Challenges, Ethics, and Cost-Effectiveness of Using Whole Exome Sequencing for Chemoprevention Assessment

Abstract

Whole-exome sequencing (WES) has emerged as a powerful tool for enhancing cancer chemoprevention by enabling genomic risk stratification, pharmacogenomic tailoring, and mechanistic insight beyond traditional clinical risk models. This comprehensive review evaluates the feasibility, ethical considerations, regulatory landscape, and cost-effectiveness of implementing WES in cancer prevention settings. We synthesize evidence demonstrating that WES can identify high- and moderate-penetrance germline variants, inform polygenic risk assessment, and guide personalized chemoprevention and surveillance strategies, particularly in enriched high-risk populations. However, widespread adoption is constrained by substantial infrastructure requirements, challenges in defining evidence-based surveillance intervals, and unresolved ethical issues surrounding incidental findings, informed consent, genetic discrimination, and equity across diverse ancestries. Regulatory frameworks for WES-guided prevention remain heterogeneous and continue to evolve, while economic evaluations suggest context-dependent cost-effectiveness influenced by population risk, healthcare system structure, and downstream intervention costs. We propose an integrated, equity-centered implementation framework emphasizing standardized risk protocols, genetic counseling integration, transparent consent processes, and prospective evidence generation to responsibly advance WES-guided precision chemoprevention.