Using a cough suppressant syrup as a probe could help physicians determine how well an individual breast cancer patient metabolizes tamoxifen, according to a study presented at the 22nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin. This would enable physicians to identify patients with altered metabolism and use this information to personalize treatment, making it more effective and reducing the risk of side effects, the researchers say.
Tamoxifen is metabolized into endoxifen, which is responsible for the drug’s anticancer activity and which can cause tamoxifen-related side effects. Two enzymes, CYP2D6 and CYP3A, are responsible for metabolizing tamoxifen into endoxifen, and the metabolite forms only if there are sufficient quantities of these enzymes.
Anne-Joy de Graan of the Erasmus Medical Centre, Rotterdam, The Netherlands, who presented the findings, explained that wide variations in toxicity and efficacy are seen in women treated with tamoxifen for prevention or treatment of breast cancer, which are thought to be the result of variance in endoxifen concentrations between patients.
In a prospective study, she and her colleagues studied the effect of dextromethorphan in 40 women with breast cancer who had been taking tamoxifen for more than 3 weeks. Dextromethorphan, the active ingredient in cough suppressant medicine, is metabolized 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,” she said.
The researchers gave their patients 30 mg of dextromethorphan as liquid cough syrup and asked them to take their oral tamoxifen 2 hours later. Over the next 24 hours, they took 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,” de Graan said.
She pointed out that measuring dextromethorphan is easier than measuring levels of the metabolite endoxifen and it can be applied to other compounds that are metabolized by CYP2D6 and CYP3A.
“Tamoxifen is prescribed to women for as much as 5 years in the adjuvant setting, so it is highly important to know beforehand if the therapy is going to be effective. When it is known that a woman metabolizes tamoxifen poorly, a switch in drugs or an increase in dose can be considered,” she said.
She advised, however, that the test needs to be refined and improved so that fewer blood samples are required and it is easier to use, and that it needs to be tested in another group of patients. If this proves successful, the researchers will have to develop a dosing strategy and test it in a phase 3 trial to compare it with current practice.
“Our dextromethorphan test could aid in future studies on the association of tamoxifen and CYP2D6 genotype and phenotype, and ultimately in the personalization of tamoxifen treatment,” de Graan concluded.