Plasma ctDNA response is an early marker of treatment effect in advanced NSCLC
Open accessAbstract
PURPOSE: Plasma circulating tumor DNA (ctDNA) analysis is routine for genotyping of advanced non–small-cell lung cancer (NSCLC); however, early response assessment using plasma ctDNA has yet to be well characterized. MATERIALS AND METHODS: Patients with advanced EGFR-mutant NSCLC across three phase I NCI osimertinib combination trials were analyzed in this study, and an institutional cohort of patients with KRAS-, EGFR-, and BRAF-mutant advanced NSCLC receiving systemic treatment was used for validation. Plasma was collected before treatment initiation and serially before each cycle of therapy, and key driver mutations in ctDNA were characterized by droplet digital polymerase chain reaction. Timing of plasma versus imaging response was compared in a separate cohort of patients with EGFR-mutant NSCLC treated with osimertinib. Across cohorts, we also studied ctDNA variability before treatment start. RESULTS: In the NCI cohort, 14/16 (87.5%) patients exhibited ≥ 90% decrease in mutation abundance by the first on-treatment timepoint (20-28 days from treatment start) with minimal subsequent change. Similarly, 47/56 (83.9%) patients with any decrease in the institutional cohort demonstrated ≥ 90% decrease in mutation abundance by the first follow-up draw (7-30 days from treatment start). All 16 patients in the imaging cohort with radiographic partial response showed best plasma response within one cycle, preceding best radiographic response by a median of 24 weeks (range: 3-147 weeks). Variability in ctDNA levels before treatment start was observed. CONCLUSION: Plasma ctDNA response is an early phenomenon, with the majority of change detectable within the first cycle of therapy. These kinetics may offer an opportunity for early insight into treatment effect before standard imaging timepoints.
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Recent data suggest that serial ctDNA analyses may have clinical value because ctDNA clearance in patients receiving systemic chemo- or immunotherapy correlates with progression-free and overall survival.
“recent data suggests that serial analyses may have clinical value as clearance of ctDNA among patients undergoing systemic chemo- or immunotherapy correlate with progression-free and overall survival.13–17”
From Early Changes in Circulating Cell-Free <i>KRAS</i> G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients (2023) · cites this paper as [17]
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- Authors
- Cheng, M. L., Lau, C. J., Milan, M. S. D., Supplee, J. G., Riess, J. W., Bradbury, P. A., Jänne, P. A., Oxnard, G. R., & Paweletz, C. P.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- UC Davis Comprehensive Cancer Center (US)
- University Health Network (CA)
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
- Corresponding author
- Cheng, Michael L.
- ORCID
- Venue
- JCO Precision Oncology
- Published
- 2021-11
- Volume
- 5
- Issue
- 5
- Pages
- 393-402
- ISSN
- 2473-4284 (ISSN-L)
- PMC
- PMC8232122
- OpenAlex
- W3130023215
- Cited by
- 29
- References
- 21
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 9
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JCO Precision Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- National Institutes of Health
- National Cancer Institute (R01CA240592, K12CA138464, UM1CA186709, UM1CA186717)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- circulating tumor DNA, liquid biopsy, non-small cell lung cancer, EGFR-mutant non-small cell lung cancer, osimertinib, early treatment response, treatment response biomarkers, ctDNA kinetics, KRAS mutation, BRAF mutation, droplet digital PCR
- MeSH terms
- Circulating Tumor DNA, Acrylamides, Aniline Compounds, Carcinoma, Non-Small-Cell Lung, Humans, Indoles, Lung Neoplasms, Neoplasm Staging, Pyrimidines, Biomarkers, Tumor, Treatment Outcome
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