Circulating tumor DNA dynamics and clinical outcome in metastatic colorectal cancer patients undergoing front-line chemotherapy

• Published in: Clinical cancer research 2024-12, p.OF1-OF12
• Main Authors: Ghidini, Michele, Hahne, Jens C, Senti, Chiara, Heide, Timon, Proszek, Paula Z, Shaikh, Ridwan, Carter, Paul, Hubank, Michael, Trevisani, Francesco, Garrone, Ornella, Cappelletti, Maria Rosa, Generali, Daniele, Cattaneo, Monica, Gnocchi, Nicoletta, Donati, Gianvito, Gobbi, Angela, Grizzi, Giulia, Lampis, Andrea, Elghadi, Raghad, Tanzi, Giulia, Tomasello, Gianluca, Ratti, Margherita, Pinato, David J, Fassan, Matteo, Vlachogiannis, Georgios, Sottoriva, Andrea, Passalacqua, Rodolfo, Valeri, Nicola
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-0924

we tested whether ctDNA changes may be used to assess early response and clinical outcome in metastatic colorectal cancer (mCRC) patients undergoing front-line systemic anti-cancer therapy (SACT). 862 plasma samples were collected 4-weekly from baseline (BL) until disease progression in mCRC patients receiving front line SACT. ctDNA normalization was defined as ≥99% clearance after 1 month of therapy (Mo1) in the 3 variants with the highest allele frequency in BL ctDNA. 83 paired samples from 75 patients were available for analysis. 12 pairs (14.4%) showed no variants in either BL or Mo1. In the remaining 71 comparisons (65 patients), 37 (52.1%) showed ctDNA normalization at Mo1. Patients that cleared ctDNA had significantly longer overall (45.6 months) and progression-free survival (13.9 months) compared to non-normalized patients [OS= 22.6 months (Log-rank p = 0.01) and PFS= 10.7 months (Log-rank p = 0.036) respectively]. In addition, higher response rate was observed in patients with ctDNA clearance (72.9%) compared to non-normalized cases (38.2%). Longitudinal sequencing of at least four timepoints in pts with a PFS>10 months showed emerging variants in 47.8% of cases; in all these patients the trajectory of these new "outlier" variants appeared in stark contrast with the clinical-radiological course of disease and the trend in other mutations. ctDNA clearance represents an early indicator of benefit from SACT in mCRC patients; serial tracking of multiple variants is warranted to improve specificity and to avoid misleading information due to the emergence of mutations of unknown clinical significance.