Circulating Tumor DNA and Survival in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Importance: Metastatic breast cancer (MBC) poses a substantial clinical challenge despite advancements in diagnosis and treatment. While tissue biopsies offer a static snapshot of disease, liquid biopsy-through detection of circulating tumor DNA (ctDNA)-provides minimally invasive, real-time insight into tumor biology. Objective: To determine the association between ctDNA and survival outcomes in patients with MBC. Data Sources: An electronic search was performed in 5 databases (CINAHL, Cochrane Library, Embase, Medline, and Web of Science) and included all articles published from inception until October 23, 2023. Study Selection: To be included in the meta-analysis, studies had to (1) include women diagnosed with MBC; (2) report baseline plasma ctDNA data; and (3) report overall survival, progression-free survival, or disease-free survival with associated hazards ratios. Data Extraction and Synthesis: Titles and abstracts were screened independently by 2 authors. Data were pooled using a random-effects model. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, and quality was assessed using the Newcastle-Ottawa Scale. Main Outcomes and Measures: The primary study outcome was the association between detection of specific genomic alterations in ctDNA with survival outcomes. Secondary objectives were associations of study methodology with survival. Results: Of 3162 articles reviewed, 37 met the inclusion criteria and reported data from 4264 female patients aged 20 to 94 years. Aggregated analysis revealed a significant association between ctDNA detection and worse survival (hazard ratio, 1.40; 95% CI, 1.22-1.58). Subgroup analysis identified significant associations of TP53 and ESR1 alterations with worse survival (hazard ratios, 1.58 [95% CI, 1.34-1.81] and 1.28 [95% CI, 0.96-1.60], respectively), while PIK3CA alterations were not associated with survival outcomes. Stratifying by detection method, ctDNA detection through next-generation sequencing and digital polymerase chain reaction was associated with worse survival (hazard ratios, 1.48 [95% CI, 1.22-1.74] and 1.28 [95% CI, 1.05-1.50], respectively). Conclusions and Relevance: In this systematic review and meta-analysis, detection of specific genomic alterations in ctDNA was associated with worse overall, progression-free, and disease-free survival, suggesting its potential as a prognostic biomarker in MBC. These results may help guide the design of future studies to determine the actionability of ctDNA findings.