Circulating tumor <scp>DNA</scp> monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab

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.

Authors

Institutions

Publication Details

Journal
Molecular Oncology
Published
2025-05-28
DOI
https://doi.org/10.1002/1878-0261.70054
Citations
2
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
1.87

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab

Jason D. Hughes, Lincoln W. Pasquina, Christopher J. Sweeney, Claire F. Friedman et al.
2 citations
Molecular Oncology
Cancer Genomics and Diagnostics
1.87
article

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab

Jason D. Hughes, Lincoln W. Pasquina, Christopher J. Sweeney, Claire F. Friedman, Charles Swanton, David R. Spigel, Russell W. Madison, Katja Schulze, Julia Malato, Hanna Tukachinsky, Cheryl Schwab, Tania Szado, Amaya Gascó, Howard A. Burris, Candice Francheska B. Tambaoan, Funda Meric‐Bernstam, Razelle Kurzrock, Bongin Yoo
article en
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.

Molecular OncologyVol. 19(11)
Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), Medical College of Wisconsin (US), Cornell University (US), The Francis Crick Institute (GB), Royal London Hospital (GB), Sarah Cannon (US), Weill Cornell Medicine (US), Foundation Medicine (United States), University College London (GB), The University of Adelaide (AU)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Gilead Sciences, Purdue University, Spectrum Pharmaceuticals, Celgene, Array BioPharma, Intuitive Surgical, Aeglea BioTherapeutics, Celldex Therapeutics, TG Therapeutics, Clovis Oncology, Purdue Pharma, Jounce Therapeutics, BeiGene, Incyte, XBiotech, NGM Biopharmaceuticals, Revolution Medicines, Puma Biotechnology, Moderna, MacroGenics, G1 Therapeutics, Astellas Pharma, PharmaMar, Ipsen, Genentech, EMD Serono, Foundation Medicine, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 14%
Cancer Genomics and Diagnostics
1.87
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.