Transcriptome-based classification to predict FOLFIRINOX response in a real-world metastatic pancreatic cancer cohort

IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY
Marjolein F. Lansbergen , Mark P.G. Dings , Paul Manoukian , Arantza Fariña , Cynthia Waasdorp , Gerrit K.J. Hooijer , Joanne Verheij , Jan Koster , Danny A. Zwijnenburg , Johanna W. Wilmink , Jan Paul Medema , Frederike Dijk , Hanneke W.M. van Laarhoven , Maarten F. Bijlsma
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引用次数: 0

Abstract

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 GATA6low 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.

基于转录组的分类预测真实世界转移性胰腺癌队列中的 FOLFIRINOX 反应。
胰腺导管腺癌(PDAC)通常在确诊时已处于转移阶段,通常采用氟尿嘧啶、亮菌素、伊立替康和奥沙利铂(FOLFIRINOX)治疗。很少有患者能从这种治疗中获益。分子亚型对特别是可切除的PDAC具有预后作用,并可预测治疗反应。本研究旨在利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,为患者提供咨询帮助。我们收集了 131 份经 RNA 测序的转移性活检样本,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。为了进行验证,我们利用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例福尔马林固定石蜡包埋的晚期PDAC样本。最后,我们在 PDAC 有机体和细胞系中建立了 GATA6 基因敲除模型。我们发现 PurIST 分类器是最合适的分类器。与基底样肿瘤相比,经典型肿瘤的PFS和OS更长(PFS:216天 vs. 78天,p = 0.0002;OS:251天 vs. 195天,p = 0.049)。验证队列也显示了类似的趋势。重要的是,接受FOLFIRINOX治疗的IHC GATA6低患者生存期明显缩短(323天 vs. 746天,p = 0.006),但未接受治疗的患者无差异(61天 vs. 54天,p = 0.925)。这表明,GATA6 H-score可预测治疗反应。GATA6 基因敲除模型不会导致 FOLFIRINOX 反应性增加。这些数据表明,亚型分析(转录组学和 GATA6 IHC)具有预测作用,尽管在 GATA6 表达与化疗耐药性之间没有发现直接的因果关系。GATA6 免疫组化应无缝添加到目前的诊断方法中,并纳入即将开展的临床试验中。
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来源期刊
Translational Research
Translational Research 医学-医学:内科
CiteScore
15.70
自引率
0.00%
发文量
195
审稿时长
14 days
期刊介绍: Translational Research (formerly The Journal of Laboratory and Clinical Medicine) delivers original investigations in the broad fields of laboratory, clinical, and public health research. Published monthly since 1915, it keeps readers up-to-date on significant biomedical research from all subspecialties of medicine.
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