探讨RAS-/ braf突变的转移性结直肠癌患者CEA、ctDNA和cfDNA的早期动力学特征

IF 3.3 3区医学 Q2 ONCOLOGY

Clinical colorectal cancer Pub Date : 2024-12-03 DOI:10.1016/j.clcc.2024.11.004

Julian Hamfjord , Tormod Kyrre Guren , Bengt Glimelius , Halfdan Sorbye , Per Pfeiffer , Olav Dajani , Ole Christian Lingjærde , Kjell Magne Tveit , Karen-Lise Garm Spindler , Niels Pallisgaard , Elin H. Kure

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引用次数: 0

摘要

简介转移性结直肠癌（mCRC）患者对一线化疗的反应各不相同。及早发现临床获益有限或无临床获益的患者，可促使患者更及时地接受二线治疗，并有可能改善总体疗效。癌胚抗原（CEA）是目前临床上唯一用于监测 mCRC 疾病控制情况的血液标记物。包括循环肿瘤DNA（ctDNA）在内的循环游离细胞DNA（cfDNA）可能成为肿瘤预后的有用替代物：纳入前瞻性 NORDIC-VII 试验（NCT00145314）中的 40 例 RAS/BRAF 突变 mCRC 患者。建立了一个探索性模型系统，以描述一线奥沙利铂化疗期间CEA、cfDNA和ctDNA的早期治疗动力学，并研究其与放射学反应、无进展生存期（PFS）和总生存期（OS）之间的关联：总结指标包括：从治疗开始到时间网格第 7 天（P7）、第 14 天（P14）和第 49 天（P49）的百分比变化；从时间网格第 0 天到第 7 天（S7）、第 8 天到第 14 天（S14）和第 15 天到第 49 天（S49）的斜率；以及从时间网格第 0 天到第 49 天的曲线下面积（AUC）。值得注意的是，ctDNA 和 CEA 的 P49 和 S49 与放射学反应和/或 PFS 相关。两种标记物的早期动态变化差异很大，ctDNA的变化比CEA更快、更明显。9名患者在首次评估（第8周）时未达到完全/接近完全的分子ctDNA反应，这种状态与较短的PFS（HR 2.72；95% CI，1.22-6.06；P = .01）和OS（HR 3.12；95% CI，1.35-7.23；P < .01）相关。相反，有22名患者在首次评估时未达到放射学反应（即完全或部分反应），但这与PFS（HR 1.21；95% CI，0.64-2.30；P = .55）和OS（HR 1.37；95% CI，0.70-2.68；P = .37）无关：结论：以奥沙利铂为基础的一线化疗期间ctDNA的早期动态变化具有预后价值，支持在mCRC患者的早期治疗路径中对ctDNA-RECIST框架进行前瞻性验证的观点：试验注册：ClinicalTrials.gov，NCT00145314。

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Exploring Early Kinetic Profiles of CEA, ctDNA and cfDNA in Patients With RAS-/BRAF-Mutated Metastatic Colorectal Cancer

Introduction

Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes.

Materials and Methods

Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS).

Results

Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P₇), day 14 (P₁₄), and day 49 (P₄₉); slope from time-grid day 0 to 7 (S₇), day 8 to 14 (S₁₄), and day 15 to 49 (S₄₉); and area under the curve from time-grid day 0 to 49 (AUC). Notably P₄₉ and S₄₉ for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (∼week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37).

Conclusion

Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.

Trial registration: ClinicalTrials.gov, NCT00145314

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来源期刊

Clinical colorectal cancer 医学-肿瘤学

CiteScore

5.50

自引率

2.90%

发文量

审稿时长

27 days

期刊介绍： Clinical Colorectal Cancer is a peer-reviewed, quarterly journal that publishes original articles describing various aspects of clinical and translational research of gastrointestinal cancers. Clinical Colorectal Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of colorectal, pancreatic, liver, and other gastrointestinal cancers. The main emphasis is on recent scientific developments in all areas related to gastrointestinal cancers. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.