miR-21, miR-99b and miR-375 combination as predictive response signature for preoperative chemoradiotherapy in rectal cancer

IntroductionPreoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer patients. Despite the benefits of CRT, its use in non-responder patients can be associated with increased toxicities and surgical resection delay. The identification of CRT response biomarkers, such as microRNAs, could improve the management of these patients. We have studied the microRNA expression in pretreatment endoscopy biopsies from rectal cancer patients treated with CRT to identify potential microRNAs able to predict CRT response and clinical outcome of these patients.Material and methodsRNA from pretreatment endoscopy biopsies from 96 rectal cancer patients treated with preoperative CRT were studied. Pathological response was graded according to the tumor regression grade (TRG) Dworak classification. In the screening phase, 377 miRNAs were studied in 12 patients with extreme responses (TRG0-1 vs TRG4). The potential role as predictive biomarkers for CRT response, disease-free survival (DFS) and overall survival (OS) of the miRNAs identified in the screening phase were validated in the whole cohort.ResultsIn the screening phase, an 8-miRNAs CRT-response signature was identified: let-7b, let-7e, miR-21, miR-99b, miR-183, miR-328, miR-375 and miR-483-5p. In the validation phase, miR-21, miR-99b and miR-375 emerged as CRT response-related miRNAs while miR-328 and let-7e emerged as prognostic markers for DFS and OS. Interestingly, ROC curve analysis showed that the combination of miR-21, miR-99b and miR-375 had the best capacity to distinguish patients with maximum response (TRG4) from others.ConclusionsmiR-21, miR-99b and miR-375 could add valuable information for individualizing treatment in locally advanced rectal cancer patients.

【研究背景】术前放化疗（chemoradiotherapy, CRT）是局部晚期直肠癌患者的标准治疗方案。尽管术前放化疗具有明确临床获益，但对于治疗无应答的患者而言，该治疗可能增加毒性反应风险并导致手术切除延迟。识别放化疗应答相关生物标志物（如微小RNA（microRNAs）），有望优化此类患者的诊疗管理流程。本研究针对接受术前放化疗的直肠癌患者，分析其治疗前内镜活检标本中的微小RNA表达谱，以期筛选出可预测放化疗应答及患者临床结局的潜在微小RNA。【材料与方法】本研究纳入96例接受术前放化疗的直肠癌患者，提取其治疗前内镜活检标本中的RNA进行分析。采用德沃拉克（Dworak）肿瘤退缩分级（tumor regression grade, TRG）系统对患者的病理应答情况进行分级。在筛选阶段，我们针对12例具有极端治疗应答的患者（TRG0-1组 vs TRG4组），对377种微小RNA进行了检测。随后在全队列中验证了筛选阶段鉴定出的微小RNA作为放化疗应答、无病生存期（DFS）及总生存期（OS）预测生物标志物的潜在价值。【研究结果】在筛选阶段，本研究鉴定出包含8种微小RNA的放化疗应答特征标记：let-7b、let-7e、miR-21、miR-99b、miR-183、miR-328、miR-375及miR-483-5p。在验证阶段，miR-21、miR-99b及miR-375被证实为与放化疗应答相关的微小RNA，而miR-328与let-7e则可作为无病生存期及总生存期的预后标志物。值得注意的是，受试者工作特征（ROC）曲线分析显示，miR-21、miR-99b与miR-375的联合检测，对区分最大程度应答（TRG4）患者与其他患者具有最优的区分效能。【研究结论】miR-21、miR-99b及miR-375可为局部晚期直肠癌患者的个体化治疗提供有价值的参考信息。