Circulating tumour cells & circulating tumour DNA in patients with resectable colorectal liver metastases (MIRACLE): a prospective, observational biomarker study.
Lissa Wullaert, Maurice P H M Jansen, Jaco Kraan, Yannick M Meyer, Kelly Voigt, Stavros Makrodimitris, Vanja de Weerd, Corine M Beaufort, Mai Van, Maarten Vermaas, Eric J T Belt, Paul D Gobardhan, Stefan Sleijfer, Henk M W Verheul, John W M Martens, Dirk J Grünhagen, Saskia M Wilting, Cornelis Verhoef
{"title":"Circulating tumour cells & circulating tumour DNA in patients with resectable colorectal liver metastases (MIRACLE): a prospective, observational biomarker study.","authors":"Lissa Wullaert, Maurice P H M Jansen, Jaco Kraan, Yannick M Meyer, Kelly Voigt, Stavros Makrodimitris, Vanja de Weerd, Corine M Beaufort, Mai Van, Maarten Vermaas, Eric J T Belt, Paul D Gobardhan, Stefan Sleijfer, Henk M W Verheul, John W M Martens, Dirk J Grünhagen, Saskia M Wilting, Cornelis Verhoef","doi":"10.1016/j.eclinm.2025.103406","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need to identify prognostic markers enabling more individualised treatment approaches.</p><p><strong>Methods: </strong>In the MIRACLE, a prospective, observational biomarker study, a total of 188 patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy were included between October 2015 and December 2021. Blood samples were collected before surgery (baseline) and three weeks after surgery. The primary objective was to assess the potential association between postoperative circulating tumour DNA (ctDNA) detection and recurrence of disease for patients with resectable CRLM within one year after resection. The secondary objective was the association between recurrence of disease within one year and detection of circulating tumour cells (CTCs). Baseline ctDNA was measured by next generation sequencing using a targeted panel (Oncomine Colon cell-free DNA assay) and postoperatively by digital PCR on genetic variants found preoperatively with the Oncomine panel. CTCs were enumerated using the FDA-approved CellSearch system.</p><p><strong>Findings: </strong>ctDNA was detected in 117/187 patients (63%) at baseline, and 28/104 evaluable patients (27%) still had detectable ctDNA postoperatively. CTC enumeration resulted in positivity for 37/183 patients (20%) at baseline and 14/158 patients (9%) postoperatively. No association was found between 1-year recurrence-free survival (RFS) and the presence of CTCs or ctDNA at baseline. In contrast, patients with postoperative undetectable ctDNA had a significantly improved 1-year RFS compared to patients with postoperative ctDNA (54% [95% CI 44%-67%] vs. 25% [95% CI 13%-47%], log-rank p = 0.0011). Similarly, patients with postoperative detectable CTCs had a significantly shorter 1-year RFS compared to patients without postoperative CTCs (15% [95% CI 4%-55%] vs. 53% [95% CI 45%-62%], log-rank p 0.0004). Also in multivariable analysis, detectable ctDNA and CTCs after surgery remained independently associated with a shorter 1-year RFS (HR 2.35; 95% CI 1.34-4.11; p = 0.0028 and HR 2.98; 95% CI 1.56-5.71; p = 0.0010, respectively).</p><p><strong>Interpretation: </strong>This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of postoperative detectable circulating tumour load on 1-year RFS. Postoperative ctDNA and CTC detection both represent strong, independent predictors for a shorter RFS after local treatment, as opposed to preoperative detection.</p><p><strong>Funding: </strong>This work was supported by KWF Kankerbestrijding (Dutch Cancer Society, EMCR 2014-6340).</p>","PeriodicalId":11393,"journal":{"name":"EClinicalMedicine","volume":"87 ","pages":"103406"},"PeriodicalIF":10.0000,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361997/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EClinicalMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.eclinm.2025.103406","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need to identify prognostic markers enabling more individualised treatment approaches.
Methods: In the MIRACLE, a prospective, observational biomarker study, a total of 188 patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy were included between October 2015 and December 2021. Blood samples were collected before surgery (baseline) and three weeks after surgery. The primary objective was to assess the potential association between postoperative circulating tumour DNA (ctDNA) detection and recurrence of disease for patients with resectable CRLM within one year after resection. The secondary objective was the association between recurrence of disease within one year and detection of circulating tumour cells (CTCs). Baseline ctDNA was measured by next generation sequencing using a targeted panel (Oncomine Colon cell-free DNA assay) and postoperatively by digital PCR on genetic variants found preoperatively with the Oncomine panel. CTCs were enumerated using the FDA-approved CellSearch system.
Findings: ctDNA was detected in 117/187 patients (63%) at baseline, and 28/104 evaluable patients (27%) still had detectable ctDNA postoperatively. CTC enumeration resulted in positivity for 37/183 patients (20%) at baseline and 14/158 patients (9%) postoperatively. No association was found between 1-year recurrence-free survival (RFS) and the presence of CTCs or ctDNA at baseline. In contrast, patients with postoperative undetectable ctDNA had a significantly improved 1-year RFS compared to patients with postoperative ctDNA (54% [95% CI 44%-67%] vs. 25% [95% CI 13%-47%], log-rank p = 0.0011). Similarly, patients with postoperative detectable CTCs had a significantly shorter 1-year RFS compared to patients without postoperative CTCs (15% [95% CI 4%-55%] vs. 53% [95% CI 45%-62%], log-rank p 0.0004). Also in multivariable analysis, detectable ctDNA and CTCs after surgery remained independently associated with a shorter 1-year RFS (HR 2.35; 95% CI 1.34-4.11; p = 0.0028 and HR 2.98; 95% CI 1.56-5.71; p = 0.0010, respectively).
Interpretation: This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of postoperative detectable circulating tumour load on 1-year RFS. Postoperative ctDNA and CTC detection both represent strong, independent predictors for a shorter RFS after local treatment, as opposed to preoperative detection.
Funding: This work was supported by KWF Kankerbestrijding (Dutch Cancer Society, EMCR 2014-6340).
背景：结肠直肠癌肝转移（CRLM）根治性手术后的复发风险仍然很高，强调需要确定预后标志物，从而实现更个性化的治疗方法。方法：MIRACLE是一项前瞻性、观察性生物标志物研究，在2015年10月至2021年12月期间，共纳入188例分离的、可切除的无（新）辅助化疗的CRLM患者。术前（基线）和术后3周采集血样。主要目的是评估可切除的CRLM患者术后循环肿瘤DNA （ctDNA）检测与术后一年内疾病复发之间的潜在关联。次要目的是一年内疾病复发与循环肿瘤细胞（ctc）检测之间的关系。基线ctDNA通过下一代测序使用靶向小组（Oncomine结肠无细胞DNA测定）和术后数字PCR对术前Oncomine小组发现的遗传变异进行测量。使用fda批准的细胞搜索系统枚举ctc。结果：基线时，117/187例患者（63%）检测到ctDNA， 28/104例可评估患者（27%）术后仍可检测到ctDNA。CTC计数在基线时为37/183例（20%），术后为14/158例（9%）。1年无复发生存期（RFS）与基线时ctc或ctDNA的存在没有关联。相比之下，术后未检测到ctDNA的患者与术后ctDNA患者相比，1年RFS显著改善（54% [95% CI 44%-67%]对25% [95% CI 13%-47%]， log-rank p = 0.0011）。同样，术后可检测到ctc的患者与术后无ctc的患者相比，1年RFS显著缩短（15% [95% CI 4%-55%]对53% [95% CI 45%-62%]， log-rank p 0.0004）。同样在多变量分析中，术后可检测到的ctDNA和CTCs仍然与较短的1年RFS独立相关（HR 2.35; 95% CI 1.34-4.11; p = 0.0028; HR 2.98; 95% CI 1.56-5.71; p = 0.0010）。解释：这是首个在可切除的CRLM患者中进行的无（neo）辅助化疗的研究，该研究证明了术后可检测的循环肿瘤负荷对1年RFS的影响。与术前检测相比，术后ctDNA和CTC检测都是局部治疗后较短RFS的强大、独立的预测指标。本研究由KWF Kankerbestrijding（荷兰癌症协会，EMCR 2014-6340）资助。
期刊介绍：
eClinicalMedicine is a gold open-access clinical journal designed to support frontline health professionals in addressing the complex and rapid health transitions affecting societies globally. The journal aims to assist practitioners in overcoming healthcare challenges across diverse communities, spanning diagnosis, treatment, prevention, and health promotion. Integrating disciplines from various specialties and life stages, it seeks to enhance health systems as fundamental institutions within societies. With a forward-thinking approach, eClinicalMedicine aims to redefine the future of healthcare.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
