Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Amsterdam, the Netherlands.
Department of Medical Oncology, Cancer Center Amsterdam, VU University Amsterdam, The Netherlands.
Ann Surg. 2020 Jun;271(6):1137-1147. doi: 10.1097/SLA.0000000000003084.
The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles.
FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed.
We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin.
Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability.
Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.
本研究旨在鉴定用于分层和监测接受 FOLFIRINOX 治疗的局部晚期或转移性胰腺导管腺癌（PDAC）患者的血浆 microRNA（miRNA）生物标志物，并研究其功能作用。
FOLFIRINOX 已成为晚期 PDAC 患者的标准治疗方法，并且可以用于潜在地使疾病降期。但是，只有一部分患者有反应，迫切需要指导决策的生物标志物。
我们使用基于微阵列的分析方法，根据 FOLFIRINOX 治疗后患者的无进展生存期（PFS），从化疗前后的血浆样本中发现失调的 miRNA。在独立队列（n = 43）中验证了 9 个候选血浆 miRNA。最具鉴别力的血浆 miRNA 与临床病理因素和生存相关，并在接受吉西他滨加 nab-紫杉醇治疗的另一个队列中进行了研究。还进一步在匹配的肿瘤组织中评估了表达模式。体外研究探索了其功能、关键下游基因靶标以及与 5-氟尿嘧啶、伊立替康和奥沙利铂的相互作用。
FOLFIRINOX 后非进展患者的血浆 miR-181a-5p 明显下调。多变量分析显示，这种下降与 PFS和总生存期的改善相关，尤其是与 CA19-9 下降相结合时[风险比（HR）=0.153，95%置信区间（CI）0.067-0.347 和 HR = 0.201，95%CI，0.070-0.576]。在接受吉西他滨加 nab-紫杉醇治疗的患者中，这种组合与生存无关。miR-181a-5p 的组织表达反映了血浆水平。在胰腺细胞系中，抑制 miR-181a-5p 并暴露于奥沙利铂可降低细胞活力。
血浆 miR-181a-5p 是监测 FOLFIRINOX 反应的特异性生物标志物。FOLFIRINOX 后血浆 miR-181a-5p 和 CA19-9 水平的下降与预后改善相关，可能有助于指导治疗选择和手术探索。
