New international guidelines have been published about how genetics guide Tamoxifen use, specifically polymorphisms in the gene CYP2D6. Let’s see what our genes can tell us.
Tamoxifen is a hormonal agent used in women for the prevention and treatment of both premenopausal and postmenopausal estrogen receptor positive (ER+ve) breast cancer (BC). It is also used as a treatment for breast cancer in men. New guidelines help physicians figure who to prescribe this drug for, based on gene polymorphisms.
What is Tamoxifen?
Tamoxifen is known as a selective estrogen-receptor modulator (SERM) and as an anti-estrogen. It binds to estrogen receptors and thus helps prevent estrogens from having biological effects in the body, as they can then no longer bind to those receptors.
This sounds good and just what you might want after ER+ve BC. However, there are some serious side effects associated with their use including a small increased risk of uterine cancer, stroke, pulmonary embolism, along with common side effects like hot flashes, irregular periods. This means that we need to consider the risk: benefit ratio, especially as Tamoxifen is often used for 5 or 10 years. We want to make sure that it is working well, particularly if we are suffering side effects or it increases our risk of other conditions.
Metabolism is important
Tamoxifen is actually a pro-drug. What this means is that it has very little affinity for the estrogen receptor (ER) itself. Rather, it needs to be metabolized first and its two metabolites are what impact the ER. The two metabolites are Afimoxifene and Endoxifen. They bind 30-100 times more strongly than tamoxifen does to the ER.
This means that how you metabolize tamoxifen makes all the difference to how well it works. Polymorphisms mean that one person may be an ultrarapid metabolizer while someone else may be a poor metabolizer. The “dose” level of metabolites will vary considerably in these two people, even when they take the same dose level of tamoxifen.
This means that people with certain CYP2D6 polymorphisms may have lower concentrations of the tamoxifen metabolites, and thus the medication may be less effective, resulting in a higher risk of disease recurrence.
For this reason, some new international practice guidelines have come out for clinicians using CYP2D6 genotypes to guide tamoxifen treatment. The consortium who wrote the guidelines felt there was sufficient evidence to use CYP2D6 genotype to assist with clinical recommendations for women with early stage ER+ve BC.
Can I use my 23andme data to find out my CYP2D6 polymorphisms?
Many people have tested some of their genes using 23andme or another similar service through a practitioner. These tests show us polymorphisms in certain genes. However, they are not suitable to determine your potential response to tamoxifen.
That is because CYP2D6 has many, many polymorphisms and over 100 known variants. The guidelines detail a specific combination of polymorphisms that are used to determine their potential response to tamoxifen. All these are not covered by the usual consumer or practitioner DNA tests. Instead, there are recommended tests that your oncologist can order.
What does this all mean?
This means that if you have early-stage ER+ve BC, and are discussing possibly using tamoxifen, then it is recommended that you talk to your oncologist about testing your CYP2D6 genes to see if tamoxifen is suitable for you.
If you have a certain combination of polymorphisms, using a higher dose of tamoxifen may be appropriate to increase the metabolite levels, and still not be toxic. For other combinations of polymorphisms, maybe using an aromatase inhibitor or other medication may be more appropriate for you. Your treatment plan can be adjusted according to your genes.
Like all decisions, there is more than just CYP2D6 for your oncologist to consider, but it is another biomarker that can help in the decision process. It is part of the complex picture that can guide us.
Does anything else affect Tamoxifen metabolism?
In addition to polymorphisms, certain medications can inhibit the action of CYP2D6 while others can increase the activity. Again, your doctor should check the medications you are on to see if they can affect Tamoxifen metabolism. This link is a partial list of inducers and inhibitors but check with your doctor.
Genetics guide tamoxifen use …..and more
These guidelines are another example of how we are continuing to personalize treatment for cancer. Tamoxifen is not just a simple drug, but a pro-drug and so how our body deals with it (metabolizes it) is an important part of the picture. CYP2D6 also metabolizes other drugs so this may apply to more than Tamoxifen.
While personalization for cancer treatment is making strides, personalization is also important for other chronic illnesses, and optimal health. Talk to all your health care providers and practitioners about personalization for medications, treatments, nutrition, and lifestyle. You are unique. In so many ways. 😉 One size does not fit all.