Background
Breast cancer is a heterogeneous disease driven by diverse somatic alterations that impact tumor biology and treatment response. Although tissue-based genomic profiling is the standard, it is invasive and limited by tumor accessibility and sampling constraints, potentially leading to delays in prompt results. Liquid biopsy using circulating tumor DNA (ctDNA) offers a minimally invasive alternative for detecting actionable mutations and copy number changes, providing real-time insights into tumor evolution and resistance. Additionally, in advanced breast cancer, clinical guidelines recommend molecular profiling through liquid biopsy, particularly for identifying resistant alterations such as ESR1 and PIK3CA, PTEN, AKT for therapeutic implications in hormone receptor–positive disease. This study characterizes the genomic landscape of advanced breast cancer using ctDNA-based next-generation sequencing (NGS).
Materials and Methods
A retrospective analysis was conducted using data from a reference laboratory on 236 patients with advanced breast cancer who underwent blood-based NGS with Labcorp Plasma Complete as part of standard-of-care management. Samples were collected between January and November 2025. The assay evaluates a comprehensive panel of cancer-related genes to identify single nucleotide variants, insertions/deletions, gene amplifications, and structural rearrangements. Microsatellite instability (MSI) status was also assessed.
Results
Among 236 cases, the most frequent alterations included PIK3CA mutations (27.1%), TP53 mutations (25.0%), and ESR1 mutations (12.7%), notably Y537S and D538G, which are associated with resistance to endocrine therapy. Additional findings included ERBB2 amplifications (3.0%), CCND1 amplification (6.4%), and mutations in PTEN (2.1%), AKT1 (2.5%), and AKT3 (1.7%). MSI was detected in 1 case.
Conclusions
ctDNA-based NGS provides a comprehensive and minimally invasive approach to identify actionable genomic alterations in breast cancer. Detection of ESR1 mutations and PI3K/AKT pathway alterations highlights key mechanisms of endocrine resistance with direct implications for therapy selection. These findings support the integration of liquid biopsy into routine clinical practice to optimize targeted treatment strategies and enable ongoing monitoring of resistance evolution while overcoming tumor accessibility and sampling-constraints barriers seen with tissue-based tumor molecular profiling.
