Evaluating Longitudinal ctDNA Testing for Molecular Progression During CDK4/6 Inhibitor Therapy

Longitudinal circulating tumor DNA (ctDNA) surveillance represents a paradigm shift from traditional imaging-based progression monitoring to molecular-based treatment decisions. Findings from the PADA-1 trial initially demonstrated benefits of switching therapy upon ESR1 mutation emergence rather than waiting for radiological progression. Patients on first-line aromatase inhibitor plus CDK4/6 therapy who developed ESR1 mutations were randomly assigned to switch to fulvestrant plus CDK or continue their original regimen, showing positive outcomes for the switching strategy.

The Serena-6 trial expanded this concept using oral selective estrogen receptor degraders, collecting ctDNA every 3 months and randomly assigning patients with emerging ESR1 mutations to camizestrant plus CDK continuation vs continuing aromatase inhibitor plus CDK therapy. This approach demonstrated progression-free survival benefits, supporting molecular progression–guided treatment changes. Quality-of-life improvements and prolonged time to deterioration were observed with the camizestrant/CDK switch approach.

Critical questions remain about whether molecular progression–based interventions will ultimately improve overall survival or simply advance effective treatments earlier in the treatment journey without significant survival impact. The approach faces practical considerations, including the screening requirements (3000 patients screened for 300 randomly assigned) and median time to ESR1 mutation emergence of 22 months. Until mature overall survival data become available, treatment decisions should involve careful patient-physician discussions weighing potential benefits against current evidence limitations.