Longitudinal ctDNA profiling reveals genomic risk and molecular response to bireociclib in advanced breast cancer

Bireociclib plus fulvestrant improves outcomes in hormone receptor-positive, HER2-negative advanced breast cancer, but molecular determinants of benefit and resistance remain unclear. Here we report an exploratory longitudinal circulating tumor DNA (ctDNA) analysis of the randomized phase Ⅲ BRIGHT-2 trial (ClinicalTrials.gov, NCT05077449) in female patients, profiling 596 plasma samples collected at baseline, on treatment, and at end of treatment with a 1,021-gene panel. Detectable baseline ctDNA and higher molecular tumor burden are associated with shorter progression-free survival in both arms, consistent with greater disease burden and intrinsic risk. MYC, PI3K–AKT and gBRCA/HRR alterations define adverse genomic risk, whereas PIK3CA–ESR1 status shows an exploratory treatment-informative signal. Landmark analyses link on-treatment ctDNA clearance or molecular tumor burden reduction with favorable subsequent outcomes. End-of-treatment profiling identifies candidate resistance-associated alterations after bireociclib, including FGFR1, MDM2, and MYC amplifications and MAPK pathway activation. Longitudinal ctDNA profiling may refine risk stratification, response monitoring, and resistance tracking during CDK4/6 inhibitor-based therapy. This study shows that tracking tumor DNA in blood can help predict outcomes, monitor treatment response, and reveal resistance in women receiving bireociclib plus fulvestrant for hormone receptor-positive, HER2-negative advanced breast cancer.