CIRCULATING tumour DNA levels can predict response to targeted therapy in advanced breast cancer, with both baseline measurements and early on treatment dynamics showing strong associations with clinical outcomes. Data from the plasmaMATCH trial demonstrate that ctDNA assessment may offer a valuable surrogate marker for progression free survival and objective response across multiple treatment settings.
Baseline ctDNA and Clinical Response
The analysis included 167 patients with advanced breast cancer who had assessable ctDNA results at baseline on cycle one day one and before treatment on cycle two day one. Patients were enrolled in mutation targeted therapy cohorts A–D or a triple negative breast cancer cohort treated with olaparib and ceralasertib, defined as cohort E. Baseline ctDNA levels were evaluated in relation to progression free survival and confirmed objective response rates.
In cohort E, low baseline ctDNA levels were strongly associated with improved outcomes, including longer progression free survival with a hazard ratio: 0.33; p=0.001 and higher objective response rates of 40% compared with 9.7%; p=0.02. In cohorts A–D, baseline ctDNA showed a weaker association with progression free survival, hazard ratio: 0.60; p=0.03 and objective response rates of 15.2% versus 5.7%; p=0.17. Associations between baseline ctDNA and objective response were validated in an independent study population.
On Treatment ctDNA Dynamics
Changes in ctDNA during treatment provided additional prognostic information. Suppression of ctDNA below the median level at cycle two day one was predictive of improved progression free survival in cohorts A–D, with a hazard ratio: 0.47; p=0.001, but not in cohort E. Importantly, undetectable ctDNA at cycle two day one was associated with favourable outcomes across treatment groups. In cohort E, undetectable ctDNA correlated with improved progression free survival, hazard ratio: 0.25; p=0.01, and markedly higher objective response rates of 86% compared with 11%; p=0.01. Most patients with undetectable on treatment ctDNA were wild type for BRCA1, BRCA2, and PALB2.
Implications for Drug Development
The findings suggest that low baseline ctDNA levels may reflect shared biological mechanisms between tumour DNA release and sensitivity to therapy. Both baseline ctDNA and early on treatment dynamics appear to be promising surrogate endpoints for drug development, with ctDNA clearance emerging as a robust predictor of outcome across therapies.
Reference
Browne IM et al. The Prognostic and predictive impact of ctdna levels in patients with advanced breast cancer enrolled on the plasmaMATCH trial. Clin Cancer Res. 2026;32 (1): 148–58.
