Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co-Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer.

Clinical outcomes of tamoxifen (TAM) treatment show wide interindividual variability. Comedications and genetic polymorphisms of enzymes involved in TAM metabolism contributes to this variability. Drug-drug and drug-gene interactions have seldom been studied in African Black populations. We evaluated the effects of commonly co-administered medicines on TAM pharmacokinetics in a cohort of 229 South African Black female patients with hormone-receptor positive breast cancer. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in TAM metabolism, including the variants CYP2D6*17 and *29, which have been mainly reported in people of African descent. TAM and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen, and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry. The GenoPharm open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (P < 0.001 and P < 0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO metabolic ratios but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of ENDO. This study also suggests a low risk of drug-drug interaction in patients with breast cancer on TAM.

Human immunodeficiency virus infection in breast cancer patients: The prevalence thereof and its effect on breast cancer characteristics at Dr. George Mukhari Academic Hospital Breast Clinic, Ga-Rankuwa, South Africa.

BACKGROUND: Since the advent of highly active anti-retroviral therapy, improved immune functioning and prolonged survival of Human immunodeficiency virus (HIV)-positive patients has been accompanied by an increased incidence of non-AIDS-defining cancers (NADC). Breast cancer is the most prevalent NADC among HIV-positive women. However, data regarding the interaction between these two diagnoses remain limited. OBJECTIVES: To determine the effect of HIV status on the presentation of breast cancer patients at Dr. George Mukhari Academic Hospital (DGMAH). METHODS: The age, gender, HIV status, CD4 count and tumour node metastases stage at presentation were recorded from the files of patients with histologically proven breast carcinoma, who had presented to the breast clinic at DGMAH from 01 January 2013 to 30 November 2017. Histological subtypes and molecular markers were retrieved from the National Health Laboratory Service. Prevalence of HIV among breast cancer patients was calculated. Cross-tabulations compared the variables between HIV-positive and HIV-negative groups. Statistical significance was assessed using Fisher's Exact Test. RESULTS: HIV status was determined in 129 breast cancer patients. Eighty (62.02%) were HIV-negative and 49 (37.98%) were HIV-positive. All patients were female. The mean age at presentation with breast cancer in the HIV-positive group was approximately 10 years younger, compared to the entire population and to the HIV-negative group (p < 0.0001). No further statistically significant associations were observed concerning HIV status and other variables. CONCLUSION: HIV-positive women present with breast cancer at a significantly younger mean age. Breast cancer screening protocols may need to be adjusted accordingly in such patients.