TY - JOUR
T1 - Cancer treatment monitoring using cell-free DNA fragmentomes
AU - van 't Erve, Iris
AU - Alipanahi, Bahar
AU - Lumbard, Keith
AU - Skidmore, Zachary L.
AU - Rinaldi, Lorenzo
AU - Millberg, Laurel K.
AU - Carey, Jacob
AU - Chesnick, Bryan
AU - Cristiano, Stephen
AU - Portwood, Carter
AU - Wu, Tony
AU - Peters, Erica
AU - Bolhuis, Karen
AU - Punt, Cornelis J.A.
AU - Tom, Jennifer
AU - Bach, Peter B.
AU - Dracopoli, Nicholas C.
AU - Meijer, Gerrit A.
AU - Scharpf, Robert B.
AU - Velculescu, Victor E.
AU - Fijneman, Remond J.A.
AU - Leal, Alessandro
N1 - Publisher Copyright:
© 2024. The Author(s).
PY - 2024/10/21
Y1 - 2024/10/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85206965507&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-53017-7
DO - 10.1038/s41467-024-53017-7
M3 - Article
C2 - 39433569
AN - SCOPUS:85206965507
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 8801
ER -