Purpose: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data. Experimental Design: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA. Results: The most common mutations in the CONKO cohort were KRAS (75%), TP53 (60%), SMAD4 (10%), CDKNA2 (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, TP53 mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, P = 0.005). With respect to gemcitabine treatment, TP53 mutations were a positive predictive factor for gemcitabine efficacy [ TP53 mut: HR for DFS Gem vs. Obs, 0.235 (0.130 – 0.423; P < 0.001); TP53 wt: HR for DFS Gem vs. Obs, 0.794 (0.417 – 1.513; P = 0.483)] with a significant test for interaction ( P = 0.003). In the TCGA dataset, TP53 mutations were associated with shortened DFS. Conclusions: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the TP53 mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.

中文翻译：

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TP53 突变预测胰腺导管腺癌患者对佐剂吉西他滨的敏感性：CONKO-001 试验的下一代测序结果。

目的：我们在 CONKO-001 III 期试验中进行了新一代测序 (NGS)，以确定临床相关的预后和预测突变，并在癌症基因组图谱 (TCGA) 测序数据中进行功能验证。实验设计：CONKO-001 试验的患者接受了胰腺腺癌 (PDAC) 的治疗性手术，随后接受了吉西他滨 (Gem) 辅助化疗或仅观察 (Obs)。101 名患者的组织样本通过 37 个基因的 NGS 进行了评估。Cox 比例风险模型用于生存分析。此外，在来自 TCGA 的 146 个胰腺肿瘤的 NGS 和 RNA 测序数据集中进行了功能基因组分析。结果：CONKO 队列中最常见的突变是 KRAS (75%)、TP53 (60%)、SMAD4 (10%)、CDKNA2 (9%)、以及 SWI/SNF (12%) 复杂的改变。在未经治疗的患者中，TP53 突变是无病生存的负面预后因素（DFS；HR mut vs. WT 2.434，P = 0.005）。对于吉西他滨治疗，TP53 突变是吉西他滨疗效的阳性预测因素 [TP53 mut：DFS Gem 与 Obs 的 HR，0.235 (0.130 – 0.423；P < 0.001)；TP53 wt：DFS Gem 与 Obs 的 HR，0.794（0.417 – 1.513；P = 0.483）]，并进行了显着的交互测试（P = 0.003）。在 TCGA 数据集中，TP53 突变与缩短的 DFS 相关。结论：在 CONKO-001 中，吉西他滨辅助治疗的益处仅限于 TP53 突变患者组。这种潜在的临床相关观察需要在独立的前瞻性研究中得到证实。