CYP2D6 ability to metabolize tamoxifen and recurrence

Other companies may do what I'm about to describe, but my direct familiarity is with Genelex. Genelex may have changed their approach since my last contact

Genelex receives the order and the swabs from provider. Ideal is pre insurance approval. Genelex bills the provider. If insurance turns down reimbursement then Genelex does the appeal. If insurance turns it down after the appeal and reappeal., Genelex does not bill the patient.

They did this in the time period I was very active in my contacts with them. By law a company can't do freebies, but Genelex wasn't doing freebies. They exhausted every avenue for payment except the final route of billing the patient. It's completely legal. This was only explained to me when I asked why I never saw a bill. I have tried to do justice here, of their explanation to me. I hope I did it well. I would not want to put Genelex in a legal bind b/c I misstated something.

Solfeo, quoting you " If this is true then how can NCCN and ASCO justify continued disapproval of testing? I will look into this FDA recommendation further over the weekend and report back with what I find. I also think the numbers are higher than 7-10% (I thought closer to 30%) so I'll check into that too." This goes to the heart of what I tried to describe about the group think mentality of ASCO. I linked a study that describes the discussion on 2D6. It discusses all the conflicting findings, but the support is more for testing than not for testing, but the conclusion of the study is absolutely not definitive.

When "absolute defintiveness" is in question that allows for interpretation by the provider. In this case ASCO is taking the role of the provider in writing the guidelines. Lack of "absolute" allowed them to conclude that it wasn't an "absolute" requirement to test.

The FDA can and does make recommendations based on the science that is more proactive to the patients benefit. The problem is the provider can because of their licensure interpret how they will use a drug or treatment. A physicians license is a powerful document. Powerful. It's way beyond the scope here to describe how powerful.

Along time ago the recognition that there had to be better system to provide patient care than depending on the individual licensed doc's choice of management. That's when Agency on Health Care Policies and Research was formed in the early 1980's There mission was to create Standards of Care. The documents produced by the AHCPR were called Clinical Practice Guidelines. Notice it doesn't say Clinical Practice Absolutes. NO matter what is written in a GUIDELINE an individual practitioner can choose to treat as they wish. That's how powerful a physicians licensure is. Because we live in a litigious society most physicians choose to use the guidelines. Some will not vary from them one iota b/c they can use the guidelines as a defense when sued.

The original guidelines written by the AHCPR were so much more patient proactive it was seen as a problem by individual AMA subspecialty groups, they fought for the dissolution of AHCPR. The process of the Guidelines were taken over by each subspecialty. This occurred in the early 1990's. The AHCPR was changed to Agency for Healthcare Research & Quality

The Guidelines now are not written to the proactive patient level that the early guidelines were, this is my conclusion. I was very active in a 10 year period using the AHCPR material when all this transitioning occurred. It eviscerated the high standard of care that the AHCPR brought to medicine.

Solfeo and all. Their is an undercurrent in the guidelines to protect the physician from not rendering the highest standard of care. You won't find this in print. You would have to read all the different literature of the time to understand this. It's a black eye to medicine.

Jojo. Total D testing, HBA1c, TSH, Free T3 & FreeT4, Thyroglobulin and thyroglobulin autoantibodies

Total D=D3+D2. This is a big controversy in endocrine circles, but it's easier now than even two years ago. The is the accepted normal range, in bold is the more usual range' "The normal range of vitamin D is measured as nanograms per milliliter (ng/mL). Many experts recommend a level between 20 and 40 ng/mL. Others recommend a level between 30 and 50 ng/mL."

The controversy is that it is now accepted that higher ranges way over 50 is better in cancer prevention. BUT it's not universally accepted. The last to come to the acceptance of this higher level is the endocrinologist subspecialty. They are being very rigid about it. We are at a moment in time that this is very much in flux. Studying D is very important to you

I will try to write an explanation for the other tests I recommended, But I just got an invitation to lunch by my DBF Donnie. BBL

Jojo reread your post I missed that it was an Endocrin doc that specializes in breast cancer hormone issues. Cool. Menopause is in the usual trick bag of an endocrine doc, BC is extra. YAY So, the list I wrote up top is what I suggest. Shouldn't be a problem for any of them to ask to be done.

Shep 2B6, OPRM1, COMT were not in the panels yet when I last talked to Dan.

OPRM1 yours is intermediate- correct? The way I read that-- is your good to go on opiods or may need a bit more than standard dosing right?

COMT low activity. Whoa Nelly, I can't jump on that one. I use to teach cylic AMP and affect on Dopamine/adrenaline / noreandrenaline.but haven't used those brain cells in allot of years. Can't remember if COMT was even identified then. Couldn't determine from the one textbook how the two are related. BUT I can tell you where it all happens LOL. AT the synapse. If we go further than that than we will all drown in to much neuro chemistry.

Remember when I said your doc wasn't wrong about saying Lyrica and Neurontin weren't the same drug. You and Junie were questioning where he got his license. Neuro chemistry. You change a molecule, and you get something different. Not that that isn't true about all chemicals, but there are so many chemicals and receptors in the brain. Sheesh. He was right. All the other docs were wrong. But wrong in the lets "keep it simple" kind of way. Your neurologist job is to know these differences. Neurologists don't know what it means to keep it simple b/c they are so immersed in the very highly complex. Like Sheldon.

I do though-----------don't go there when it's not a need to know. Like Penny

(YOOHOO Solfeo jump in here. barred owl too)

The need to know for our docs and for us is what drugs to take, when they aren't compatible with your genetics, and what is safe alternative.

At Genelex they pioneered application of the drug to the genetics. It's all software driven. You list your drugs and genetics. Hit get interactions. Then the answers come up in columns. interaction are identified. Click on interaction column comes up and you can retrieve data by drug, metabolism, alternatives. They do keep it simple.

I had a subscription from 2010 till recently. I let it lapse simply b/c I didn't pay attention to my email. Last subscription was under 25$. Worth every penny. Catn't tell you how many members drug lists I've run. You can do it without the genetics. Obviously, the beauty of knowing the genetics is lost.

Solfeo, I told Dan those reference things on the intro material were out of date several years ago. They actually could be up to date and the way to solve that was to assign some one to review it every year and mark as such. I suggested that could hurt them when folks like you and I were detail searchers. I'll mention it again when I talk to him. (If he's still there?). Plus, there could be a reason they are left as such for legal reasons unknown to me.

I need to take a break and think about something else See ya soon.

Sassy, have I told you lately how much I appreciate all the time and energy you put into sharing your medical knowledge around here? Keep it coming!

I do some volunteer work as an advocate for patient victims of a certain corrupt HMO and I have some familiarity with clinical practice guidelines through that. They write their own guidelines, which almost always involves dumbing down the standards of the various medical societies for the purpose of increasing profits (always number one) and avoiding lawsuits (also about the money). It's like pulling teeth to get anyone within the organization to do anything differently. Then they lobby hard to get their sub-standard versions accepted as the new standard nationwide to legitimize their negligence. They are often successful.

I know you know this, but an example for others: Guidelines are "population based." If a particular test or procedure is known to not benefit 95% of people who present with certain symptoms, then they are going to deny that test to everyone except under extraordinary circumstances. That's great if you're in the 95%, but the 5% are screwed, and maybe dead if you're talking about a cancer that doesn't get diagnosed early enough to treat successfully. Sometimes it makes medical sense - you can't give a CT scan to everyone with a cough because the extra radiation exposure comes with risks of its own - but the tests we're talking about here are virtually risk-free. But not cost-free. It's always about the money. The health care system will save more money denying everyone certain tests than it will cost to treat the few who slip through the cracks. A lot of the talk about "quality control" in recent years is just a euphemism for rationing. They want to punish doctors for ordering "unnecessary" tests.

Love all the sharing of info.....much to learn!

I used Genelex. Customer support was excellent as far as setting up the test and payment processing. If insurance doesn't cover, they offer payment plans as well as financial assistance - possibly free if income qualifies. As for support after....not so great. Your results are available for a short time online for free. After that it is a pay service. Their website has many dead links and there is little useful info on their pay site; most of what I learned I found from other websites.

Sister in Law used Alpha-Genomix. My complete report was 2 pages - hers was 11. I've attached her test results below. Alpha-Genomix website provides much info and their testing is much more extensive. The individual report provided with the completed test is detailed and indepth. I would have gone with them if I had known........

Sas ~ my OPRM1 is intermediate. Opiates do nothing for my pain, even when taken at ridiculous amounts. All I get is a little spacey and a lot of vomiting. Yes, my COMT is low......no schizophrenia though Low COMT is also supposed to be an indication of the likelihood of developing breast cancer. SIL is also low COMT and has a strong family history of cancer - she hasn't been dx'd with any type of cancer. SIL suffers from clinical depression, not sure if COMT relates to that or not. Lunch and dinner out? Yay! Have fun!

http://www.alphagenomix.com/empowering-personalize...

SIL Alpha-Genomix Report:

I have to say, this topic makes me want to bang my head against a wall. Why is cytochrome P450 genetic testing not done as a matter of course? In a country where our healthcare is so drug-centric, where 60% of adults have at least one drug prescription, and where we consume 75% of all the prescription drugs produced in the WORLD (despite being only 5% of the world's population), how is this information not vital? It can't be that costly, when the cost of sequencing an entire human genome is down to $1,000. And it would only have to be done once, right? With the negative health impacts and costs associated with adverse drug events alone, you'd think there would be an incentive for insurance companies to cover testing. So much for personalized medicine.

jojo...OMG! Ive been saying we need an endocrinologist on our team forever! One that specializes in BC is even better! Where do you live?

Fallleaves:

Regarding methodology, at least some methods of CYP2D6 genotyping do not appear to be based on whole-scale DNA sequencing and comparison of any difference(s) observed with a reference sequence. 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: 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.

I am not sure if there is a more recent version of the ACMG document or not.

Solfeo:

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)."

From the discussion above, I suspect you are already looking at these aspects (inquiring what platform is used by each vendor you are considering, extent of coverage, and report format).

As medical devices, you could inquire if the platform has FDA approval, and the type of approval (e.g., 510(k)):

General Info: http://www.fda.gov/MedicalDevices/ResourcesforYou/...

I am not sure exactly what sections of FDA law CYP2D6 genotyping tests may be approved under. However, my crude search of the Section 513(a)(1)("de novo"); the 510(k); the PMA; and the CLIA databases for "CYP2D6" under "Device Name" yielded two Luminex entries with Decision Summary (includes technical details). More comprehensive searching could be done if you have the Applicant Name or actual Device Name.

510(k) Database and See Other Databases at Right: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm

(1) 510(k) number K130189: XTAG CYP2D6 KIT V3 (INCLUDING TDAS CYP2D6 SOFTWARE): http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130189

Decision Summary: http://www.accessdata.fda.gov/cdrh_docs/reviews/K130189.pdf

(2) 510(k) number K093420: XTAG CYP2D6 KIT V3, MODEL I030C0300 (96 TESTS/KIT), TDAS CYP2D6 SOFTWARE (2030-0254): http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K093420

Decision Summary: http://www.accessdata.fda.gov/cdrh_docs/reviews/K093420.pdf

BarredOwl

Genelex didn't answer their phone so I had to leave a message. This is what the website has to say about accuracy and reliability. I'll ask for more details but proprietary usually means "we're not telling!"

Genelex has been a leader in pharmacogenetic testing since 2000. Our high-complexity laboratory facilities feature:

• Robotic DNA extraction and testing, to ensure high accuracy and low error
• Proprietary test platforms and methodologies
• Testing for more allele mutations than any other system
• Test validation across multiple platforms
• Rapid 2-day turnaround available
• Ability to test non-invasive swab samples or blood
• Forensic-level protocols for sample accessioning
• Dedicated customer support

The Genelex laboratory is fully accredited and consistently maintains the highest standards:

• College of American Pathologists (CAP) accreditation; 100% pass rate on CAP efficiency tests
• Clinical Laboratory Improvement Amendments (CLIA) certification; licensed to perform testing in all U.S. states
• State of New York Department of Health-accredited clinical laboratory for molecular genetic testing
• Secure Laboratory Information Systems (LIS)
• Code of Federal Regulations (CFR) 21 compliant
• Health Insurance Portability and Accountability Act (HIPAA) compliant

Solfeo, it came as a pdf. I would have preferred to post the whole group b/c it includes individual test as well as the panels. I will see if the link works.

Remember on Toradol, we had trouble opening pdf files. I had to take the link off b/c it kept going back to my email. It clearly is not a restricted piece. We will work on it. Send me your email and I will send it on

BBL

I saw the endocrinologist. We had a great talk but I didn't take any notes (I should have learned by now). I didn't press for metabolism testing, but he did explain that it is expensive and they tend to do it only if they believe there to be a problem - as in someone with severe side effects. He said that they worry that the dosage needs to be adjusted. He said that the 20 mg standard dose came about rather haphazardly, and that in the future it will be more patient specific. (how about now??) He agreed that for me tamox is the best course of action. He doesn't think that the small increase in absolute benefit from an AI over tamox that some studies indicate would be worth the risk. So no real answers but he was very interesting to talk to.

Does anyone here know of good data/studies supporting or refuting the idea that the presence of side effects means that tamox is working (converting into the active form)? I know this has been on the boards in the past.

Busy place here, lots to catch up......

Sas ~ I ran into the same PDF problem when I wanted to post SIL's test results. I scanned her printout, saved it to my computer as a JPEG and then posted it as a photo.

Fallleaves ~ I was treated by an endo for several years before my cancer dx. He was able to determine that my thyroid had been misdiagnosed as hypo by the original endo I had seen. I had extensive testing to try to figure out what was causing my increased pain and fatigue......all tests came back as normal. Estrogen was 105 (low normal) in early 2012 when I was 46. One year later I was dx'd ER+ Stage IV with extensive bone mets. I'll have to check with my MO what my estrogen was at that time. Had it been known I was Low COMT I wonder what could of been done differently?. Possibly nothing... I haven't any markers that show in my blood work and my breast tumor and lymph-node were too small to be seen in a mammogram. The cancer was found in an MRI when my spine started to fall apart. I have 0 history of family cancer and was not considered to be at risk. (sigh)

Jojo ~ Yay for seeing the endo! Boo for not getting the answers you wanted. I keep a little notebook in my bag to take to my appointments. I've gotten in the habit of keeping it in my lap so I'll be prepped when the doc comes in. I make a list of things I want to discuss and then leave space under each item to jot notes. Processing and retaining info is hard with our appointments.....fear, fatigue, pain, fear....oncology is not fun If you are stable, you can stay on the Tamoxifen menopause or not. I didn't think it was rx'd for over 20 mg? Did the dr. test your estrogen levels?

Thoughts on Tamoxifen; Generally, the presence of SEs indicate the drug is working. Some women do well and never have SEs. I always had a tremendous amount of SEs, even when the Tamoxifen failed and I had progression to the subclavicular nodes on the same side as my defective breast. The first 2 years the Tamoxifen worked great. I am now on Femara, an AI, and find it much easier than Tamoxifen - only SE is less severe hot flashes than before. Tamoxifen can fail and then be tried later on. After time, the cancer buids up resisitence to it and/or the body itself becomes confused and starts recogizeing the drug as an estrogen producer instead of blocker. Discontinuing and then returning to it later can trick the cancer/body into responding as it should.

Tamoxifin is the "beginner" drug. If it works, stay on as long as possible. If it doesn't, oh well. There are plenty more options and there are more and more drugs becoming available.

I was dx'd Stage IV from the get go. My perspective is probably different than most of you. Death sentence? Probably. When? Who knows. My MO takes great pride in me. The first time he saw me I was wheelchair bound. Two months later, after rads, Zometa, and Tamoxifen, I was walking again. I still have mets to most of my skeletal system, so far they haven't spread. I've been stable just over 3 years now. Things aren't perfect; I have ongoing issues with my spine and hips, pain is usually bad, I get easily fatigued. But...I'm not where I was 3 years ago (on the floor unable to get up), I have an outstanding medical team, and I truly believe the advances in research will "save" us all. Educating ourselves is crucial. We are our own best advocates.

Bless you Sas for giving this place to learn, Blessings to all here sharing and learning together

shepkitty, your story is an inspiration. can you tell me what you mean when you say that your response to tamox was exceptional? did you have active disease that they were monitoring and could see shrinkage/ less progression?

My gyn tested by estrogren last month - came back pretty high (estradoil360,estrone 337) - i figured I was ovulating (have not officially entered menop.) but didn't get a period. the endocrinologist remarked that the high estrogen is also evidence that tamox is working - because the tamox blocks the receptors, the body tries to make more to compensate. sounds kind of scary that the treatment is causing my body to make more estorgren.

fallleaves, thanks for the info on the polish study. sounds like we need some good measurements. I should have asked about measuring the endoxifen in my blood. Will in the future. It seems like that is really the issue, isn't it?