Exploring early kinetic profiles of CEA, ctDNA and cfDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer

Abstract

IntroductionPatients 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 methodsForty 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). ResultsSummary 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 = 0.01) and OS (HR 3.12; 95% CI 1.35 – 7.23; P < 0.01). 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 = 0.55) nor OS (HR 1.37; 95% CI 0.70 – 2.68; P = 0.37). ConclusionEarly 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. Micro AbstractMetastatic colorectal cancer (mCRC) patients respond differently to chemotherapy, and early identification of patients with limited or no clinical benefit could prompt treatment switching with improved outcomes. We examined CEA and circulating tumor DNA (ctDNA) dynamics during first-line oxaliplatin-based chemotherapy, and their association with radiological response/survival (N=40). ctDNA dynamics hold prognostic value, supporting the idea of prospectively validating a ctDNA-response framework early in the care pathway.