Kailos Test for Tamoxifen

RedemptiveSufferer

Hi! I recall reading on one of these threads about the Kailos test to determine if Tamoxifen will work for you based on a specific gene some women have called "CYP2D6" that makes them resistant to this medicine. I'm about to meet w/my MO who will tell me I need to start taking this. I will certainly try it if I think it will work though I'm concerned about its many potential side effects. My question is, does the medical community recognize this test as a legitimate test, like the Oncotype? I haven't heard much about it but if its accurate I'd want to take it before I start putting this drug in my body. Thank you!

farmerlucy

This is BarredOwl's amazingly comprehensive post re: research on the matter. I'm doing it to help me gain insight into whethercontinuing HT beyond five years would be helpful. I am interested in knowing what other have to say about this.

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Jan 4, 2017 01:39PM - edited Jan 4, 2017 02:50PM by BarredOwl

I. CYP2D6 Genotyping - Clinical Consensus Guidelines from NCCN and ASCO

I understand why people are interested in this type of testing at the individual level. However, for complete information, please note that clinical consensus guidelines from the NCCN (Version 2.2016), which are population-based, currently do not recommend routine CYP2D6 testing for the purpose of selecting adjuvant endocrine therapy. The NCCN guidelines state (Version 2.2016):

"The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature.(378) Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen.(379) However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer.(380) The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects.(380) A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes.(381) Given the limited and conflicting evidence at this time,(382) the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines.(383) When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists."

ASCO recently took a similar position, triggering some vigorous debate (typical in this field):

ASCO Biomarker Guideline (2016): "Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline"

http://ascopubs.org/doi/full/10.1200/JCO.2015.65.2289

"Recommendation 2.1

The clinician should not use CYP2D6 polymorphisms to guide adjuvant endocrine therapy selection.

Type: evidence based. Evidence quality: intermediate. Strength of recommendation: moderate. [Note:These ratings have specifically defined meanings.]

Clinical interpretation of literature review. The ability of polymorphisms in CYP2D6 to predict tamoxifen benefit has been extensively studied.47-50 The results of these pharmacogenomics studies have been controversial, with more recent studies being negative. At this point, data do not support the use of this marker to select patients who may or may not benefit from tamoxifen therapy."

Goetz Letter to the Editor (2016): "Providing Balance in ASCO Clinical Practice Guidelines: CYP2D6 Genotyping and Tamoxifen Efficacy":

http://ascopubs.org/doi/full/10.1200/JCO.2016.68.5214

Harris Reply (2016): http://ascopubs.org/doi/full/10.1200/JCO.2016.68.7020

[Note: The above is cited regarding CYP2D6 only. With regard to MammaPrint, the recent MINDACT trial results have not yet been addressed by ASCO.]

II. Genotyping Methods and ACMG Guideline:

Regarding CYP2D6 test methodology, patients should be aware that at least some methods of CYP2D6 genotyping do NOT appear to be based on the exhaustive DNA sequencing (of the entire coding sequence and intron borders) and comparison of any difference(s) observed with a reference sequence (as is the case for BRCA testing and testing for breast cancer predisposition mutations). I am not sure why, but it may be due to certain technical challenges, for example due to gene deletions, gene duplications, and gene multiplications, and nearby "pseudogenes" (non-functional versions of the gene), as described:

http://jnci.oxfordjournals.org/content/107/2/dju437.full

"The CYP2D6-tamoxifen story is complicated. Genotyping this gene is difficult in normal settings, because it has a large number of single-nucleotide polymorphisms, gene deletions, duplications, and multiplications, along with adjacent pseudogenes, all of which make determination of the CYP2D6 genotype–determined phenotype the most complicated in pharmacogenetics."

Some may have noted the star (*) system for naming genotypes. With CYP2D6, it appears that an allele designation may not represent a single change like we are used to seeing with BRCA variants. See e.g., Genetics in Medicine, ACMG Standards and Guidelines (2012):

ACMG (2012): http://www.nature.com/gim/journal/v14/n12/pdf/gim2012108a.pdf

"Unlike many heritable disease mutations, each CYP2D6 allele may include several single-nucleotide polymorphisms — a haplotype, rather than a single-site mutation."

For more information, see the section entitled, "CYP2D6 Genotypes" at page 991.

The ACMG link above describes some of the different platforms used for genotype determination as of 2012 at least (See the complete section re Commercial Platforms, page 995):

"Several commercial CYP2D6 genotyping assay platforms are available (Table 3). Although all of them test for the presence of most common variants, they differ with respect to the range of variants detected. They also differ in how they call alleles and in whether or not an allele designation is provided as part of the result. Also, for some combinations of alleles, the classification into metabolic phenotypes is not yet standardized. Here we describe and compare three commercial platforms (Table 1)."

III. Limitations and Actionability

Those receiving the test should keep in mind the above limitations, as well as the fact that multiple mechanisms may underlie failure of tamoxifen treatment when it occurs. Thus, the absence of a detectable issue in CYP2D6 genotype is not a guarantee that tamoxifen will work in the individual.

Tamoxifen is a "pro-drug" that can be converted by functional CYP2D6 enzyme to more active metabolites, including "endoxifen". The theory behind CYP2D6 genotyping is that the efficient conversion of tamoxifen to the highly active metabolite endoxifen by CYP2D6 enzyme explains the therapeutic efficacy of tamoxifen. However, various studies reveal that CYP2D6 genotype alone does not appear to account for all variation in endoxifen levels.

Fox (2016), "Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study":

http://clincancerres.aacrjournals.org/content/clincanres/22/13/3164.full.pdf

"Our data show that the use of CYP2D6 genotype alone gives an imperfect guide to endoxifen level on standard dose tamoxifen and after dose escalation."

The Fox article was profiled in the Highlights for that issue of the journal:

"Low endoxifen levels are associated with an impaired outcome in breast cancer patients treated with tamoxifen. Endoxifen relies on CYP2D6 metabolism but genotype does not consistently correlate with outcome. In 122 tamoxifen-treated patients, Fox and colleagues found that concomitant medications (14%), CYP2D6genotype (24%), compliance and absorption (21%), and unknown factors (52%) all contributed to low endoxifen. The authors then increased the tamoxifen dose in those with low endoxifen and found that the best predictor for reaching a therapeutic level was the baseline endoxifen level and not CYP2D6 genotype. It was concluded that therapeutic monitoring of endoxifen requires more attention."

This 2016 article from Hertz and Rae summarizes some of the major conflicting clinical studies in the area, and remaining clinical validation questions:

Hertz and Rae (2016): "One step at a time: CYP2D6 guided tamoxifen treatment awaits convincing evidence of clinical validity"

http://www.futuremedicine.com/doi/pdf/10.2217/pgs-2016-0059

"Clinical validation of the association between CYP2D6 genotype, or endoxifen concentration, and tamoxifen treatment efficacy is a necessary first step toward CYP2D6 guided tamoxifen treatment."

This is an on-going area of research, and the scientific literature is extensive and at times contentious, in view of the conflicting studies. Some patients may reasonably choose to await further data, while some remain interested in such testing. For more information, see this long thread:

https://community.breastcancer.org/forum/73/topics/798301?page=1#post_3359098

Those receiving such testing should seek expert guidance from their medical oncologist regarding their test results, the implications and limitations of same.

Last but not least, CYP2D6 has a role in the metabolism of certain other drugs, and patients should seek current, case-specific medical advice from a person with appropriate expertise regarding whether and how to act on such information for each drug in question. In cases where a dose adjustment may be considered based on clinical evidence of long-term safety and efficacy of particular adjusted doses (if available), the nature of the drug as the "active" or as a "pro-drug" will lead to opposite recommendations as explained here:

https://community.breastcancer.org/forum/78/topics/848288?page=1#post_4807818

Patients should never alter the dose of a prescription drug without first consulting their doctor.

BarredOwl

Lisey

I took the test and believe in it - the NCCN guidelines do NOT ever recommend anything promising until it's been fully and completely accepted into the medical world. So saying what the NCCN suggests isn't really the point - of course they won't recommend a new test.

Not only did I find out about my cyp1d6 pathways, I found out why I absolutely can't do Oxycodine. I also found out I'm a Met/Met - which explains a ton about my personality (flooded with dopamine 24/7) due to the double variation. And being a Met/Met means that green tea helps me far more than a non-variant person. I also can't get rid of environmental estrogen as easily due to that COMT allele.

For $150 it was so worth it. I got a 60+ page report, and My oncologist said it was fascinating - particularly that the chemo regime that was on the table is one that would be toxic for me.

Customized medicine is the wave of the future- less so the present - so many doctors and obviously the NCCN are going to be much slower taking it up. We were so impressed with my report, we did our children and my husband as well. I view these tests as like newborn screenings. My children going forward will have this information in the cloud and in an emergency their genetic profiles for medicines will be used. My husband has already used his results when he had surgery and they switched anestestics based on the results.

The test we all got was the Kailos Complete. I highly recommend.

RedemptiveSufferer

Farmer Lucy, thank you for all of the data!! I will read through it more closely later when I have more time, but doesn't sound as if "the powers that be" are supportive. Makes me wonder how my doctor will review the results should I have it done, which I think I will. At least it would give me comfort if results indicate Tamoxifen WOULD be a good fit for me. I'm just so reluctant to take it, though I know some women have few SEs with it. Such tough decisions.

Thank you, Lisey, for taking the time to respond! This may be a dumb question, but when you did the complete version did that include the info you would need to determine if Tamoxifen would be beneficial? Interestingly, I had a horrible reaction to Demerol while on this journey, wonder if the test would indicate why? Guess I don't really understand the test at this point but will certainly look more closely at it!

Lisey

The Complete pGX gives 8 different reports, Tamoxifen included. I'm an ultra rapid metabolizer (so far no Side effects 6 months in) and Tamoxifen should work great for me. The poor metabolizers are the ones who need to up their dosage to see more beneficial effect.

RedemptiveSufferer

Lisey, thank you for the response. I guess I completely ignorant because I would think if you metabolized meds quickly you would need more of it vs. someone who metabolizes meds slowly. Seems slow metabolizers could potentially have meds build up in their system, causing toxic buildup and more SEs. I'm obviously not grasping something correctly. But I'm thrilled to hear you've had no SEs!! That's very encouraging for me! :-D

BarredOwl

Hi RS:

Here is a link to my original post, with formatting that may be helpful:

https://community.breastcancer.org/forum/78/topics/851618?page=1#post_4876161

It is important to understand that CYP2D6 genotype testing does NOT tell you "whether tamoxifen will work for you". Multiple different cellular mechanisms may underlie failure of tamoxifen treatment when it occurs. Thus, the absence of a detectable issue in CYP2D6 genotype is not a guarantee that tamoxifen "will work" in the individual. In addition, because such testing is not comprehensive, it probably cannot completely eliminate any possibility of a clinically meaningful problem with CYP2D6 function.

On the other hand, if a problem is identified, one might act on that information in some way, with guidance from a medical oncologist. For example, one might consider pursuing a different type of endocrine therapy. Yet the pharmacogenomics of aromatase inhibitors are not completely understood. See e.g.,

Gervasini (2016): "Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients"

http://onlinelibrary.wiley.com/doi/10.1111/bcp.13130/abstract

The NCCN and ASCO positions on CYP2D6 testing reflect a population-based approach, and their expert assessment that the results of clinical studies in the area are conflicting.

NCCN and ASCO guidelines expressly do not mandate individual treatment. Individual patients may decide to pursue such testing. However, those who do so should understand the caveats and limitations.

While Kailos may be a new venture, CYP2D6 testing is not really "new". I have numerous clinical study publications in my files, some dated as early as 2005, which means the trials were started years before.

Lastly, I do not agree with the broad assertion that "the NCCN guidelines do NOT ever recommend anything promising until it's been fully and completely accepted into the medical world." The NCCN guidelines include category ratings that reflect various degrees of evidence and consensus, and expressly include interventions for which there is lower-level evidence and/or a lower level of consensus.

"NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted."

For example, NCCN guidelines were rapidly updated in 2015 shortly after the fall publication of the results of a Phase II, non-randomized clinical trial of paclitaxel plus herceptin in small, node-negative HER2+ tumors. For the smallest tumors (less well-represented in the study), there was lower-level of evidence, and accordingly, the relevant recommendations reflected a Category 2B designation. However, the intervention was included within the guidelines.

Another area in which NCCN guidelines can hardly be accused of being overly conservative is the adjuvant use of pertuzumab (Perjeta), as explained here:

https://community.breastcancer.org/forum/80/topics/846661?page=1#post_4774842

As I said before regarding CYP2D6 testing:

"This is an on-going area of research, and the scientific literature is extensive and at times contentious, in view of the conflicting studies. Some patients may reasonably choose to await further data, while some remain interested in such testing."

BarredOwl

RedemptiveSufferer

Barred Owl, thank you for sharing! I'm sure some would say, "Quit your whining and just take the Tamoxifen, already!" I just want to ensure to the best of my ability that this is the right course of action. I'll share this literature w/my MO. Bless you for putting so much thoughtful time into this and for passing on to others.

Lisey

Redemptive, as to your question... there are two types of drugs. Pro-drugs and active drugs. Tamoxifen is a pro-drug (which means the active drug only occurs after metabolism) and therefore is the reverse of a drug like you are thinking.. You are correct about what would happen with an active drug, but not pro-drugs. Our bodies need Endoxifen, not Tamoxifen. Once tamox is metabolized Endoxifen comes out - so my Ultra Rapid status is actually beneficial for me. If this was an active drug, then yes... I'd need more rather than less to be able to metabolize it.

RedemptiveSufferer

Lisey, thank you for that explanation. Makes complete sense! I get to end my day a tad smarter than how I started it.