Cough medicine could help doctors identify how breast cancer patients metabolize tamoxifen

Cough medicine could be used as way of predicting how well individual patients metabolise tamoxifen used in the treatment of their breast cancer, according to new research presented at the 22nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin today (Friday).

The findings suggest that it could be possible to use cough suppressant syrup as a probe, which would enable doctors to identify patients with altered metabolism and use this information to improve individual treatment, making it more effective and reducing the chances of side-effects.

Tamoxifen, which is widely used both to treat and prevent breast cancer, is metabolised by the body into endoxifen, which is responsible for the drug's anti-cancer activity and which can cause tamoxifen-related side-effects. Two enzymes, CYP2D6 and CYP3A, are responsible for metabolising tamoxifen into endoxifen, and the metabolite forms only if there are sufficient quantities of these enzymes.

Mrs Anne-Joy de Graan, a PhD student in the medical oncology department at the Erasmus Medical Centre in Rotterdam (The Netherlands), who presented the study, explained: "At present, all patients treated with tamoxifen in The Netherlands are prescribed a fixed dose of 20 mg or 40 mg. But there is a large difference in the toxicity (for example, hot flushes, endometrial cancer and thrombosis) and efficacy of this agent. This is thought to be the result of variance in endoxifen concentrations between patients. Recently, research has focused on whether this variation in endoxifen levels is caused by patients' individual genetic make-up. We know that there are genetic variations that cause women to be 'poor metabolisers'. This means that these women cannot form enough endoxifen due to absence of CYP2D6 enzymatic activity." In addition, other factors can influence a way a woman metabolises tamoxifen, such as CYP3A enzymatic activity, the use of other medicines, alcohol consumption and smoking.

Mrs de Graan and her colleagues at Erasmus studied the use of dextromethorphan, the active ingredient in cough suppressant medicine, in 40 breast cancer patients who had been taking tamoxifen for more than three weeks. Dextromethorphan is metabolised in the same way as tamoxifen and is harmless to the patient. "It is a so-called 'probe' drug, a harmless substance that can be used to predict the metabolism of another drug. We used dextromethorphan to evaluate its use as a probe drug for tamoxifen metabolism," she said.

The researchers gave their patients 30mg of dextromethorphan as liquid cough syrup and then asked them to take their oral tamoxifen two hours later. Over the next 24 hours they took different blood samples to measure both dextromethorphan and tamoxifen metabolites, and then calculated how well dextromethorphan metabolism predicted and correlated with tamoxifen metabolism.

"We found that dextromethorphan is a very good way to predict endoxifen concentrations," said Mrs de Graan. One patient was taking the anti-depressant, paroxetine, which is known to inhibit CYP2D6, and the dextromethorphan probe accurately predicted the resulting lower concentrations of endoxifen.