Purpose <p>Patients with a DPYD genetic deficiency who receive capecitabine are at increased risk of severe, potentially fatal toxicities due to impaired drug metabolism. Genetic testing for this deficiency allows for proactive dose adjustments to mitigate these risks. We evaluated the cost-effectiveness of DPYD genotyping prior to capecitabine administration, followed by dose modification for patients with metastatic breast cancer.</p> Methods <p>We developed a state-transition model to simulate health outcomes and costs for a cohort of 62-year-old women with metastatic breast cancer from the perspective of the U.S. healthcare payer. Costs and utilities were derived from the literature to calculate quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) for DPYD genotyping compared to no DPYD genotyping. We conducted deterministic and probabilistic sensitivity analyses to identify factors influencing cost-effectiveness.</p> Results <p>The genotyping strategy was cost-effective, with a cost of $2,832 yielding 1.16 QALYs, compared to $2,677 and 1.15 QALYs for the no-genotyping strategy. This resulted in an ICER of $12,916/QALY and $10,333 per life-year-gained. In probabilistic sensitivity analysis, the genotyping strategy was cost-effective in 99% of the simulations, using a willingness-to-pay threshold of $100,000/QALY. Results from scenario analyses testing key assumptions also showed that genotyping is cost-effective.</p> Conclusion <p>Our findings support the implementation of DPYD genotyping prior to capecitabine initiation in metastatic breast cancer patients. This strategy exemplifies the value of personalized medicine and pharmacogenomics in improving treatment safety and effectiveness. As sequencing technologies advance and become affordable, integration of genotyping into routine oncology care is increasingly feasible.</p>