CYP2D6 genotype and tamoxifen response: meta-analysis of heterogeneous population

Tamoxifen treatment results in substantial inter-individual variability of outcome, possibly due to genetic variability in CYP2D6. The clinical usefulness of CYP2D6 genotyping for prediction of tamoxifen outcome has not been established because of conflicting reports.   This controversy is well illustrated by secondary analyses from 3 large adjuvant tamoxifen trials (ATAC, BIG 1-98, and ABCSG 8), which came to different conclusions regarding the association between CYP2D6 genotype variants.  The International Tamoxifen Pharmacogenomics Consortium (ITPC) was established to aggregate the worldwide experience regarding CYP2D6 and the clinical outcomes of tamoxifen as adjuvant therapy for breast cancer. It comprises twelve research projects from nine countries and three continents that contributed clinical and genetic data for a total of 4,973 breast cancer patients treated with tamoxifen. Investigators from ITPC performed a meta-analysis on data from 4,973 tamoxifen treated patients and the result was just released in Journal Clinical Pharmacology and Therapeutics. The meta-analysis showed that “CYP2D6 poor metabolizer status was associated with poorer Invasive Disease-Free Survival (IDFS: HR=1.25; 95% CI 1.06, 1.47; P=0.009)” in patients meeting strict criterion. “However, CYP2D6 was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (Criterion 2, n=2443; 49%; P=0.25) nor when no exclusions were applied (Criterion 3, n=4935; 99%; P=0.38)”. This study demonstrates the complexity of performing a retrospective biomarker study. The lack of effect in the entire heterogeneous population highlights the need for prospective studies to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.The data used in the meta-analysis are available for download on the PharmGKB. --Blog post written by Li Gong