been thinking about this after reading a few posts here about Tamoxifen side effects being bad enough to warrant stopping or surgical intervention. Tamoxifen is a prodrug - CYP2D6 converts it to endoxifen, which is the thing actually doing the work. poor metabolizers (maybe 7-10% of European-ancestry populations, varies a lot by ancestry) produce way less endoxifen. the assumption has always been that this makes Tamoxifen less effective for poor metabolizers, which is the main clinical concern. but here’s what I haven’t seen addressed cleanly: does CYP2D6 status also affect the side effect profile? you’d think less active metabolite = milder side effects, but the parent compound and other intermediates aren’t inert either.
some of the hot flash and mood-related effects may come from pathways that don’t depend on CYP2D6 in the same way. so the paradox would be: poor metabolizer gets less efficacy AND possibly still gets significant side effects through a different mechanism. worst of both outcomes. anyone here actually had pharmacogenomic testing done before or during Tamoxifen? curious whether anyone’s oncologist even brought it up.