Background/Objectives: Breast cancer (BC) is a highly prevalent neoplasm worldwide. Despite the wide range of therapeutic options currently available, it remains the leading cause of cancer-related mortality among women. Capecitabine, a prodrug of 5-fluorouracil (5-FU), is widely used in the treatment of advanced BC. However, despite its efficacy, capecitabine exhibits considerable interindividual variability in therapeutic response. This study aimed to evaluate the effect of single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine bioactivation on progression-free survival (PFS) in patients with BC. Methods: An ambispective cohort study was conducted. Four relevant SNPs in the CES1, CDA, and TYMP genes were analyzed in 85 Caucasian patients with BC using real-time polymerase chain reaction (PCR) with TaqMan® probes. Results: A significant association was observed between shorter PFS and the GA genotype of the CES1 rs71647871 SNP (p = 0.010; HR = 7.46; 95% CI = 1.24–122.52), as well as with the TT genotype of the CDA rs602950 SNP (p = 0.009; HR = 3.50; 95% CI = 1.36–9.03). Conclusions: These findings suggest that CES1 rs71647871 and CDA rs602950 may serve as predictive biomarkers of capecitabine effectiveness in patients with BC. Further studies involving larger cohorts are needed to validate these findings and generate additional evidence to support their potential implementation in clinical practice.
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