Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples.
Hepatobiliary Surgical Oncology Unit, Istituto Nazionale Tumori-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli.
ESMO Open. 2023 Jun;8(3):101198. doi: 10.1016/j.esmoop.2023.101198. Epub 2023 Apr 27.
BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.
背景：转移性结直肠癌（mCRC）患者从分子驱动的治疗中获益有限。患者来源的肿瘤类器官（PDTOs）是一种无与伦比的模型，可以阐明肿瘤对治疗的耐药性，因为它们具有高度模拟肿瘤特征的能力。
材料与方法：我们分别使用来自 mCRC 初治和治疗耐药患者的可存活肿瘤组织来生成 PDTOs。将衍生的模型进行为期 6 天的药物筛选试验（DSA），该试验使用了针对几乎所有可操作的 mCRC 分子驱动因素的化疗和靶向药物的综合管道。对于第二个队列，DSA 数据与 PDTO 基因分型相匹配。
结果：总共从 mCRC 原发性肿瘤或转移灶中获得了 40 个纳入两个队列的 PDTOs。第一个队列包括 31 个来自一线治疗的患者的 PDTOs。对于该队列，DSA 结果与患者的反应相匹配。此外，RAS/BRAF 突变状态与 DSA 西妥昔单抗反应相匹配。12 个 RAS 野生型 PDTO 中有 10 个（83.3%）对西妥昔单抗有反应，而所有的突变型 PDTO （100%）都有耐药性。对于第二个队列（化疗耐药患者），我们使用部分肿瘤组织进行基因分型。9 个 DSA/基因分型数据中有 4 个在临床上适用。根据 DSA 结果，两名 RAS 突变型 mCRC 患者分别在三线接受 FOLFOX-贝伐珠单抗和米托蒽醌-卡培他滨治疗，获得疾病控制。一名患者由于基因分型时肿瘤突变负担高而接受了nivolumab-第二线粒体衍生的半胱天冬酶激活剂模拟物（I 期试验）治疗，病情稳定。在一个病例中，BRCA2 突变的存在与 DSA 对奥拉帕利的敏感性相关；然而，该患者无法接受该治疗。
结论：我们使用 CRC 作为模型，设计并验证了一种具有临床应用潜力的方法，可以使用功能数据为临床决策提供信息。毫无疑问，需要进一步进行更大规模的分析，以提高方法的成功率，并为 mCRC 患者提出合适的治疗策略。
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