Table 1_Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer.xlsx

BackgroundThe utilization of modified FOLFIRINOX (mFFX) therapy has shown notable advancements in patient outcomes in both localized and metastatic PDAC. Nevertheless, the effectiveness of mFFX treatment comes at the cost of elevated toxicity, leading to its restriction to patients with adequate performance status. Consequently, the administration of mFFX is contingent upon patient performance rather than rational criteria. The ideal scenario would involve the ability to assess the sensitivity of each drug within the mFFX regimen, minimizing unnecessary toxicity without compromising clinical benefits.
MethodsWe developed transcriptomic signatures for each drug of the mFFX regimen (5FU, oxaliplatin and irinotecan) by integrating transcriptomic data from PDC, PDO and PDX with their corresponding chemo-response profiles to capture the biological components responsible for the response to each drug. We further validated the signatures in a cohort of 167 patients with advanced and metastatic PDAC.
ResultsAll three signatures captured high responder patients for OS and PFS in the mFFX arm exclusively. We then studied the response of patients to 0, 1, 2 and 3 drugs and we identified a positive correlation between the number of drugs predicted as sensitive and the OS and PFS, and the with objective response rate.
ConclusionsWe developed three novel transcriptome-based signatures which define sensitivity for each mFFX components that can be used to rationalize the administration of the mFFX regimen in patients with metastatic pancreatic cancer and could help to avoid unnecessary toxic effects.

背景
改良型FOLFIRINOX（modified FOLFIRINOX, mFFX）方案在局限性及转移性胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）患者中的应用，已被证实可显著改善患者预后。然而，mFFX方案的治疗获益伴随毒性升高的代价，这使得该方案仅能应用于体能状态良好的患者。因此，mFFX方案的临床应用仅依据患者体能状态进行选择，而非基于合理的筛选标准。理想的临床策略应当能够评估mFFX方案中各单药的敏感性，从而在不牺牲临床获益的前提下，减少不必要的药物毒性暴露。

方法
本研究针对mFFX方案中的三种药物（5-氟尿嘧啶（5FU）、奥沙利铂、伊立替康）分别构建转录组特征标签：通过整合患者来源肿瘤细胞（patient-derived cancer cells, PDC）、患者来源类器官（patient-derived organoids, PDO）及患者来源异种移植瘤模型（patient-derived xenografts, PDX）的转录组数据，及其各自对应的化疗应答特征谱，以捕捉与各药物应答相关的生物学组分。随后，本研究在167例晚期转移性PDAC患者队列中对上述特征标签进行了验证。

结果
三种转录组特征标签仅在mFFX治疗组中，可精准识别出总生存期（Overall Survival, OS）和无进展生存期（Progression-Free Survival, PFS）均表现优异的应答患者。本研究进一步分析了患者对0、1、2、3种敏感药物的应答情况，结果显示，被预测为敏感的药物数量与患者的OS、PFS及客观缓解率（objective response rate, ORR）均呈正相关。

结论
本研究构建了三种基于转录组的新型特征标签，可分别判定mFFX方案中各组分药物的敏感性，能够为转移性胰腺癌患者的mFFX方案临床应用提供合理的筛选依据，并有助于避免不必要的药物毒性反应。