原发性肿瘤中叶酸相关基因表达与接受基于5-氟尿嘧啶/亚叶酸钙联合化疗的转移性结直肠癌患者的肿瘤反应及无进展生存期相关。

Folate-Associated Gene Expression in Primary Tumors Is Associated With Tumor Response and Progression-Free Survival of Patients With Metastatic Colorectal Cancer Undergoing 5-FU/Leucovorin-Based Combination Chemotherapy.

作者信息

Odin Elisabeth, Carlsson Göran, Saksena Pushpa, Edsjö Anders, Di Cara Alessandro, Tell Roger, Gustavsson Bengt, Wettergren Yvonne

机构信息

Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Department of Surgery, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.

出版信息

Cancer Med. 2025 May;14(9):e70895. doi: 10.1002/cam4.70895.

DOI:10.1002/cam4.70895

PMID:40357991

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12070377/

Abstract

BACKGROUND

5-Fluorouracil (5-FU) and the Folate Leucovorin (LV) form the chemotherapy backbone for metastatic colorectal cancer (mCRC). Tumoral expression of specific folate-associated genes is associated with the risk of recurrence in stage III CRC following adjuvant 5-FU/LV (FLV)-based combination chemotherapy according to the Nordic bolus regimen. The aim was to evaluate whether expression of folate-associated genes in Pre-therapeutic tumor samples is associated with outcomes of patients with mCRC undergoing palliative FLV-based combination chemotherapy.

PATIENTS AND METHODS

Patients treated with FLV (n = 113), FLV + oxaliplatin (FLOX, n = 102), or FLV + irinotecan (FLIRI, n = 75) were included. ABCC3, RFC-1, PCFT, MFT, MTHFD2, and TYMS expression was determined by qPCR and related to tumor response and 3-year progression-free survival (PFS). Analyses were conducted on the entire cohort and on subgroups (group 1: stage I-III; group 2: stage IV, at primary surgery). Multivariate Cox proportional hazard models were applied to assess associations between covariates and PFS.

RESULTS

Low TYMS and high MFT expression in group 1, and high ABCC3 expression in group 2 correlated with better PFS (HR 1.37 (1.04-1.82), HR 0.49 (0.30-0.80), and HR 0.74 (0.60-0.93)), respectively. In addition, high MFT expression was associated with better PFS of patients treated with FLIRI (HR 0.47 (0.27-0.81), p = 0.007) whereas high expression of ABCC3 was associated with better PFS of patients treated with FLOX (HR 0.46 (0.23-0.92), p = 0.029).

CONCLUSION

While pretherapeutic tumoral expression of specific folate-associated genes may not serve as a universal predictive marker for FLV-based treatment, it might predict response and outcomes in patients receiving FLOX or FLIRI. Evaluating the impact of gene expression in primary tumors should consider subgrouping of patients by disease stage at diagnosis as well as the applied chemotherapy regimen. Prospective clinical studies on patients with mCRC are warranted to validate these findings.

摘要

背景

5-氟尿嘧啶（5-FU）和亚叶酸钙（LV）构成转移性结直肠癌（mCRC）化疗的基础方案。根据北欧推注方案，特定叶酸相关基因的肿瘤表达与III期结直肠癌患者接受基于5-FU/LV（FLV）的辅助联合化疗后的复发风险相关。目的是评估治疗前肿瘤样本中叶酸相关基因的表达是否与接受基于FLV的姑息性联合化疗的mCRC患者的预后相关。

患者与方法

纳入接受FLV治疗的患者（n = 113）、FLV + 奥沙利铂治疗的患者（FLOX，n = 102）或FLV + 伊立替康治疗的患者（FLIRI，n = 75）。通过qPCR测定ABCC3、RFC-1、PCFT、MFT、MTHFD2和TYMS的表达，并将其与肿瘤反应和3年无进展生存期（PFS）相关联。对整个队列和亚组（组1：I-III期；组2：IV期，初次手术时）进行分析。应用多变量Cox比例风险模型评估协变量与PFS之间的关联。

结果

组1中TYMS低表达和MFT高表达，以及组2中ABCC3高表达分别与更好的PFS相关（风险比[HR] 1.37[1.04 - 1.82]、HR 0.49[0.30 - 0.80]和HR 0.74[0.60 - 0.93]）。此外，MFT高表达与接受FLIRI治疗患者的更好PFS相关（HR 0.47[0.27 - 0.81]，p = 0.007），而ABCC3高表达与接受FLOX治疗患者的更好PFS相关（HR 0.46[(0.23 - 0.92]，p = 0.029）。