and Genetic Variants Modulate Side Effect Profiles in South African Breast Cancer Patients Treated with Tamoxifen.

: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. : A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including , , , , , and , was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. : Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with copy number variation ( = 0.030) and rs3736599 ( = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with rs7439366 ( = 0.040) and rs2242480 ( = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to ( = 0.050), rs3736599 ( = 0.016), and rs4148269 ( = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. : This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy.