ctDNA Patterns Track Genomic Risk and Treatment Response in Advanced Breast Cancer

An exploratory analysis of the randomized phase III BRIGHT-2 trial found that circulating tumor DNA (ctDNA) profiles collected during treatment were associated with progression-free survival, molecular response and candidate resistance alterations in advanced breast cancer. Researchers profiled 596 plasma samples from female patients with hormone receptor-positive, HER2-negative advanced breast cancer using a 1,021-gene panel. Samples were collected at baseline, on treatment and at the end of treatment, allowing the investigators to examine changes in tumor-derived genetic material over time.

At baseline, detectable ctDNA and a higher molecular tumor burden were each associated with shorter progression-free survival in both treatment arms. The authors said the pattern was consistent with greater underlying disease burden and intrinsic risk; the observational associations do not show that ctDNA detectability or molecular burden caused the poorer outcomes. The genomic analysis also identified adverse risk features involving MYC, the PI3K–AKT pathway and BRCA or homologous recombination repair genes.

These features characterized an adverse genomic-risk profile among the patients analyzed. PIK3CA and ESR1 status produced an exploratory treatment-informative signal, indicating that their relationship with outcomes differed according to treatment context in the analysis. In separate landmark analyses, on-treatment ctDNA clearance and reductions in molecular tumor burden were associated with favorable subsequent outcomes.

Profiling at the end of treatment identified candidate resistance-associated alterations following bireociclib, including FGFR1, MDM2 and MYC amplifications and activation of the MAPK pathway. These are candidate markers associated with treatment-emergent genomic changes, not definitive resistance biomarkers or evidence of a causal resistance mechanism. Overall, the results indicate that longitudinal ctDNA profiling may provide information for risk stratification, response monitoring and resistance tracking during CDK4/6 inhibitor-based therapy, with the analysis presented as exploratory.

Subject of Research: Longitudinal ctDNA profiling of bireociclib in advanced breast cancer

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

Article References: Wang, Y., Xu, H., Zhou, Y., Cui, L., Sa, Q., Cheng, H., Gao, R., Zhang, Q., Li, H., Tong, Z., Ouyang, Q., Tan, X., Bai, J., Wang, L., Duan, X., Yang, F., Wang, J., & Xu, B. (2026). Longitudinal ctDNA profiling reveals genomic risk and molecular response to bireociclib in advanced breast cancer. Nature Communications. https://doi.org/10.1038/s41467-026-78782-5

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78782-5

Keywords: ctDNA, bireociclib, advanced breast cancer, BRIGHT-2 trial, genomic risk, molecular response, drug resistance, CDK4/6 inhibition, progression-free survival, PIK3CA, ESR1, MAPK pathway