Cancer treatment monitoring using cell-free DNA fragmentomes

Iris van 't Erve, Bahar Alipanahi, Keith Lumbard, Zachary L. Skidmore, Lorenzo Rinaldi, Laurel K. Millberg, Jacob Carey, Bryan Chesnick, Stephen Cristiano, Carter Portwood, Tony Wu, Erica Peters, Karen Bolhuis, Cornelis J.A. Punt, Jennifer Tom, Peter B. Bach, Nicholas C. Dracopoli, Gerrit A. Meijer, Robert B. Scharpf, Victor E. VelculescuRemond J.A. Fijneman*, Alessandro Leal*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number8801
Number of pages12
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 21 Oct 2024

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