The Prognostic and Predictive Impact of ctDNA Levels in Patients with Advanced Breast Cancer Enrolled on the plasmaMATCH Trial.
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Authors
Browne, IM
Pascual, J
Cutts, RJ
Kingston, B
Hrebien, S
Kilburn, LS
Pearson, A
Moretti, L
Wardley, AM
Macpherson, IR
Baird, RD
Roylance, R
Gil-Gil, MJ
Guerrero-Zotano, ÁL
Garcia-Murillas, I
Bliss, JM
Ring, A
Martín, M
Turner, NC
Pascual, J
Cutts, RJ
Kingston, B
Hrebien, S
Kilburn, LS
Pearson, A
Moretti, L
Wardley, AM
Macpherson, IR
Baird, RD
Roylance, R
Gil-Gil, MJ
Guerrero-Zotano, ÁL
Garcia-Murillas, I
Bliss, JM
Ring, A
Martín, M
Turner, NC
Document Type
Journal Article
Date
2026-01-06
Date Accepted
2025-10-27
Abstract
PURPOSE: ctDNA dynamic levels may identify patients who will respond to therapy. We assessed ctDNA baseline levels and on-treatment dynamics in patients with advanced breast cancer on the plasmaMATCH trial with mutation-targeted therapies (cohorts A-D) and triple-negative breast cancer on olaparib and ceralasertib combination (cohort E). EXPERIMENTAL DESIGN: Blood samples were collected at baseline [cycle 1 day 1 (C1D1)] and before treatment on cycle 2 day 1 (C2D1). Samples were sequenced using error-corrected targeted panels (Guardant360/GuardantOMNI). Circulating DNA ratio was calculated as the ratio of C2D1/C1D1 circulating DNA ratio, and baseline ctDNA levels were associated with progression-free survival (PFS) and confirmed objective response rates (ORR). RESULTS: A total of 167 patients had assessable C1D1-C2D1 ctDNA results. There was a strong association between baseline ctDNA levels and response in cohort E; low baseline levels were associated with longer PFS (HR, 0.33; P = 0.001) and higher ORR (40% vs. 9.7%; P = 0.02). In cohorts A to D, there was a weaker association with PFS (HR, 0.60; P = 0.03) and ORR (15.2% vs. 5.7%; P = 0.17). Associations of baseline ctDNA level and ORR were validated in the independent PEARL study. For on-treatment dynamics, suppression of ctDNA below median was predictive in cohorts A to D (HR, 0.47; P = 0.001) but not in cohort E (HR, 1.02; P = 0.94). Undetectable ctDNA levels at C2D1 were associated with good outcomes in both cohorts: in cohort E with improved PFS (HR, 0.25; P = 0.01) and improved ORR (86% vs. 11%; P = 0.01). Six of seven patients with undetectable on-treatment ctDNA were BRCA1/BRCA2/PALB2 wild type. CONCLUSIONS: Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcomes.
Citation
Clinical Cancer Research, 2025, pp. OF1 - OF11
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Molecular Oncology
Clin Trials & Stats Unit
Clin Trials & Stats Unit