Circulating tumour DNA (ctDNA) levels may serve as a powerful early indicator of how patients with advanced breast cancer respond to targeted therapies, according to new findings from the plasmaMATCH trial. Researchers reported that both baseline ctDNA measurements and early changes during treatment were strongly associated with clinical outcomes, including progression-free survival (PFS) and objective response rates (ORR), suggesting ctDNA could function as a valuable surrogate marker across multiple treatment settings.
Baseline ctDNA Linked to Clinical Outcomes
The analysis included 167 patients with advanced breast cancer who had evaluable ctDNA results at baseline on cycle one day one and again before treatment on cycle two day one. Participants were enrolled in mutation-targeted therapy cohorts A–D or in cohort E, which comprised patients with triple-negative breast cancer treated with a combination of olaparib and ceralasertib.
In cohort E, low baseline ctDNA levels were strongly associated with better outcomes. Patients with lower ctDNA experienced significantly longer progression-free survival (hazard ratio [HR] 0.33; p=0.001) and higher objective response rates (40% versus 9.7%; p=0.02). In contrast, cohorts A–D showed a more modest relationship between baseline ctDNA and outcomes, with a weaker but still significant association with progression-free survival (HR 0.60; p=0.03) and a non-significant trend toward higher response rates (15.2% versus 5.7%; p=0.17). The link between baseline ctDNA and objective response was further validated in an independent study population.
On-Treatment ctDNA Dynamics Add Prognostic Value
Changes in ctDNA levels during therapy provided additional insight into patient prognosis. In cohorts A–D, suppression of ctDNA below the median level by cycle two day one was predictive of improved progression-free survival (HR 0.47; p=0.001), although this effect was not observed in cohort E.
Notably, achieving undetectable ctDNA at cycle two day one was associated with favourable outcomes across all treatment groups. In cohort E, patients with undetectable ctDNA demonstrated significantly longer progression-free survival (HR 0.25; p=0.01) and markedly higher objective response rates (86% versus 11%; p=0.01). Most patients who achieved undetectable ctDNA during treatment were wild type for BRCA1, BRCA2, and PALB2.
Implications for Drug Development
The investigators suggested that low baseline ctDNA levels may reflect underlying biological mechanisms shared between tumour DNA shedding and sensitivity to therapy. Both baseline ctDNA and early on-treatment dynamics appear to be promising surrogate endpoints for drug development. In particular, ctDNA clearance emerged as a robust predictor of outcome across therapies, underscoring its potential role in guiding treatment decisions and accelerating clinical research in advanced breast cancer.
