TY - JOUR
T1 - Exploring Early Kinetic Profiles of CEA, ctDNA and cfDNA in Patients With RAS-/BRAF-Mutated Metastatic Colorectal Cancer
AU - Hamfjord, Julian
AU - Guren, Tormod Kyrre
AU - Glimelius, Bengt
AU - Sorbye, Halfdan
AU - Pfeiffer, Per
AU - Dajani, Olav
AU - Lingjærde, Ole Christian
AU - Tveit, Kjell Magne
AU - Spindler, Karen-Lise Garm
AU - Pallisgaard, Niels
AU - Kure, Elin H
N1 - Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2025/6
Y1 - 2025/6
N2 - 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.
AB - 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.
KW - Carcinoembryonic Antigen/blood
KW - Proto-Oncogene Proteins p21(ras)
KW - Prospective Studies
KW - Prognosis
KW - Humans
KW - Middle Aged
KW - Biomarkers, Tumor/blood
KW - Proto-Oncogene Proteins B-raf/genetics
KW - Colorectal Neoplasms/genetics
KW - Male
KW - Circulating Tumor DNA/blood
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Oxaliplatin/administration & dosage
KW - Progression-Free Survival
KW - Female
KW - Adult
KW - Aged
KW - Mutation
KW - Survival
KW - Radiological response
KW - Recist
KW - First-line chemotherapy
U2 - 10.1016/j.clcc.2024.11.004
DO - 10.1016/j.clcc.2024.11.004
M3 - Article
C2 - 39743478
SN - 1533-0028
VL - 24
SP - 153
EP - 158
JO - Clinical Colorectal Cancer
JF - Clinical Colorectal Cancer
IS - 2
ER -