Cancer treatment monitoring using cell-free DNA fragmentomes

• Published in: Nature communications Vol. 15; no. 1; pp. 8801 - 12
• Main Authors: van ’t Erve, Iris, Alipanahi, Bahar, Lumbard, Keith, Skidmore, Zachary L., Rinaldi, Lorenzo, Millberg, Laurel K., Carey, Jacob, Chesnick, Bryan, Cristiano, Stephen, Portwood, Carter, Wu, Tony, Peters, Erica, Bolhuis, Karen, Punt, Cornelis J. A., Tom, Jennifer, Bach, Peter B., Dracopoli, Nicholas C., Meijer, Gerrit A., Scharpf, Robert B., Velculescu, Victor E., Fijneman, Remond J. A., Leal, Alessandro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-10-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/67/1857; 692/53/2421; Aged; Biomarkers, Tumor - genetics; Cancer; Cancer therapies; Cell-Free Nucleic Acids - blood; Cell-Free Nucleic Acids - genetics; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Circulation; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Deoxyribonucleic acid; DNA; DNA sequencing; Female; Gene sequencing; Humanities and Social Sciences; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Middle Aged; Monitoring; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - mortality; Neoplasms - therapy; Patients; Prognosis; Science; Science (multidisciplinary); Survival; Telemedicine; Tumors; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53017-7

Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically rely on prior identification of tumor-specific mutations. Here, we develop a tumor-independent and mutation-independent approach (DELFI-tumor fraction, DELFI-TF) using low-coverage whole genome sequencing to determine the cfDNA tumor fraction and validate the method in two independent cohorts of patients with colorectal or lung cancer. DELFI-TF scores strongly correlate with circulating tumor DNA levels (ctDNA) (r = 0.90, 
p
 < 0.0001, Pearson correlation) even in cases where mutations are undetectable. DELFI-TF scores prior to therapy initiation are associated with clinical response and are independent predictors of overall survival (HR = 9.84, 95% CI = 1.72-56.10, 
p
 < 0.0001). Patients with lower DELFI-TF scores during treatment have longer overall survival (62.8 vs 29.1 months, HR = 3.12, 95% CI 1.62-6.00, 
p
 < 0.001) and the approach predicts clinical outcomes more accurately than imaging. These results demonstrate the potential of using cfDNA fragmentomes to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.
Circulating cell-free DNA (cfDNA) assays for monitoring individuals with cancer typically use tumor-specific mutations that may not be detected in many patients. Here, the authors develop a tumor-independent and mutation-independent approach (DELFI-TF) to estimate tumor burden in cfDNA for treatment response monitoring and clinical outcome prediction.