Real-World Use of Highly Sensitive Liquid Biopsy Monitoring in Metastatic Breast Cancer Patients Treated with Endocrine Agents after Exposure to Aromatase Inhibitors

Endocrine-resistant, hormone receptor-positive, and HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) is largely governed by acquired mutations in the estrogen receptor, which promote ligand-independent activation, truncal alterations PI3K signaling pathway, with a broader range of gene occurring less prevalence. Circulating tumor DNA (ctDNA)-based technologies are progressively permeating clinical setting. However, their utility for serial monitoring has been hindered significant costs, inter-technique variability, real-world patient heterogeneity. We interrogated longitudinal collection 180 plasma samples from 75 HR+/HER2- mBC patients who progressed or relapsed after exposure to aromatase inhibitors were subsequently treated endocrine therapy (ET) means highly sensitive affordable digital PCR SafeSEQ sequencing. Baseline PIK3CA TP53 prognostic shorter progression-free survival our population. Mutant was subset receiving fulvestrant monotherapy progression CDK4/6 inhibitor (CDK4/6i)-containing regimen, its suppression predictive case long-term benefit alpelisib. ESR1 did not receive concurrent CDK4/6i, an impact influenced variant allele frequency, early strongly efficacy associated whole cohort. Mutations ESR1, TP53, KRAS emerged as putative drivers resistance. These findings collectively contribute characterization ctDNA cases previously exposed support ongoing studies either targeting actionable leveraging ultra-sensitive tracking ctDNA.