Prognostic and predictive impact of circulating tumor DNA levels in patients with advanced breast cancer in the phase 2 plasmaMATCH trial

Post hoc analysis of the phase 2 plasmaMATCH trial (18 UK centers) investigated whether circulating tumor DNA (ctDNA) dynamic levels can identify patients who will respond to therapy among patients with advanced breast cancer (aBC) who received mutation-tergeted therapies (cohorts A-D) or olaparib plus ceralasertib for triple-negative breast cancer (cohort E). Blood samples were collected at baseline (C1D1) and before treatment on cycle 2 day 1 (C2D1). Circulating DNA ratio (CDR) was calculated as the ratio of C2D1/C1D1. 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 (40.9% versus 9.7%; p=0.02). In cohorts A-D there was a weaker association with PFS (HR 0.60; p=0.03) and ORR (15.2% versus 5.7%; p=0.17). For on-treatment dynamics, suppression of ctDNA below the median was predictive in cohorts A-D (HR 0.47; p=0.001) but not in cohort E (HR 1.02; p=0.94). Undetectable ctDNA levels at C2D1 was associated with good outcomes in all cohorts. The authors conclude that 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 outcome.