Metastatic breast cancer is a heterogeneous disease entity with varying genomic alterations. Mutations may be acquired through tumor evolution under the pressure of treatment. While both tumor tissue genotyping and cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) may be used to identify actionable mutations for therapeutic intervention, cfDNA/ctDNA offer the advantages of being less invasive and more feasible for serial sampling, which make them conducive for real-time tumor genotyping. In addition, due to heterogeneity within a tumor, a single tumor tissue biopsy may not capture all mutations present. This article examines cfDNA assays, which may serve as a complementary tool to tumor tissue genotyping for guiding treatment selection in metastatic breast cancer. The biology of cfDNA release, preanalytical handling, assay platforms, and detection limits are summarized here. Actionable genomic mutations such as PIK3CA, ESR1, ERBB2, BRCA1/2, and AKT/PTEN are reviewed in relation to their corresponding therapeutic agents. Implementation challenges, pre-analysis pitfalls, uncertain sampling cadence, cost barriers, and disparities in access are discussed, along with potential solutions.
Bello et al. (2026) studied this question.