Pharmacogenetic Determinants of Chemotherapy Response in Breast Cancer: A Comprehensive Review of Chemotherapeutic Agents

Background: Tumor organoids and pharmacogenetic profiling represent two rapidly advancing tools in precision oncology. Organoids provide physiologically relevant three-dimensional models that retain the genomic, architectural and functional features of patient tumors, enabling high-fidelity drug testing. In parallel, germline pharmacogenetic variation significantly influences chemotherapy metabolism, efficacy and toxicity, particularly in breast cancer. Integrating these approaches offers a powerful framework for individualized therapy selection. Methodology: A narrative review methodology was used to synthesize recent evidence (2006–2025) from PubMed, Scopus, Web of Science and ScienceDirect. Eligible studies included original research on tumor organoid engineering, microenvironmental modelling, drug-response profiling, vascular and immune co-culture systems, and pharmacogenetic determinants of chemotherapy response. Findings were organized thematically across domains of organoid fidelity, microenvironment reconstruction, drug-response prediction, and clinically relevant pharmacogenetic variants. Results: Organoid studies demonstrated high establishment rates, preservation of tumor heterogeneity and improved modeling of stromal, vascular and immune components. Drug-response patterns in organoids correlated strongly with patient outcomes, supporting their role in personalized therapeutic stratification. Parallel evidence shows that key pharmacogenetic variants, including ABCB1, ABCG2 and CBR3 for anthracyclines; CYP2B6 and ALDH1A1 for cyclophosphamide; CYP2C8, CYP3A4 and TUBB2A for taxanes; DPYD and TYMS for fluoropyrimidines; ERCC1 and XRCC1 for platinum agents; and CYP2D6 for tamoxifen, significantly influence treatment toxicity and efficacy. Together, organoid phenotyping and genotype profiling provide complementary insights for clinical decision-making. Conclusion: Advances in biomaterials, microengineering and multi-omic integration are rapidly enhancing organoid reliability, while robust pharmacogenetic markers continue to inform safe and effective chemotherapy use. Combining organoid-based functional testing with pharmacogenetic data offers a strong platform for next-generation precision oncology, enabling more accurate prediction of therapy response and toxicity in breast cancer.