Rationale & Objectives: This research proposal seeks to understand the pharmacogenomic and pharmacokinetic basis of tamoxifen (TAM) treatment failure for breast cancer in black African women.

Objective 1a: validate known ADME variants of enzymes involved in TAM metabolism for the prediction of treatment failure (sub-therapeutic plasma concentrations of endoxifen).

Objective 1b: evaluate the impact of confounding co-treatment for common co-infections (HIV, TB) and co-morbidities (hypertension and depression) in the prediction of treatment outcome.

Progress to date: We enrolled 640 participants at three sites; (b) From 369 participants from CHBAH and CMJAH we measured concentrations of TAM and its metabolites and genotyped known genetic variants of enzymes involved in tamoxifen metabolism, with 90 more planned for the Dr George Mukhari Academic Hospital site (SMU) where 90 participants were enrolled and the balance from the CHBAH and CMJAH sites.

Results are i) the urban cohort is generally poorly adherent, and we have submitted a paper for publication in early August 2022. We anticipate better adherence from the rural SMU patients ii) HIV/ART is associated with nonadherence to tamoxifen treatment. iii) There is lack of risk for drug-drug interactions in our cohort of African breast cancer patients on tamoxifen and on efavirenz- based ART treatment, anti-hypertensive or antidiabetic medications routinely prescribed. The African specific CYP2D6*17 and *29 are clearly associated with the reduced metabolism of N-Desmethyl-tamoxifem (NDM) to endoxifen (ENDO) in the order CYP2D6*17>*29. These data are presented in the manuscript that is under review for publication.

Objective 2: i) discover novel variants in a subset of the cohort whose TAM treatment failure is not explained by current known ADME variants.

Progress to date: We have discovered 100 participants that will be deep sequenced.

Objective 3: Conduct pharmacokinetic modelling to inform current treatment guidelines for TAM use and dosing based on findings

Progress to date: A structural model has been developed that captures exposure levels of tamoxifen and its metabolites as shown in the literature. This model is now being interrogated for the effects of the variants in each of the drug metabolising enzymes, CYP2B6, 2D6, 2C9, 2C19, 3A4 and 3A5 to explain the variable exposure of tamoxifen and metabolites in the patient study population.