Xu Caiming, Mannucci Alessandro, Esposito Francis, Oliveres Helena, Alonso-Orduña Vicente, Yubero Alfonso, Fernández-Martos Carlos, Salud Antonieta, Gallego Javier, Martín-Richard Marta, Fernández-Plana Julen, Guillot Mónica, Aparicio Jorge, Fakih Marwan, Kopetz Scott, Feliu Jaime, Maurel Joan, Goel Ajay
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California.
Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Clin Cancer Res. 2025 Mar 17;31(6):1002-1015. doi: 10.1158/1078-0432.CCR-24-1934.
The EXOsome and cell-free miRNAs of anti-EGFR ResistAnce (EXONERATE) study was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC).
Patients with newly diagnosed RAS wild-type, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in two nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRCs to predict PFS, OS, and ORR.
Genome-wide small RNA sequencing identified 12 cell-free and 14 exosomal candidates that were differentially expressed in both plasma and tumor tissue of good versus poor responders (based on PFS <12 months). The 8 and 9 best performing candidates, respectively, were used to generate the EXONERATE assay. In left-sided mCRC, 65% were EXONERATE-high, correlating with shorter median PFS (9.5 vs. 18.5 months; P < 0.001). In the independent right-sided mCRC cohort, 80.8% were EXONERATE-high and experienced a similarly shorter median PFS (8.6 vs. 41.2 months; P = 0.0004). In the right-sided group, EXONERATE predicted PFS ≥12 months with 100% sensitivity. A linear relationship existed between EXONERATE values and response depth. Multivariate analysis revealed that EXONERATE predicts PFS and OS independently of tumor sidedness.
The EXONERATE assay robustly predicted PFS and OS outcomes in patients with mCRC, both right- and left-sided, before they received either panitumumab or cetuximab. It stratified PFS, OS, and ORR better than a right versus left approach.
抗表皮生长因子受体（EGFR）耐药外泌体与无细胞微小核糖核酸（miRNA）研究（EXONERATE）是一项开放标签的生物标志物干预性研究，旨在开发、测试和验证一种液体活检方法，用于预测转移性结直肠癌（mCRC）患者一线EGFR抑制剂治疗的无进展生存期（PFS）、总生存期（OS）和客观缓解率（ORR）。
新诊断的RAS野生型、未接受过化疗的mCRC患者，包括右半结肠癌和左半结肠癌患者，入组两项全国性试验，接受西妥昔单抗或帕尼单抗联合化疗。主要终点为12个月的PFS，在左半结肠癌和右半结肠癌中进行分层检验，以预测PFS、OS和ORR。
全基因组小RNA测序鉴定出12种无细胞和14种外泌体候选物，在反应良好者与反应不佳者（基于PFS<12个月）的血浆和肿瘤组织中差异表达。分别使用表现最佳的8种和9种候选物生成EXONERATE检测方法。在左半结肠癌中，65%的患者EXONERATE检测结果为高，与较短的中位PFS相关（9.5个月对18.5个月；P<0.001）。在独立的右半结肠癌队列中，80.8%的患者EXONERATE检测结果为高，中位PFS同样较短（8.6个月对41.2个月；P = 0.0004）。在右半结肠癌组中，EXONERATE预测PFS≥12个月的敏感性为100%。EXONERATE值与缓解深度之间存在线性关系。多变量分析显示，EXONERATE可独立于肿瘤部位预测PFS和OS。
EXONERATE检测方法能可靠地预测接受帕尼单抗或西妥昔单抗治疗前mCRC患者（包括右半结肠癌和左半结肠癌患者）的PFS和OS结局。与按肿瘤部位区分右半结肠癌和左半结肠癌的方法相比，它能更好地对PFS、OS和ORR进行分层。
