Phenotyping CYP2D6 in localized and in metastasized breast cancer patients using tamoxifen (metCYP study)

Tamoxifen is commonly used for the treatment of localized (LBC) and
advanced/metastatic hormone positive (HR+) breast cancer (MBC). One third of
women with HR+ LBC does benefit from adjuvant tamoxifen, where in two thirds
disease recurs. Similar, In MBC, objective responsive rate is only 27%. This
variable response on tamoxifen treatment may be partially explained by
individual variability in tamoxifen biotransformation to active metabolites, of
which endoxifen is the thought to be most important[3]. CYP2D6 mediated
metabolism is considered the main route of activation into active endoxifen.
CYP2D6 predicted phenotype is an important predictor of treatment outcome in
women who are receiving tamoxifen for MBC where co-administration of CYP2D6
inhibitors worsens treatment outcome of tamoxifen. It was shown that by using
dextromethorphan as a CYP2D6 phenotyping probe, endoxifen exposure in patients
with breast cancer could be predicted. These studies emphasize the value of
CYP2D6 phenotyping over CYP2D6 genotyping when contributing factors like
co-medication are involved.
For CYP2C19, a discordant slow metabolizer phenotype compared to the predictive
genotype was found in patients with advanced metastatic cancer. A possible
explanation for this discordance may be the increased levels of cytokines in
metastatic disease. Cytokines such as IL6 and TNF* have been associated with
reduced CYP1A2, CYP2C and CYP3A mediated metabolism in women in vivo. Although
not studied, it is most likely that the same mechanism applies to CYP2D6
metabolism in patients with advanced cancer.
In MBC, discordance between CYP2D6 predicted phenotype and actual CYP2D6
phenotype might worsen treatment outcome when patients receive standard dose of
tamoxifen. Therefore, it is important to compare the actual CYP2D6 phenotype by
13C-DM-BT in LBC and MBC patients who are currently treated with tamoxifen.

Primary
-To compare CYP2D6 clinical phenotype by a 13C-DM-BT in LBC patients with MBC
patients, and are currently using tamoxifen
-To correlate CYP2D6 clinical phenotype by 13C-DM-BT to serum endoxifen levels
in LBC and MBC patients

Secondary
---To correlate determinants of metabolism (IL-6, TNFa and hypoalbumenia) to
CYP2D6 clinical phenotype by 13C-DM-BT and serum endoxifen levels.

The study has been designed as a cross-sectional phenotyping study in patients
with LBC and MBC, who are currently treated with tamoxifen.

Determination of CYP2D6 clinical phenotype by 13C-dextrometorphan breath test
and using 50 mg 13C-dextromethorphan as a phenotyping probe.

Patients are asked to have fasted overnight prior and during the
dextrometorphan breath test. Patients are allowed to eat again two hours after
start of the breath test.
Patients will be orally administrated 50 mg of 13C-dextromethorphan. No seriois
adverse events are expect to happen.
Duration of the breath test is 2 hours, during which period patients are not
allowed to leave the hospital (because of observation).