Faculty Collaboration Database

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab. Mol Oncol 2025 Nov;19(11):3060-3078

Date

05/28/2025

Pubmed ID

40434907

Pubmed Central ID

PMC12591311

DOI

10.1002/1878-0261.70054

Scopus ID

2-s2.0-105006911407 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade. We sequenced cell-free DNA collected at the start of therapy, on treatment, and at the end of therapy for 153 patients treated with atezolizumab as part of the pan-tumor MyPathway study (NCT02091141). ctDNA tumor fraction (TF) and bTMB were assessed for correlation with progression-free survival (PFS) and overall survival (OS). We found that molecular response (MR, ≥50% decrease in TF at cycle 3 day 1) was associated with improved PFS (9.7 vs 1.5 months from C3D1; HR = 0.27) and OS (21.1 vs 14.3 months from C3D1; HR = 0.44). These findings were consistent when limited to patients with stable disease (SD; PFS HR = 0.55; OS HR = 0.39). bTMB was correlated with tissue-based TMB (tTMB) when TF was high (≥1%), but not with OS in this cohort. In total, 61% of baseline samples had predicted clonal hematopoiesis (CH) variants. No correlation between maximum variant allele frequency (maxVAF) of predicted CH and TF was seen. In summary, MR is associated with outcomes for patients treated with atezolizumab and could stratify patients with SD. While CH was common, maxVAF for CH variants was not associated with ctDNA TF. Quantification of ctDNA enables therapy response monitoring and is critical for interpretation of bTMB as a proxy for tTMB.

Author List

Swanton C, Madison RW, Tambaoan CFB, Meric-Bernstam F, Sweeney CJ, Kurzrock R, Burris HA 3rd, Spigel DR, Tukachinsky H, Hughes J, Malato J, Yoo B, Szado T, Schwab C, Pasquina LW, Gasco A, Schulze K, Friedman CF

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Circulating Tumor DNA
Female
Humans
Male
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasms