Kailos Genetic Test for Tamoxifen users on sale for $99

how did you get your doctor to approve it? Because it is not the standard of care I can't get my MO to consider it.

I ordered it to. My OBGYN is the one who ordered my mamogram and she has agreed to stay my primary doctor so I am hoping that she will approve the test. My MO is somewhat useless with this stuff. I think he has to answer to his associates and they all try to stay pretty closely inline and don't have a lot of approval. Hopefully I can get the test approved as well. The two of us are in similar situations in that we could be on an AI (oophrectomy) but are on Tamoxifen because of the side effects. The results could give us useful information. Thanks for posting this

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%), CYP2D6 genotype (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