by ecancer reporter Janet Fricker

Cough medicine could be used as a “probe” to identify the women with breast cancer who have altered metabolism for the drug  tamoxifen, suggests an abstract presented at the 22^nd EORTC-NCI-AACR  Symposium on Molecular Targets and Cancer Therapeutics (16 to 19 November,  Berlin, Germany).   Introduction of the test, suggested the investigators, could help to individualise patient treatment.

Tamoxifen - widely used in the treatment and prevention of breast cancer-  is metabolised by CYP2D6 and CYP3A into endoxifen, the active metabolite responsible for its anticancer activity. Widespread variation in the toxicity and efficacy of tamoxifen is thought to result from variations in the concentrations of endoxifen between patients  influenced by genetic profiles, co-medications and  life style factors (such as smoking behaviour and alcohol consumption).  Dextromethorphan, the active ingredient in cough suppressant medication, is known to be metabolised in the same way as tamoxifen, with levels of dextromethorphan metabolites known to be far easier to measure than endoxifen.

In the current study, Anne-Joy de Grann and colleagues from Erasmus Medical Centre (Rotterdam, The Netherlands) gave 40 breast cancer patients who had been taking tamoxifen for more than three weeks, 30 mg of dextromethorphan in the form of a liquid cough syrup. Over 24 hours the investigators took blood samples to measure both dextromethorphan and tamoxifen metabolites and then calculate how well dextromethorphan metabolism predicted tamoxifen metabolism. Dextromethorphan and metabolites (dextrorphan, 3-metoxymorphinan, and 3 hydroxymorphinan) and tamoxifen and metabolites  (4-hydroxy tamoxifen, N-desmethyl tamoxifen and endoxifen) were quantified.

Results showed a  highly significant correlation was found between the clearance of dextromethorphan and endoxifen (r=-0.72,p=0.0001).  In one patient the effect of use of the strong CYP2D6 inhibitor paroxetine on endoxifen levels was accurately predicted by levels of dextromethorphan.

 “Tamoxifen is prescribed to women for as much as five years in the adjuvant setting, so it is highly important to know beforehand if the therapy is going to be effective,” said de Grann. “When it is known that a woman metabolises tamoxifen poorly, a switch in drugs or an increase in dose can be considered.”

Using the probe, she added, is more effective than genotyping since it can also take into account additional individual differences such as co-medications and life-style factors.

Reference

AJ de Graan, SF Teunissen, FY de Vos et al. Hormonal agents. Predictive value of a dextromethorphan phenotyping test for endoxifen exposure. Abstract no 654. . EORTC-NCI-AACR Symposium.