Abreu MH, Gomes M, Menezes F, Afonso N, Abreu PH, Medeiros R, Pereira D, Lopes C.
Breast. 2015 Aug;24(4):481-6. doi: 10.1016/j.breast.2015.04.010. Epub 2015 May 8.
Cytochrome P450 2D6 is an enzyme that in humans is encoded by the CYP2D6 gene, and is primarily expressed in the liver. CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, and is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, in a process referred to as O-demethylation. (Wikipedia)
In the case of tamoxifen it is known to convert the drug that is in the pill (tamoxifen) to the active drug (4-hydroxytamoxifen). This is not unusual – very often the molecule in the medication is not the actual active molecule, and the final conversion to the active form occurs in the body.
Not all forms of CYP2D6 are equal – there are so called polymorphisms in the gene that have subtle effects on the efficiency of the enzyme produced. You can think of this as similar to small differences between, say, different versions of the same car. Some may have differences in engine size, for example, and so although they are basically the same car, performance may vary slightly. In the case of CYP2D6 this difference in performance could be how quickly and completely it metabolizes the tamoxifen into 4-hydroxytamoxifen.
The polymorphism being studied here is the ‘*4’, which shows lowered activity. About 10% of caucasians carry this polymorphism. All samples in this study were from caucasian men which is presumably why the authors chose to study this particular allele. People who have *4 are intermediate metabolizers as a result. Remember you have two versions of most genes, one from mom and one from dad – it is very rare to have two copies of a poorly functioning gene of this kind – probably not viable. So with one functioning allele and one non-functioning, you have half the metabolizing power (more or less).
There are quite simple genetic tests that allow you to determine which form of CYP2D6 a person has, and then correlate that to how well a drug therapy works – this was done here for the first time for male breast cancer and tamoxifen.
When the disease free survival of men with breast cancer was measured, it was found that overall men with the *4 allele had an estimated disease free survival of 13.1 years vs men who did not carry this allele who had an estimated disease free survival of 17.9 years. So normal metabolizers had survival of almost half as much again as the poorer metabolizers! Another way to think of this is perhaps that the men with the *4 experienced lower effective doses of tamoxifen.
When other factors were taken into account, and there were enough people in the sample to be able to do statistics, the authors found that there was always a benefit to not having the 4* allele. Here is a summary of the mean disease free survivals reported for different groups, in years:
|Group||Mean disease free
survival – no *4
|Mean disease free
survival – with *4
|Tumors larger than 2 cm||17.9||3.6|
|Node status of N0||17.7||11.7|
|Node status of N+||14.3||13.1|
This suggests that the *4 polymorphism has impact on survival in addition to these other factors. It also means that knowing this status could guide decisions even when these other factors are taken into consideration.
First some caveats: there have been many studies of this issue in women, and the results have not always agreed with each other. It is therefore not impossible that another study in men would also have contradictory results. As always, more study is probably needed (I know – I say this in every paper report post… but unfortunately at this early stage in the field, it is going to be the case – we need to await large, definitive studies for men). Also, as often/always, there were not that many patients in this study – 53 to be exact. For now, let’s continue on the basis that this study is correct (at least for caucasian men).
Given the information in the study, it might be worth knowing the metabolizer status if only to be more vigilant for men who are poorer metabolizers. Of course most cancer patients are closely followed anyway… or should be.
Given that the problem lies in the metabolism of tamoxifen into the active 4-hydroxytamoxifen, an obvious work around is to just deliver the active 4-hydroxytamoxifen itself. While this is not possible orally (probably doesn’t survive in the digestive system or is not absorbed) it might work via another route. Interestingly a trans-dermal formulation of 4-hydroxytamoxifen is being developed. Perhaps a clinical trial for people who are poorer metabolizers could be considered?
Another consideration, given my recent post about the possibility that aromatase inhibitors might be effective for men, is that poor metabolizers of tamoxifen might be considered more carefully for this class of agents. (I don’t know if the aromatase inhibitors have the same dependence on CYP2D6, but of course this would need to be factored in.)
Lastly, if you are a poor metabolizer and stuck with oral tamoxifen, perhaps adjusting the time of day when you take it, might make a difference if recent animal experiments showing cooperation between tamoxifen and melatonin are correct and borne out in humans.