Tamoxifen Pharmacogenomics and the Prevention of Recurrent Breast Cancer

Trial Information

Tamoxifen Pharmacogenomics and the Prevention of Recurrent Breast Cancer

Tamoxifen is a non-steroidal hormonal drug with weak estrogen agonist and potent estrogen
antagonist actions. The liver CYP450 metabolic enzyme systems are responsible for
metabolizing tamoxifen (the pro-drug form) into its active metabolites. A secondary
tamoxifen metabolite known specifically as 4-hydroxy-N-desmethyl-tamoxifen or endoxifen is
recognized as the principal potent metabolite responsible for tamoxifen suppression of
estrogen-dependent cell proliferation, the stimulus for breast tumor growth.
Biotransformation to endoxifen is through the CYPP450 2D6 pathway; therefore, the ability of
tamoxifen to effectively suppress breast cancer is jeopardized in patients with certain
CYP450 2D6 genetic variants and/or those receiving drug therapy that are known to alter
CYP450 2D6 function (i.e., with CYP450 2D6 inhibitors).

Four phenotype expressions classified as ultrarapid, extensive, intermediate and poor
metabolizers can be discerned from genotype testing for CYP450 2D6 activity. Patients with
normal metabolic activity are known as extensive metabolizers given that they possess either
two (genotype = wt/wt) or one (genotype = wt/vt) functioning CYP450 2D6 gene that converts a
sufficient amount of tamoxifen in to its active form. Intermediate metabolizers have at
least some or very low CYP450 2D6 activity and there does not appear to be uniform consensus
on the impact of this phenotype on tamoxifen drug disposition. Poor metabolizers lack any
functional CYP450 2D6 activity, and therefore, they do not metabolize tamoxifen enough to
produce sufficient endoxifen activity. Approximately 10% of patients (7% of Caucasians and
1-3% of other ethnic groups) are poor metabolizers with a complete absence of CYP450 2D6
activity.

The genetic variants associated with diminished or absent CYP450 2D6 activity are found on
CYP450 2D6 alleles *3, *4, *5, *6 and *10. The *3, *4, *5 and *6 alleles, when present in
variant form (genotype = vt/vt), account for approximately 97% of nonfunctional CYP450 2D6
variants in caucasians. Of these mutations, those in CYP450 2D6 *4 are most significant for
endoxifen.

Poor metabolizer phenotype has been associated with worse relapse-free breast cancer
survival and increased risk (up to three times that of intermediate metabolizer status who
have some CYP450 2D6 activity) for breast cancer recurrence.

Diagnostic technology now exists to aid in determining which tamoxifen patients are
potentially receiving suboptimal treatment from existing alterations in one or more of the
approximately 80 alleles of the gene coding for the CPYP450 2D6 enzyme. Recognition of this
phenomenon provides physicians and their patients the opportunity for considering the use of
other anti-estrogen drugs such as aromatase inhibitors in women whose CYP450 2D6 phenotype
puts them at risk for poor response to tamoxifen therapy.

This study will use this diagnostic technology to determine a patient's phenotype provide
additional clinical information and alternative drug therapies to the patient's physician.