kayb, yes, it does look like that clinical trial may be a dead letter.

sas, thank you for putting together that letter. I will print it out to keep in my hip pocket should I ever need it. 

I have really learned a lot from everyone's posts. I have also started reading "The Creative Destruction of Medicine," which was recommended by voraciousreader, and am learning a lot from that, as well. The author, Eric Topol, mentions a CDC statistic that 7% of hospital admissions each year are related to adverse drug reactions, so I am realizing this is a huge issue. It would certainly behoove the insurance companies to approve more testing for drug metabolism related genes! 

Also, was just reading this study, which was very interesting, "Polymorphic Cytochrome P450 Enzymes (CYP's) and Their Role in Personalized Therapy." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC385833...  Good overview, and I thought this paragraph was intriguing: "Apart from altered drug metabolism, CYP polymorphisms were also potentially associated with neoplastic growth, adverse psychological behavior and other diseases. In women, polymorphisms in CYP 1A1 seemed to increase susceptibility to genital cancers [57,58]. Conversely, the CYP 2D6*4 polymorphism has been shown to have a protective effect against breast cancer [59]. Furthermore, 2C19*2, 2D6*4, 2D6*10 and 1A1*2A have been associated with increased risk of head and neck squamous cell carcinoma [60].

Kayb  don't short yourself, one article can turn the tide. The article regarding the acceptance that In Vitro (in glass)analysis published in 2000 ( pg 2 or 3), was the seminal piece concluding that enzyme path analysis for drugs in the lab, instead of waiting for the drugs to be processed through the body(In Vivo) then analyzed from the urine was acceptable. What was fun, is it was only the second abstract I looked at in that search. It was WOW-COOL. 

A few weeks previously, I spent a total of about 8 hours sifting through abstracts and articles re: whether or not senna could be habit forming? Never found a seminal evidence based article or abstract. I was so tired of reading about poop.

Hugz4u (love the screen name) LOL, it's too deep for us too. We try where we can, and direct elsewhere to better knowledged people when we haven't got a clue. The KEY is to work on getting tested. The science is ready. The testing is affordable with insurance. Insurance carriers  and docs should be pestered till they test.

As much as we all hate the word "awareness" with BC. People are not aware of the significance of testing NOW. My abnormal '3's besides confirming that Taxotere and the AI's were not dosed right, showed that I had a major drug interaction between Coreg and Wellbutrin. This was not caught by any of my docs or pharmacist. Why? My abnormal metabolism wasn't known. Wellbutrin is out of my drug basket now.

Included in the panel is VKROC1  which is specific to coumadin. Testing showed I am an intermediate metabolizer. If I ever need Coumadin/warfarin, I need to start at a lower than standard dose. Our Dear ChrissyB ended up with a bleed for this very reason. Odd though when I researched it for her, my own genetics weren't known. Serendipity.

Testing NOW for your genetics, will help prevent present and future problems

Edit 5/24/2014 Wellbutrin & Coreg were a problem at 2D6. There are two places in these post that I mention the two drugs as a problem at 3A4. Too many pain meds since surgery, to remember the what and why of what I posted in regard to Wellbutrin and Coreg. Well, at least I can try and blame anesthesia/ pain med brain.

Not a single brain cell willing to work----there will be another day sassy

http://www.ccjm.org/content/78/4/243

This is one of the articles that VR linked. I took time to take a gander, when I was trying to find another link. They are not up to date and it's the Cleveland Clinic. Cleveland Clinic is a premier institution in the USA and world. 

They don't get that many more than a few perceived important drugs can be tested  ---thousands more drugs can be found to have their metabolism altered, interactions occurring by blocking, inhibition, or inducing  a change in how another drug acts. 

I say this because they place the application in the future. The application is available NOW.

"Disturbing: the initial pharmacist in each case were unfamiliar about the Cytochrome 450 pathways. SO, those reading this have more knowledge than some pharmacists that have taken minimum 7-8 years of schooling."

Wow, really frustrating. I keep hearing about personalized medicine, yet it doesn't seem like the medical establishment is using the tools already available. They act like it's about to happen, when it could be happening now with better implementation!

What really caught my eye about Dr. Topol was an article last year that gave me some indication he had some "outside the box" thinking.

According to Dr. Eric Topol, Director, Scripps Translational Science Institute, recent studies have highlighted the potential value of whole genome or exome sequencing to precisely guide therapy for patients with cancer. However, almost all samples today go into formalin-fixed, paraffin embedded (FFPE) blocks, which alters the DNA and makes sequencing quite compromised and difficult.

He told Medscape Connect that the company, Foundation Medicine, which works with formalin-fixed paraffin-embedded (FFPE) blocks, and gets about 250-300 genes, the exons or coding elements in those genes, and reads out any potential links to drugs. But the rate-liimiting step appears to be getting something beyond these paraffin blocks. This is, we could do better if we could use either fresh formalin-fixed or frozen tissue samples from a biopsy or surgical specimen.

Topol says the problem is that pathologists are seemingly quite ritualistic. They don't want to go to frozen samples, which would be the best for whole genome sequencing. We're just at the cusp of getting started with this type of limited, not even full exome sequencing, just a few hundred genes, but that isn't enough.

Rencent papers in multiple journals in Nature, Science, Nature Genetics and Cell have shown that with hundreds of tumor samples fully sequenced, no two cancers are the same and a lot of the action is not in the coding elements of the genes per se. Whole genome sequencing certainly appears to be an ideal path to pursue, but we can't do it with the fixed problems that we have with the way samples are handled today.

Topol thinks that maybe we could get fresh formalin-fixed samples, as those appear to be well-suited to whole genome sequencing, although this is still a somewhat bootstrapped situation, like the paraffin-embedded samples. It appears that the long those samples are embedded, the harder it is to get a reasonable sequence beyond very targeted regions.

There are no two cancer tissues that are the same on a molecular basis. There's quite a bit of heterogeneity within the samples and multiple sequencing could account for that. And we also want to anticipate recurrence, match up the right driver mutations and the backseat passenger mutations, whether or not there's needed immunotherapy; all those things that could be done if we could get the right information from the get go.

So Dr. Topol asks this: How are we going to move to a world with a clinic of the future where patients with cancer can get whole genome sequencing rapidly? That is, to have annotation and interpretation of the genome with a day, and have your therapy precisely guided genomically?

I note that Foundation Medicine is not any different than Caris Diagnostics in Phoenix (now Miraca Life Sciences), beyond testing for standard pathology "targets" such as ER, PR, Her2, EGFR mutations, KRAS, BRAF. They aren't worth much for the sorts of chemotherapy which is used in 95% of all cancers and useless with respect to drug combinations. While fresh tissue is very dear and hard to come by, function trumps structure, in terms of potency and robustness of information provided than using archival paraffin blocks.

VR. Methinks they are all talking, instead of doing. All are getting published. Very nice in the publish or perish community. The time now, is to get to work. 

I know you are oh so busy with DH. 

Your DH is the absolute classic of the need for this testing. His inborn defects in metabolism already present in the liver, makes me wonder "Does it involve the drug enzyme pathways?" I know you've always had to be the Lioness watching every drug being given to him b/c of errors in the past.

You've read above about identifying right away re: the Coreg and Wellbutrin interaction. At first I thought it maybe okay. My pressure was under better control. I continued on the Wellbutrin. I started it 12 days before the 28th sx b/c I was getting OCD (wacko---lol) worried. 

Wellbutrin( half recommended dose) and Zoloft were prescribed months ago at the time of the first thyroid bx, and I had a vulva bx same time period. I had a meltdown worrying. BX results due back at same time. Counselor and PCP thought it best to start both. I didn't b/c of past experience with meds. More afraid of the drugs than the relief they might bring.

Coreg affect was increased by Wellbutrin. Still haven't deduced what caused the affect of wanting to uncontrollably scream at people. After third episode of trying to take out someone's carotid through the phone, I stopped Wellbutrin. This drug is unlike other psych drugs, weaning isn't necessary. Affect gone within 2 days. I've called an apologized to all involved, but during the occurrence it was like watching/listening to a freak show. OH WELL, it's over. 

Never took the Zoloft , only now plugged it into YouScript, it's major path is 3A4 for conversion to it's active component. So, consideration of dose alteration would need to be done. It's a blessing I decided not to take it. But not necessary now, it won't ever pass my lips

But back to you and DH, sure wish you could convince the "Powers" that it may be life saving for him.

Thanks for your thoughts towards me sassy

In regards to the fresh freeze tissue samples, when you snap freeze cells, the water inside of them swells, breaking them open upon thawing. So snap frozen tissue, which may be okay for some assays like molecular profiling, is not okay for functional profiling.

What needs to be done is cryopreserve, as opposed to merely "freeze" the cells in culture medium containing 10% DMSO at a rate of one degree celsius per minute. This makes the cell membranes pliable and when the water inside the cells swells, the cell membranes stretch, but don't break.

When cells cytopreserved in this way are thawed, carefully, they remain viable and can be suitable for various assays. Even laboratory oncologists cryopreserve "leftover" tumor cells whenever possible. I got a confirmation from one laboratory to see whether they were in fact cryopreserving tumors and not just freezing them. They were actually cryopreserving.

VR sorry missed that last line about liver enzymes. The Ast, Alt, other alterations when  myoglobulins break down,  have nothing to do with the drug enzyme pathways. Unless they are totally destroyed in the liver destruction process. But drug metabolizing enzymes wouldn't be measured by any standard lab equipment(as urine below)

A standard urinalysis that is also looking for evidence of myoglobulins will have changes as the breakdown of the myoglobulins clog up the kidney works. But what is measured, is the standard things that can be seen on a standard urine analysis lab slip and a separate order for myoglobulins---forgte how it would be written. Nonetheless, drug enzyme paths wouldn't be identified

As far as urine, if used for In Vivo studies of how drugs are metabolized  there would be a chemical extraction process. No clue how they do it, but it wouldn't show up in a standard urine. The test would be done by very sophisticated laboratory equipment.

VR, Please, practice on the YouScript software. 

These people can debate all day long, all decade long, all century long. 

Let them live through one bad preventable drug reaction that almost kills them. That is compounded by the hospitalist that hangs the wrong IV fluid which then puts them into acute renal failure. This causes the relative overdose of the drug that should have been at a reduced dose b/c of a faulty metabolic enzyme pathway, to circulate longer. Circulating longer at a higher dose than needed, this did what to the bodies cells? Because of the IV error that caused the acute renal failure the overdose of the medicine couldn't be flushed out. Totally trashes the immune system. Temp 104.8, wbc's 1.5, neuts 0.5

Not made up to sound disasterious for impact. It was me. The MO, and the pharmacist when asked why it happened had no clue. They refused to try to play Sherlock Holmes to figure it out. I said in that case, I wasn't willing to trade off all my organs for adjuvant chemo. 

If I recounted all the errors made regarding my DH, only word that comes to mind---unbelievable. The MO, 2 pharmacist (hospital and healthplan pharmacist), cardiologist all refused to look at the monographs to see how to reduce drug interactions based on metabolic enzyme paths identified in the PDR/drug checkers/ monographs as per FDA rule to be included in these documents for > than 10 years. Why were they included if they weren't expected to be used?

I had to make a chart myself. It worked. His chemo's after the first awful one improved dramatically after I, a non physician, defined what drugs to interrupt and which to change to other drugs to free up collisions at paths.

The time for debate is over when there are tests that will not only prevent chemo related errors and collisions, but other drug errors and collisions

The time for debate is over when those taking Aromatase Inhibitors that are crippling them b/c metabolic pathways are faulty. Resulting in the patient receiving too much drug.

The time for debate is over.

Did I chase to many windmills? Or is everyone enjoying the weather?

Tamoxifen---prodrug metrabolized at 2d6 leel to endoxifen. Notes:Calcium Increasing Drug Combinations[vitamin D2]

Effects
Combining drugs that can increase calcium can cause additive effects.

Management
Consider monitoring calcium levels if necessary.

Confidence
The evidence in this note is based on one clinical trial and/or the product insert.

Note 7761 reviewed on 2013-04-09 01:16:59

CYP2D6 Genetics

Effects
This medication is metabolized by CYP2D6 which is highly polymorphic. DNA testing identifies common variants that result in dramatic differences in patient exposures. More than 50% of the population carries these variations that may lead to adverse reactions or lack of efficacy at normal therapeutic doses. 

CYP3A4 Genetics

Effects

This medication is metabolized by CYP3A4. CYP3A4 metabolism may be reduced in CYP3A4 intermediate metabolizers (*1/*22 or *22/*22).
The liver enzymes CYP3A4 and CYP3A5 are the most common drug-processing enzymes in the body and about half of most common drugs are metabolized by them, including medications used to treat heart disease, pain, cancer and infectious disease.
Until recently the clinical actionability of known CYP3A4 variants was questionable. However, in 2011 a new variant, *22, was discovered. This variation has been shown to have a correlation with the exposure of many common medications.

Metabolite endoxifen

• SUBSTRATES

http://www.sciencedaily.com/releases/2013/12/131212185835.htm

 "Endoxifen may turn out to be a better drug than Tamoxifen and not just in patients who have limited CYP2D6 metabolism. This is something that has to be prospectively tested."

Wish they would hurry.

Elements of the case[edit]

A plaintiff must establish all four elements of the tort of negligence for a successful medical malpractice claim.^[4]

1. A duty was owed: a legal duty exists whenever a hospital or health care provider undertakes care or treatment of a patient.
2. A duty was breached: the provider failed to conform to the relevant standard care.
3. The breach caused an injury: The breach of duty was a direct cause and the proximate cause of the injury.
4. Damage: Without damage (losses which may be pecuniary or emotional), there is no basis for a claim, regardless of whether the medical provider was negligent. Likewise, damage can occur without negligence, for example, when someone dies from a fatal disease.

As per my url post on page one of this thread, the Agency for Healthcare Research and Quality (AHRQ) found there was no consistent associations between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy.

http://cancerfocus.org/forum/showthread.php?t=3061