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

<b>Background</b>: 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. <b>Methods</b>: 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 <i>CYP2D6</i>, <i>CYP3A4/5</i>, <i>UGT1A4</i>, <i>UGT2B7/15</i>, <i>SULT1A1/2</i>, and <i>SULT1E1</i>, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. <b>Results</b>: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with <i>SULT1A1</i> copy number variation (<i>p</i> = 0.030) and <i>SULT1E1</i> rs3736599 (<i>p</i> = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with <i>UGT2B7</i> rs7439366 (<i>p</i> = 0.040) and <i>CYP3A4</i> rs2242480 (<i>p</i> = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to <i>SULT1A2*2</i> (<i>p</i> = 0.050), <i>SULT1E1</i> rs3736599 (<i>p</i> = 0.016), and <i>UGT2B15</i> rs4148269 (<i>p</i> = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. <b>Conclusions</b>: 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.