Pharmacogenetics of Breast Cancer Treatments: A Sub-Saharan Africa Perspective.

Breast cancer is the most frequent cause of cancer death in low- and middle-income countries, in particular among sub-Saharan African women, where response to available anticancer treatment therapy is often limited by the recurrent breast tumours and metastasis, ultimately resulting in decreased overall survival rate. This can also be attributed to African genomes that contain more variation than those from other parts of the world. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to specific available treatments and the known genetic variabilities associated with metabolism and/or transport of breast cancer drugs, and treatment outcomes when possible. The emphasis is on the African genetic variation and focuses on the genes with the highest strength of evidence, with a close look on CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, CYP19A1, UGT1A4, UGT2B7, UGT2B15, SLC22A16, SLC38A7, FcγR, DPYD, ABCB1, and SULT1A1, which are the genes known to play major roles in the metabolism and/or elimination of the respective anti-breast cancer drugs given to the patients. The genetic variability of their metabolism could be associated with different metabolic phenotypes that may cause reduced patients' adherence because of toxicity or sub-therapeutic doses. Finally, this knowledge enhances possible personalized treatment approaches, with the possibility of improving survival outcomes in patients with breast cancer.

Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer.

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment.

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites.

BACKGROUND: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4'-endoxifen and Z-4'-OHtam, have also been reported to be associated with tamoxifen efficacy. METHOD: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. RESULTS: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. CONCLUSION: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen.

Low steady-state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor-positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4-hydroxy-tamoxifen (Z-4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC -specific survival in patients with the previously described serum concentration threshold of Z-4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02-5.48, P = 0.039). The 'dose-response' survival trend in patients categorized to ordinal concentration cut-points of Z-4OHtamoxifen (≤ 3.26, 3.27-8.13, > 8.13 nm) was also replicated (P-trend log-rank = 0.048). Z-endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.