Tamoxifen has an established role in the treatment of hormone receptor positive invasive breast cancer.1 Evidence has emerged in recent years that the main pharmacological effects of tamoxifen are not mediated by the parent drug itself but by an active metabolite called endoxifen (4-hydroxy-N-desmethyltamoxifen).2 The bioactivation of tamoxifen to endoxifen is mainly catalysed by the cytochrome P450 isoenzyme 2D6 (CYP2D6).2 Certain drugs inhibit the activity of CYP2D6, and this results in decreased plasma concentrations of endoxifen.2 3

In the linked observational study (doi:10.1136/bmj.c693), Kelly and colleagues show that the risk of breast cancer related death is higher in women taking tamoxifen plus the selective serotonin reuptake inhibitor (SSRI) paroxetine. The authors suggest that this is explained by inhibition of CYP2D6.4

SSRIs are prescribed for women with breast cancer who are taking tamoxifen for two main reasons. Firstly, to treat depression or anxiety, and, secondly, to reduce hot flushes, which are a common side effect of tamoxifen. Some SSRIs such as paroxetine are strong inhibitors of CYP2D6. It is reasonable to suggest that concomitant use of these drugs attenuates the clinical effectiveness of tamoxifen, but observational data supporting this hypothesis were lacking until …