态及TP53突变相关，而LOH降低与KRAS变异相关。纳入TMB/MSI数据后，NGS导向治疗的潜在获益率从1.91%提升至13.74%（高MSI：0.3%，TMB > 10 muts/MB：12.78%）。女性（4.75 vs. 4.46 muts/MB）及年龄>60岁个体（4.77 vs. 4.40 muts/MB）的TMB值略高。约28.41%的患者在肿瘤或免疫细胞中显示PD-L1 > 1%，15.75%表达PD-L1 ≥ 10%，仅1.18%达到PD-L1 ≥ 50%。本研究首次大规模描绘了欧洲PDAC患者的真实世界基因组特征，为临床实践和科学研究提供了重要参考。
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