CYP2D6 ability to metabolize tamoxifen and recurrence

Kayb, I didn't see your post before I posted mine. I thought testing for cyp2d6 cost between $350 and $600, which didn't seem like that much compared to the costs of treatment. But looking at Amplichip, which seems to be the most accurate, it looks more like the $600-$1300 range. Still, for something that can have such a big impact on treatment, it seems very much worth it. 

I am an ultra rapid metabolizer and as a result only taking 10mg of Tamoxifen. I feel so much better now than on the one-size fits all Femara dose. There are other things though that affect Tamoxifen metabolism, including CYP3A gene, smoking, alcohol consumption, grapefruit, certain anti-depressants, and lack of Vitamin D.

http://www.sciencedaily.com/releases/2013/04/130418142328.htm

Linda thanks, oh so thank you, ---will delve into it, But in the mood post court for DBF's child support case to delve back into the elements of negligence and malpractice. Partly, cuz I used to teach it to medics. Therefore, have better than a rudimentary understanding, but not a law training understanding.

It's an exercise in the mind---LOL of what I remember. I do believe at the moment that Heidhils link showed that NIH knew in 2008 and before that tamox's transition through 2d6 was a problem. OR at least approved Mayo's research b/c they showed it was a problem. Ergo, the outcome may be a better drug that doesn't have to use 2d6.  YAY. So, no drug interactions at 2d6. YAY. Again SSRI's and other psychotropics that primarily use 2d6 etc could be given with out fear.

BUT my soapbox is ALL drugs. Science has at least identified 5 paths. Repeating paths only b/c each repeat, they are further stuck in the brain LOL.  2d6, 2c9, 2c19, 3a4, 3a5. Thousands of drug interactions can be avoided a year. Yes, there are other paths. Over time other paths may be identified as major players. But these paths HAVE been identified as the major players. 

I think it unconscionable, that there are only 5 and EVERY person isn't routinely tested once in their life. I'll concede at reasonable time of testing. Placed on one permanent drug or drug for cancer. This would avoid Paintball therapy.

OH Linda----so much fun being on the soapbox LOL. We'Ve talked so much, I know you get my intensity.

Was going to use this box to continue the game of looking at the elements of negligence. Decided it would break the continuity.

I totally agree, there is still much that is unknown. Like I stated before, genomics is far too limited in scope to encompass the vagaries and complexities of human cancer biology, when it comes to drug selection. Efforts to administer these drugs often result in low response rates at significant toxicity and cost. The genetic sequence of a known gene (genotype) does not equate to having the disease state (phenotype) represented by that gene.

I finished "playing" with the elements of negligence. I'm sure a lawyer would be able to tear apart what I've written. That's fine. I simply wanted to see if the elements could be applied. 

As limited as my legal knowledge is, I do conclude that it is in the physicians best interest not to test for known paths BECAUSE then they WOULD be held accountable for not altering medicine dose or combination.

In today's medical recommendations re :testing of the CYP paths. The physician can use the defense that any reasonable physician is following recommended guidelines that testing not be done. Therefore, they had not breached their duty to the patient b/c a drug dose amount or interaction was not forseeable. Any damage as a result of treatment can not be causally related. 

Is that why Paintball therapy is the accepted practice?

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I looked at the views when I posted my post in Jan. 2014. The counter was 1033. The counter is as above. You are reading . You are interested. You are talking to the patient in the next chair. You are reading articles. You are questioning? Why? Question more? 

Ask why---"WHY Haven't I been tested to make sure the drug is right for me?".... It will set off a chain of events.

Carpe Diem Thank you that was a very sweet thing to wake up too

There are many positives in what you have written. You are reading and questioning. Every time a person brings this up to their docs, the doc will consider the question more. The more questions from patients under their care, the more they will study the question. In studying the question the more they will learn. The more they learn, the more the implications of how drugs work will cause them to consider the total picture of how drugs work either individually or together. Very positive.

You are stable on Anastrozole for three years. You don't mention s.e.'s . All AI's are metabolized through 3A4. This is a guess, but a reasonable guess is that your 3A4 is normal. My "3's" are not, but this was just tested in Jan 2014. The s.e.s of each AI's were so crippling, I was placed on Fentanyl , Oxycodone, and Savella(SSNRI). In each case after a period of time, I chose to stop each drug. What this means to my future is unknown. Had we known the defects at the 3's. My dose could have been altered. I may have been able to receive the treatment.

Tamox as a substitutue would likely have been a problem too b/c it is metabolized by 2D6 and 3A4. Plus, the YS program indicates that there is a major interaction between Tamox and Norvasc( a blood pressure med) @3A4. Would this have been identidied. Unknown. The YS program identifies the interaction, but it's not known to me if all drugs checker programs do. Plus, the abnormality of the 3's was only identified in 2011. All drugs then had to, or should have been re-evaluated for how they worked individually, or in combination through the 3's. once the abnormal allele's were discovered.

Your statement "I do want to keep up with research on this topic so that when I have the inevitable progression I know whether I need to push for testing before a change in treatment plan." Is a very reasoned approach. At present,  no s.e.'s are present, but you are aware that a change may occur in the future. As any cook knows the addition of one item to a recipe can change the outcome of a dishes taste from wonderful to awful. 

Your statement "that there was no evidence that selecting treatment based on testing had any advantage over best practice." In all of science, what was accepted to be as absolute at one time, was later to be found false. For example, the belief that the sun revolved around the earth, was later disproved. It rocked the thinking of the time. Galileo spent a long portion of the remainder of his life under house arrest for writing of his deductions. But eventually, it became the accepted fact.

In medicine, it is the same. What was considered "best practice" at one time was later disproved. One question from a patient to her doc re:whether she should taken an aspirin a day is tremendous example of this. The doc realized she really didn't know. The question caused the doc to research the question. What this doc identified was that no aspirin studies included women in the research. She, also, identified that no women were usually in ANY drug research unless it was a drug specifically for women.

This lead to legislation that required that a certain percentage of women be involved in all new drug research. Women's response to new drugs were required be evaluated separately. What has been learned from this was that women's body respond to chemicals differently than men. Retroactive studies on drugs have been done to determine how we respond to drugs already approved.

One question during a routine office visit changed the world of research.  

As a young nurse in the 70's, I was fascinated by the new knowledge about the cardiovascular system that could be monitored by telemetry. The identification of the beta and alpha receptors. By the time I started to teach medics, beta and alpha turned into beta1/beta2/ alpha 1/ alpha 2-----bought a new book.--4 years.later.

4 years..... a lesson

We then went on  to, calcium channel blockers, then the renal blockers. With each new class of drugs, it was so exciting.

But I learned along the way that problems occurred. I learned that nurses would give drugs b/c they were ordered without considering the consequences. They would give them b/c they were ordered. Docs didn't either. I studied hard to understand the drugs and what drugs could interact. 

I did this b/c I saw to many situations that the whole drug scenario wasn't being watched.

That was the 70's and 80's through to relief in 2009-----nothing had changed---------if you believe, your drug interactions are being evaluated call your pharmacist and ask what drug interaction checker has been run?

Ask your doc how your drugs interact?

Even before CYP was required to be documented in monographs, drug interactions were known. But those that were lazy didn't pay attention. Use of drugs was required to be understood, but documentation wasn't required

Drug indicated, drug ordered, drug given.

An example, Verapamil indicated for fast heart rates. Nurse comes to me and says this patients heart rate is really slow. I asked why the patient admitted---fast heart rate -verapamil appropriate drug---Reviewed sequence of telemetry. Yes, the drug slowed the really fast rate heart rate --now in the 30's Asked if she had given the dose now ordered---no---said you made a good decision, one more dose could have flat-lined the patient.

The point being drugs work as they are supposed too, the deliverer of the drug has to understand the consequences of delivery. The nurses previous to her indescrimantely gave the drug after the patient came into normal range---b/c it was ordered.  They should have reported it to the doc and a dosage change made.

That was along ago occurrence. WE are beyond giving drugs as ordered. Nurses have a responsibility to understand dose, relationship, and action. Always have, but accountability was then as now--- know your drugs .

Why the story, I believe doc's have accountability for how drugs work.

I believe that accountability should be based on the patients genetics.

Your genetics can determine outcome. 

Do you accept Paintball therapy or targeted therapy?

For some reason I'm alive. No known reason, except I went for a prophy, then BC was found. Of 21 women on paternal side, inclusive of 3 aunts and 19 first cousins, I'm still writing.  9 of 21 had BC. The most recent death was Joanie, March 31st, 2014

Hi Carpe, Thanks for writing back

 Not sure why I threw in the cancer stats in my April 6th post, I was drinking wine, feeling the sadness over most recent cousins losses. 

That family got hit hard in 4 days. Her son died Friday, before the Sunday that she passed. Over 7 years, he had kidney, colon, liver and prostate cancer. He was her oldest of six children.

She had BC 2 years ago and mets'd to the liver last fall. Her decision was to let nature take it's course. I then learned of her eldest son's cancer history in that call last fall. That was our last chat. Huge family and the kind that you cannot talk for years , but when you do, it's like yesterday.

That wing of the family was at the beginning of a bell curve on cousins. Many of them were having children when I was born. I was on the down swing of the curve. Frankly, the contact that we've all had is unusual since the grandparents of all passed prior to 1962.

I had been intensely thinking of her over multiple days. Decided to call Monday, left a message on the recorder." Hi, blah, blah". Decided to call her sister right after leaving the message. It was 5:30 pm. One of the sisters Dh's, died at 4pm on Monday. Joanie passed the afternoon before. In 4 days three were lost to cancer. Two blood relatives, one not. 

My call last fall, was to try and get the family on that wing to do a cancer tree. I had done one when I was dx'd in 2009. I received genetic counseling that was through Shands Health Systems in Gainsesville, Florida. It was a grant study program studying BC it was free. The numbers to me were staggering. My intent was to alert the family ---we have a problem. 

The numbers are getting worse

The numbers now are 53 blood relatives on the paternal side, with 23 major primary cancers and 3 skin cancers(non melanoma) that I know of. Of the 23 major cancers,  there have been mets which I have not counted, but are numerous. There have been several that have multiple primaries. Joanie's son, I didn't know of his problems. So, it's into the next generation. 

 I can't seem to make a dent in the family regarding surveillance.

I'm on my second primary--thyroid. But on the day I was dx'd with BC, I was given the diagnosis of a brain tumor. Lost my career same day----bad 4 hours. I had a colonoscopy last summer that dx'd a precancerous polyp. So, follow up scope this summer will be interesting. Had I not been going for a prophy bmx, I would not be writing this, the BC was very aggressive.

I think I have more than enough info to get genetic testing----I have concluded on research that Chek2, LiFraumenea, Lifrumenea Like Syndrome apply. P-Ten I will have to look into--thanks. There's one more that sounded like it applied---in decluttering, I lost the notes. 

I've called Genetech and Dr Susan love foundation but don't fit there criteria for testing. I believe we should meet someone's criteria as a cluster. Haven't found anyone interested.  I'm not just worried about me--it's the cousins and their kids, and of course DS.

I believe the genetic break occurred with paternal grandmother b/c there are lots of cancers on her side. Regarding: Paternal GF, a full second cousin researched geneology back to Ireland as a hobby,  only cardiovascular problems recorded on that side. All Paternal GM's side, were farm families in the early 1900's when pesticides and fertilizers became into use. Indiscriminate amounts and exposure was not known to be a problem. We now know that they were.

I can't control my genetic break.

But the defects in the CYP450 system, I can at least try and help control the response of drugs given to me. 

Hence , the soapbox on CYP known drug metabolism. Let us control what we can, b/c it may influence our response to that which we can't control.

Again , thanks Carpe Diem, another stretch in the story, yours and mine, may cause someone else to think question to question the same.

Called youscript pharmacist and radiation oncogolist today-----to see if defects in 3's were a concern---for Ra 131 scheduled for April 21st...fot Thyroid  ca......neither knew-----they have time to work before the 21st. 

Cool they have to figure it out before I'me given the drug versus after. Particularily since I pointed out that the defect in 3A4 has extrahepatic, effect in the Gi tract skin and kidney.

The Youscript person wasn't a Pharmacist, it was an intake person for none medical people that have subscriiptions  

The RO, did a dr.zeus questionaire. He really was challenged, but was great about saying he would look into it. COOL. He's challenged to review something, not brought up before.

I can tell he's a doc that will be hitting the books and seeking advice on this one.------cuz he admitted he didn't know-------plus, he acknowledged what I said about the previous taxotere exposure----not that he agreed to all the complications. He listened.

Listening is better than being blown off.

cypher---well.. tough question

Again, I believe all 5 should be tested for, if you've read my posts since Jan. My 2's were normal...I was surprised at that when they came in b/c response to meds , I long ago learned to be very careful--decades..... then when the three's came in in Jan, 2014, it explained most everything.

I'm opposite of the norm. If you look back and read the stats that Kayb wrote, and is on Youscripts site, abnormal's are perdomaintently in the 2's. My 3's abnormal's fall in a much smaller percentage. Since my 3's are abnormal, it explains a life long sensitivity to drugs. I learned early _--go low.---now it's backed up by science.-----prior to this docs varied on response -------is she being a complainer, sensitive, psychosomatic.-------you put an adjective on it.  Now I have a super legigtimate concern-------the two routes ---pathes---enzymes affecting drug work are abnormal and conflicting.  One intermediate and the other rapid.   DUH-------and 50% OF ALL DRUGS GO THROUGH BOTH. but 3A4 , SEEMS TO BE THE PREDOMINATE. So, my decades listening to my body response and always asking for the lowest dose worked. Except for the cancer drugs. No one one would listen. 

They had a one size fits all approach----------seriously, messed my body up

Cypher, reread these few pages. Read where I tried to simpilfy things since Jan post. No genius here. Just study and the ability to raise questions.

Right now I have my RO confounded re: thyroid cancer therapy----he's clueless about RA 131 metabolism and paths. I pressed him------he didn't know. 

The bottom line needs to turn from "I Think to I Know".

BTW ask for the ovaries to be taken out------Not worth the risk. They are just two little plum size white balls that can kill you.. Yeah, there are drugs to suppress them. La poop. If they are out, they are out. 

 Cyper your words." He says, the research isn't sufficiently conclusive and/or the test results are somewhat ambiguous.". No---- genetic testing done once in your life  is absolutely conclusive as to what your genetic metabolism of a drug(s) is--period. His understanding is based on lack of study.  He's taken the easy way out with NCCN guidelines.  We've already had a member show that her doc didn't have a clue about the system and he's involved in establishing national guidelines.

You've read the above posts--------they are NOT showing any understanding of how the enzyme paths work based on actual testing.

Let's take a simple approach---what's your blood type? One of a few right? O, A, AB, B. Simple. Why Identify these? Well, you mix the wrong blood types and you die. What is so hard about taking the next step---

" I want to know what drugs are going to work in my body without causing me harm or killing me?"

The testing is cheap compared to your life. 

Contact Genelex and ask for support on how to get your doc to get you tested and insurance to cover it.

Other labs test, Genelex is the ONLY company in the world that tests and then provides the drug/pharmacy consultation. 

KayB so wonderful to hear from you. Yes, I agree with you that the docs are in over their heads on this one. Reliance on NCCN guidelines and ASCO guidelines will go into a tailspin when this kind of info is brought to their attention. 

Genelex, has all their info being inputed and back up by reference from a company that only does that, and that company is the world leader in it.

What many docs do now is they carry a Blueberry or plampilot(is that old--LOL). Where they can pull up drugs.

My PCP and my counselor that I introduced to Genelex in 2010, each can bring up their patients with drugs and genetics listed. They each can check with the patient sitting right there. No Paintball Drug Therapy. It's based on my genetics and inputed drug data that is continually being updated. 

My counselor last evening told me more and more of the docs that he deals with are having their patients tested. He says they are not just doing for the patients benefit. They are doing it for legal reasons too. They see that giving drugs without the benefit of the genetics will be a legal problem for them. Lots of discussion going on. My little area of the world is on the move with it. YAY.

I've said that I believe what we are discussing here will be the norm in 5 years. My counselor believes it will happen sooner.

I'm teaching my DS the lawyer how to use it. Shall I indicate the reason, or is it self explanatory.

A pebble tossed into a pond sends out a ripple. How far and wide, we do not know. sassy

Kayb Oh  what fun with the learning with your grant program. Such a great topic too.

It's not my fear for liability for docs regarding testing and appropriate drug management. It's going to be the "driver" that will get it done. It will advance them more rapidly from Paintball Drug Therapy to targeted, non-injuring therapy. Over 40 years, what I have learned is too many docs and nurses didn't keep up with their learning, or go beyond the minimum.  I was considered to be a --go to person--on drug questions. Yes, I was. But that didn't happen without lot's of study. Drugs scared the bejessus out of me b/c they can kill if not done right. The stories of errors, I could tell b/c someone didn't adequately know what they were prescribing or giving. 

One example, a drug now pulled from the market, used to treat hypermotility (rapid movement) of the GI tract. My first contact with the patient after report (change of shift) that the patient had an ileus (Gi motility stopped) a couple of days. I look at drug list and went - no chit sherlock---drug continued to be given-- no wonder. Doc was at fault for not discontinuing drug, but his reaction was "They are still continuing it. "Er, yes, shall I discontinue it". Polite. The point being. Know your drugs, know why they are being given, know when to alter dose based on response, know when to stop.

Now we are onto the next generation and beyond..........Yay

Cypher, so sorry you couldn't follow the posts. I did seriously try to make them user friendly. Did you start at the January 2014 posts. The first 2 pages were written prior to that and those of us that posted in that time had an understanding of the system. 

The discussion has evolved to CYP450 (CYTOCHROME P450 )system in the liver inclusive of 2D6, 2C9, 2C19, 3A4, 3A5. It is done by a cheek swab. 

This is NOT a test on a tumor.

After I found out my 3's were abnormal in Jan 2014, it became my mission to get the word out of the importance of knowing the status of the 5 major known drug metabolism enzymes pathways in the liver. These enzyme pathways show how drugs are metabolized by the liver so that they can do their work in the body. 

There are many many more pathways in the liver, but at present these are the 5 major ones that have been identified. In the future, other pathways may be identified that will be determined to be a major players. When that time comes, I recommend that people be tested for them as they are identified as to their importance.

There are some pathways that are only involved with one chemical i.e. VKROC1 path defects from normal, indicate how the dose of coumadin/warfarin a blood thinner is handled in the body. So, even though it is involved with only one drug --it's important. 1:15 hospital admissions in the USA are related to complications to coumadin /warfarin therapy. This is big. There are other mechanisms for testing for coumadin/warfarin, but this is the most accurate.

Jelson (thank you Jelson) started the thread, her specific interest at the time was 2D6. The thread has evolved as threads do to included other information.

Sorry, about the off handed comment on the oophs. I don't usually do that. It's a totally different long discussion in and of itself. I am very opinionated and long winded  about the subject, but the statement was inappropriate to the discussion here. Actually, the definition of Paintball Drug Therapy would not apply to the oophs at all. Definitely, discussion of oopherectomy and  paintball approach, shouldn't be used together. But as I said it doesn't belong here.

I do hope you re-read the section starting from January 2014 to present. Cypher, it's NOT an easy subject. It's not light material. It does take study. It's work. It's allot of memorization. There are researchers that spend their entire careers learning and studying the system. You are not unusual to not get it the first time through, but each time of reading about the system more may "gell". 

I've been reading about it for 20 years or more and there isn't a single time of reading that my brain has picked up something I may have read before, that now in a new reading can be layered into the older material that I understand.

I hope you enjoy Genelex  and their YouScript division. When I want to understand how a drug works it's my "go to" site. My other "go to" site for drugs is dailymed.nlm. It's produced by the government, but it's works LOL. The difference between the two is Genelex /YouScript is based on my genetics. Therefore, all the responses are very specific to me. Dailymed.nlm's section on metabolism is generic meaning that it's identifying a enzyme path and can't be applied to me specifically at all. So, worlds apart.