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

Abstract

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.

Figure 1.. PRISMA Flow Diagram of the Literature Search and Study Selection

ctDNA indicates circulating tumor DNA; DFS, disease-free survival; OS, overall survival; PFS, progression-free survival.

Figure 2.. Visual Summary of Study Characteristics

cfDNA indicates cell-free DNA; ctDNA, circulating tumor DNA; DFS, disease-free survival; dPCR, digital polymerase chain reaction; HR, hormone receptor; NGS, next-generation sequencing; OS, overall survival; PFS, progression-free survival.