Medium-throughput drug screening of patient-derived organoids from colorectal peritoneal metastases can be used to guide therapy

Purpose: Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We aimed to determine whether organoid testing could help guide precision treatment for CRPM patients, as the clinical utility of prospective, functional drug screening including non-standard agents is unknown. Experimental Design: CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Results: Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. Conclusions: Our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies. Overall design: Fourteen patient derived metastatic CRC peritoneal lesion were sequenced. In addition to this, 3 paired primary CRC resected lesions were sequenced as controls. All samples were subjected to CMS analyses using CMS caller package.

研究背景与目的：结直肠癌（Colorectal cancer, CRC）伴腹膜转移（peritoneal metastases, PM）患者的治疗选择有限，且是结直肠癌中生存率最低的亚型。本研究旨在明确类器官检测能否助力结直肠癌腹膜转移（CRPM）患者的精准治疗，因为包括非常规用药在内的前瞻性功能药物筛查的临床应用价值尚不明确。实验设计：我们从患者体内分离获得结直肠癌腹膜转移类器官（腹膜类器官，peritonoids），并行二代测序（next-generation sequencing）与中通量药物组合体外检测，以明确每位患者的特异性药物敏感性。本研究评估了该检测服务的实用性，包括腹膜类器官构建成功率、培养周期、中通量药物检测的可重复性，以及检测结果引发的临床治疗方案调整情况。研究结果：在接受标准治疗的患者中，68%（19/28）成功构建并验证了腹膜类器官。基因组与药物谱分析可在8周内完成，且在患者标准治疗失败后，会向肿瘤内科团队提交一份标注药物敏感性排序的正式报告。该检测结果使2例患者的治疗方案发生调整，其中1例在既往多轮标准化疗进展后，仍获得了部分缓解。在澳大利亚推广该技术的障碍在于需要获取非常规适应症的药物以及相关经费支持。研究结论：本研究的方法具备可行性与可重复性，可为这类预后极差、亟需新型治疗方案的患者群体提供新型治疗选择的指导。该平台同样适用于多种实体脏器恶性肿瘤。整体实验设计：本研究对14例患者来源的结直肠癌腹膜转移病灶进行了测序。此外，还纳入3例配对的原发性结直肠癌切除病灶作为对照。所有样本均通过CMS caller工具包（CMS caller package）进行CMS分型分析。