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
