Dynamic monitoring and identification of reliable biomarkers to predict efficacy of bireociclib and fulvestrant: An exploratory ctDNA analysis of the BRIGHT-2 study

Background Although the novel cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor bireociclib demonstrated potent efficacy for hormone receptor -positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in the BRIGHT-2 study (NCT05077449), patient exhibited substantial heterogeneity in therapeutic efficacy-some demonstrated high sensitivity, while others rapidly developed resistance. Consequently, a critical research aim is to ascertain sensitivity before treatment initiation and define biomarkers that can dynamically detect therapeutic outcomes earlier than imaging. Methods Based on the BRIGHT-2 study, longitudinal circulating tumor DNA (ctDNA) analysis was performed using a 1021-gene panel at baseline, on-treatment, and end-of-treatment timepoints. Somatic mutations were identified and molecular tumor burden index (mTBI) was calculated. Survival analyses employed Kaplan-Meier curves with log-rank tests and Cox proportional hazards models, while the interaction analysis between treatment and gene alternations were conducted using False Discovery Rate (FDR) method. All the analyses were performed using R software, with statistical significance set at p<0.05. Results The bireociclib group collected 197, 139, and 86 ctDNA samples from three timepoints, compared with 79, 46, and 49 from placebo group. The most frequently mutated genes were PIK3CA (48%), TP53 (37%), and ESR1 (23%). Patients with ctDNA-positive or high mTBI had conspicuously shorter progression-free survival (PFS) and overall survival (OS) than those with ctDNA-negative or low mTBI. The gene alterations in CCND1 and FGF19 were associated with a greater PFS benefit with bireociclib versus placebo (FDR-adjusted P values of 0.030 and 0.002, respectively). The gBRCA and homologous recombination repair genes mutation indicated poorer prognosis compared to wild-type in bireociclib group. Dynamic clearance of ctDNA or specific gene mutations was correlated with improved efficacy and survival outcomes for CDK4/6 inhibitor. Conclusions Both baseline and dynamic monitoring of ctDNA demonstrated salient predictive value for treatment response and survival outcomes in hormone receptor-positive, HER2-negative breast cancer patients receiving bireociclib plus fulvestrant. These potential biomarkers warrant further validation through larger clinical trials and basic researches. Key words: CDK4/6 inhibitor, advanced breast cancer, biomarkers, bireociclib, prognosis.