Amsterdam UMC, location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Amsterdam UMC, location University of Amsterdam, Medical Oncology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands.
Amsterdam UMC, location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Cancer Center Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Transl Res. 2024 Nov;273:137-147. doi: 10.1016/j.trsl.2024.08.002. Epub 2024 Aug 21.
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at metastatic stage and typically treated with fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX). Few patients benefit from this treatment. Molecular subtypes are prognostic in particularly resectable PDAC and might predict treatment response. This study aims to correlate molecular subtypes in metastatic PDAC with FOLFIRINOX responses using real-world data, providing assistance in counselling patients. We collected 131 RNA-sequenced metastatic biopsies and applied a network-based meta-analysis using published PDAC classifiers. Subsequent survival analysis was performed using the most suitable classifier. For validation, we developed an immunohistochemistry (IHC) classifier using GATA6 and keratin-17 (KRT17), and applied it to 86 formalin-fixed paraffin-embedded samples of advanced PDAC. Lastly, GATA6 knockdown models were generated in PDAC organoids and cell lines. We showed that the PurIST classifier was the most suitable classifier. With this classifier, classical tumors had longer PFS and OS than basal-like tumors (PFS: 216 vs. 78 days, p = 0.0002; OS: 251 vs. 195 days, p = 0.049). The validation cohort showed a similar trend. Importantly, IHC GATA6 patients had significantly shorter survival with FOLFIRINOX (323 vs. 746 days, p = 0.006), but no difference in non-treated patients (61 vs. 54 days, p = 0.925). This suggests that GATA6 H-score predicts therapy response. GATA6 knockdown models did not lead to increased FOLFIRINOX responsiveness. These data suggest a predictive role for subtyping (transcriptomic and GATA6 IHC), though no direct causal relationship was found between GATA6 expression and chemoresistance. GATA6 immunohistochemistry should be seamlessly added to current diagnostics and integrated into upcoming clinical trials.
胰腺导管腺癌（PDAC）通常在转移阶段被诊断出来，通常采用氟尿嘧啶、亚叶酸、伊立替康和奥沙利铂（FOLFIRINOX）进行治疗。少数患者从中受益。分子亚型在可切除的 PDAC 中具有预后作用，并且可能预测治疗反应。本研究旨在使用真实世界的数据将转移性 PDAC 的分子亚型与 FOLFIRINOX 反应相关联，为患者咨询提供帮助。我们收集了 131 个 RNA 测序的转移性活检，并使用已发表的 PDAC 分类器进行了基于网络的荟萃分析。随后使用最合适的分类器进行了生存分析。为了验证，我们使用 GATA6 和角蛋白-17（KRT17）开发了一种免疫组织化学（IHC）分类器，并将其应用于 86 例晚期 PDAC 的福尔马林固定石蜡包埋样本。最后，在 PDAC 类器官和细胞系中生成了 GATA6 敲低模型。我们表明 PurIST 分类器是最合适的分类器。使用该分类器，经典肿瘤的 PFS 和 OS 长于基底样肿瘤（PFS：216 与 78 天，p = 0.0002；OS：251 与 195 天，p = 0.049）。验证队列也显示出类似的趋势。重要的是，IHC GATA6 患者接受 FOLFIRINOX 治疗的生存时间明显缩短（323 与 746 天，p = 0.006），但未接受治疗的患者无差异（61 与 54 天，p = 0.925）。这表明 GATA6 H 评分可预测治疗反应。GATA6 敲低模型并未导致 FOLFIRINOX 反应性增加。这些数据表明，亚分型（转录组和 GATA6 IHC）具有预测作用，尽管未发现 GATA6 表达与化疗耐药性之间存在直接因果关系。GATA6 免疫组织化学应无缝添加到当前的诊断中，并纳入即将进行的临床试验。
