Interlesional Heterogeneity of EGFR Mutations: A Systematic Review and Meta-analysis

Area of Science:

• Oncology
• Genomics
• Translational Medicine

Background:

• Activating EGFR mutations are crucial in NSCLC and other solid tumors, guiding TKI therapy.
• Tumor heterogeneity and sampling issues can lead to discordant EGFR test results, complicating treatment.
• Limited systematic data exists on the prevalence and causes of EGFR mutation discordance.

Purpose of the Study:

• To systematically review and meta-analyze the prevalence and predictors of EGFR mutation discordance across different tumor types and biopsy strategies.
• To provide a comprehensive overview of EGFR discordance in adult solid tumors.

Main Methods:

• Systematic review and meta-analysis following PRISMA guidelines, searching MEDLINE, Embase, and Scopus (2004-2024).
• Included studies comparing primary vs. metastatic tumors, tissue vs. liquid biopsies, or different liquid biopsies.
• Random-effects meta-analysis used to estimate pooled discordance rates and explore predictors via subgroup analysis and meta-regression.

Main Results:

• 154 studies (15,560 patients) showed a pooled EGFR discordance rate of 16.1%.
• Discordance was higher in liquid-liquid biopsies (34.0%) than tissue-tissue (16.8%) or tissue-liquid (15.5%). Cerebrospinal fluid had the highest discordance (35.5%).
• Prior TKI exposure (25.8%) and developing resistance (21.0%) were associated with higher discordance.

Conclusions:

• EGFR mutation discordance is common in NSCLC and other solid tumors, influenced by sampling, biofluid, treatment, and metastatic site.
• Pooled estimates are descriptive due to heterogeneity and study population biases (NSCLC, Asian cohorts).
• Integrated and context-aware sampling strategies are recommended for EGFR-targeted therapy and monitoring resistance.