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Navigating the Science on Hormone Positive Breast Cancer

From the DUTCH Test to CYP2D6 SNPs

Many patients have been told by an integrative practitioner that their DUTCH Test indicates:

  1. Tamoxifen, Letrozole, Exemestane, or another aromatase inhibitor is giving them bad estrogen metabolites that will “drive their cancer”
  2. They don’t need to worry about using a conventional anti-estrogen medication because their DUTCH test looks favorable without them
  3. Tamoxifen is not working because their estrogens are high

There is a lot of conflicting information regarding how to use and interpret some of the hormone testing modalities. We will look at some common basic misinterpretation of the DUTCH test and conclude with a look at the current evidence about carrying the CYP2D6 genetic variant and the use of tamoxifen.

The DUTCH Test in Integrative Oncology- 

What is the Evidence Estrogen Metabolites Can Guide Cancer Treatment?

The DUTCH test is an acronym for Dried Urine Test for Comprehensive Hormones and involves collection of urine on collection strips four to five times over a 24 hour period. The company Precision Analytical has been in this space since its establishment in 2012 and though the test is not generally used by conventional practitioners or covered by insurance, it is the hormone test held in the highest regard by most integrative oncology practitioners. The DUTCH is more often used outside of cancer for general hormone health. The company has a board of accredited naturopaths who are clinical consultants- many I have personally found to have an expert, in-depth knowledge of hormone pathways and how supplements and pharmaceuticals affect them. Precision Analytical has focused on creating a quality test; in 2019 the first peer-reviewed validation of its test was published in 2019.   

Because the DUTCH tests for hormone metabolites, it is a powerful tool to look at estrogen and estrogen metabolite levels in the body- and these do have an important impact in hormone driven cancers. Three primary forms of estrogen (estrone (E1); estradiol (E2); and estriol (E3)) occur in the human body with estradiol (E2) being the most active of the three. E1 is the main estrogen in postmenopausal women, E2 predominates in premenopausal women, and E3 elevates in pregnancy. 

Hormone processing begins with the liver metabolizing these estrogens to move them continuously out of the body. The first phase metabolites are 2-OH-E1, 4-OH-E1 and 16-OH-E1. Phase 1 metabolites can last a long time in the body and have either protective or harmful effects. 2-OH-E1 is usually considered beneficial as long because it binds to estrogen receptors but does not stimulate them- so it is thought to actually block cell proliferation. 4-OH-E1 and 16-OH-E1 are considered bad metabolites as they can remain stuck to the estrogen receptor and cause proliferation of the cell. 4-OH-E1 also  has quinone metabolites that can cause DNA mutation. Unfortunately, though there are many cell line studies on the negative effects of 4-OH-E1 and breast cancer, the only population level study showed that higher 4-OH-E1 levels actually had a protective effect against breast cancer. The role of 16-OH-E1 is anything but clear- the largest >3000 women study found no clear association between the ratios of 2-OH-E1 and 16-OH-E1 levels and breast cancer risk. In endometrial cancer the effects of 2-OH-E1 and 16-OH-E1 were not found to correspond with risk of cancer. Interestingly, direct high level pellet injection of E2 versus estrogen metabolites into rat breast tissue showed 100% breast cancer induction after 3 years for estradiol. No cancer induction occurred with high level 4-OH and 16-OH metabolites! Most importantly in oncology, our patients do have cancer and studies looking at mortality and cancer remission rather than cancer risk are the relevant studies involved. There is only one clinical study looking at mortality and the ratio of 2-OH and 16-OH metabolites. It found only all cause, and not breast cancer specific reduction of mortality with a higher 2-OH/16-OH ratio, though they only measured the estrogen metabolites at diagnosis.

In summary of estrogen metabolites, there is ample evidence that they interact in the body in differentiated ways and reasonable cell-line level evidence that some of these metabolites may be protective versus carcinogenic. Unfortunately, rigorous population level studies are sparse. One study is even contradictory. Using the DUTCH test to completely guide cancer treatment is not based on a thorough understanding of how to weigh and interpret scientific information. It is also expensive- costing about $400 out of pocket per test and often recommended yearly to four times per year. In contrast, robust clinical studies support that achieving a minimum of 150 minutes of moderate intensity exercise per week has a dramatic ~60% reduction in mortality after breast cancer and this can be achieved with little monetary inputs. With this perspective setting basic fitness in place as a priority has much stronger evidence and robust effect than drilling into hormones with the DUTCH.

Reviewing this evidence, it is reasonable to use the DUTCH test as a secondary tool to attempt to perfect one’s hormone metabolites, if indicated after conventional hormonal blockade. It is unscientific to use it to guide which hormonal agent to use. 

There are studies supporting the use of several natural supplements on hormone metabolites but there are unfortunately no studies comparing them to conventional anti-hormone agents. I hope that we will have information like this in the future but the fact is that cancer is not like arthritis. In arthritis we can try a supplement or remedy that has good basic evidence to work but no big trials. If we are wrong then there is a little pain and we readjust treatments. In cancer there is a bigger consequence of being wrong. It is often useful in hormone driven breast cancer to look at the NNT (Number Needed to Treat) as these often have a large impact on quality of life for patients. In some cases it is necessary to treat 200 women to prevent one recurrence, and in others the NNT is in the single digits. Everyone weighs risk differently and deserves to make an informed decision here. 

The Fallacy of Calculating a Ratio with High Uncertainty

The following is a real world example of recommendations using the DUTCH test gone wrong. The first figure is anonymized data from before a pre-menopausal patient took letrozole, an aromatase inhibitor. The red arrow is the generally considered bad metabolite 4-OH-E1 that can become a reactive quinone and the pie chart shows she is a bit over the top of normal ratio (7.5-11%). Note her total E2 is about 3 (ng/mg) and her total 4-OH-E1 is 1.35 (ng/mg). There is a lot of other good information here that can be used for secondary fine tuning. So far there is nothing major to worry about in terms of scientific claims aside from the lack of population studies for using the metabolites.  

The patient opted to use letrozole and she had a DUTCH test to look at her estrogen metabolites again. It is below:

The patient’s naturopath told her that the letrozole was not working for her because her ratio of 4-OH-E1 was even higher than before. This appears to be true according to the pie chart. However, even the DUTCH test warns against interpreting the results at all (see the fine print in the bottom) due to very low levels of estrogen metabolites. From a purely scientific point of view they should not publish a ratio with results this low. Taking a step back it is clear the letrozole is working as the patient has low overall estrogen. The level of 4-OH metabolite has fallen to a level the DUTCH rounds down to 0. The generated pie is a literal crumb of the pie from the original test- 0.04 total metabolites versus ~24 total metabolites. So this is an independent problem- that an aromatase inhibitor generally does exactly this to the DUTCH test- lowering the metabolites into a moot range near zero. 

The next problem is one of uncertainty and something called the propagation of uncertainty. Every test has a degree to which we can be pretty confident in a measurement. 

It is reasonable to say that the above cherry tomato is about 7mm wide. I think that we might be able to measure something flat with a certainty of about half of a mm. It would be silly of me to put this ruler up against a sheet of paper and try to measure the width. This would fall outside of the measurement certainty of this device. It would be even more silly for me to also estimate an onion skin’s width using this ruler and calculate the ratio between the width of the onion to the paper. You wouldn’t trust the initial measurements and you should trust the ratio even less!

This is just what was done with the DUTCH test but because it is a high tech instrument, we don’t notice it. We can calculate, using our very small values for 4-OH and 2-OH and a reasonable uncertainty for the DUTCH test of 0.01ng/mg (not actually provided or published by this test) that at low levels we lack all confidence in the calculated percents- they can be off by a factor of 10. So the calculated 12.8% from the second test might really be as low as 1.28% and as high as 100%. What should we do with these ratios at very low levels? We should ignore them. They are mathematically meaningless. Except I am seeing patients being counseled to make life changing treatment modifications based on these mathematically meaningless ratios- including stopping their conventional medications. There may be good reasons to stop a conventional antihormonal agent but this ratio is not one of them when calculated with very low levels. Even at measurable levels of metabolites, as stated prior, the evidence is lacking to support changing a medication from this test. Adding supplements and lifestyle adjustments to modify the metabolites is definitely a reasonable idea. Removing or changing an estrogen blocker due to quality of life is absolutely reasonable and I absolutely support a woman’s right to make an informed decision here- but it has nothing to do with this test when it measures near undetectable metabolite levels. 

How Tamoxifen and Faslodex Work

In reviewing the DUTCH test it is important to understand how conventional medications work- I have seen people on either tamoxifen or fulvestrant (faslodex) counseled that these meds were not working anyways so they should stop them. The truth is that the DUTCH will not give any direct information on these two agents. That is because tamoxifen works by selectively binding with estrogen receptors and in cancer, blocking them. It does not directly change the levels of estrogen or the metabolites in the body. Fulvestrant (faslodex) works by binding to estrogen receptors and eventually causing them to disintegrate. So you should not expect to see your estrogens drop while on these medications. 

The other medications- letrozole, anastrozole, and exemestane work often in conjunction with an ovary disruptor like lupron, and the combination will be expected to drop estrogen levels. 

“Not a Candidate for Tamoxifen based off of your Nutrition Genome”

I have several patients who have been counseled that they are “not a candidate for tamoxifen” due to CYP2D6 genetic variations- otherwise known as SNPs (Single Nucleotide Polymorphism). Like many drugs, tamoxifen is not effective until it is metabolized by the body into an active molecule endoxifen. There are over a hundred variants of the enzyme required for this process (coded for by CYP2D6) and some variants of this enzyme work quite slowly compared to normal. This can lead to lower levels of endoxifen. It has been hypothesized that the slower SNPs also might have worse outcomes in breast cancer if they are treated with tamoxifen. The CPIC (Clinical Pharmacogenetics Implementation Consortium) has recommended strongly that the rare poor metabolizers be offered alternatives to tamoxifen, and if that is not possible then using a high dose of tamoxifen is acceptable. Slow responders carry two of the alleles marked with a function of 0 on this comprehensive table. In intermediate metabolizers there is a moderate recommendation from CPIC for the same from this organization. The CYP2D6 is important not just for tamoxifen, but in metabolizing about one fourth of all the pharmaceuticals a person might ever use. 

A lot of research has gone into looking at tamoxifen and CYP2D6 and like almost all science there has been controversy over how strong this effect is. One large review found that CYP2D6 genotype made no impact on outcomes in breast cancer. A current review of recent studies notes that the most important findings- that of patient outcome and CYP2D6 genotype, remain controversial with recent studies finding contradictory things. 

Researchers are concurrently studying low dose tamoxifen as the current dose has been somewhat arbitrarily determined long ago. One randomized controlled study found that tamoxifen at 5mg (conventional dose is 20mg) was as effective as 20mg in preventing progression from intraepithelial neoplasm. There are a couple other positive studies on people at risk for breast cancer. This is not absolute and certain evidence but I feel it is strong enough for consideration. 

The CYP2D6 is an important enzyme to look at- with strong evidence only with rare complete lack of function and reasonable avoidance with intermediate function impairment. However, the Nutrition Genome does not test for the entire array of SNPs- only 2 variants are looked at. Remember that strong claims can only be made about the complete lack of function of both alleles. More comprehensive testing can be obtained by regular laboratories such as Quest and Labcorp and other specialty labs. With complete lack of function I think it is worth considering whether tamoxifen is right for you. It is more debatable in the case of lower function- this is a lot like a lower dose of the medicine- the optimal dose of which was never studied. 

Hopefully this has helped clarify some of the current evidence for using and evaluating the DUTCH test and CYP2D6 in hormone positive breast cancer. As always I stand fully behind every person’s right to make an informed decision. 

References:

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https://files.cpicpgx.org/data/report/current/allele_function_reference/CYP2D6_allele_functionality_reference.xlsx

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Journal of Clinical Oncology 2019 37:19, 1629-1637

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