To my knowledge there is no effect. Conceptually, the TAM 10 year study is not based on molecular science but on statistics (and that is one of my problems with it). 

The CYP2D6 issue died down because there was insufficient evidence to determine whether it was truly prognostic of therapeutic benefit from Tamoxifen. The question remains open - we still don't know the basic thing about Tamoxifen: WHO BENEFITS. We know where to look for potential beneficiaries ( bc patients with er-pos cancer) but that is it. ATLAS is an epidemiological study of outcomes for groups. No inference can be made for individuals. We've located the neighborhood but not the house.

Reposting from the HOT FLASH FORUM,permission was received from kayb

Dec 21, 2012 11:30 AM kayb wrote:

Hi all. I haven't been on this thread in ages, but I saw this news out of San Antonio and wanted to make sure everyone knew about it because you might need to chat with your doctor. Possibly one more solution that bites the dust.

Effexor May Not Mix with Tamoxifen

Action Points

SAN ANTONIO -- The antidepressant venlafaxine (Effexor), often given to breast cancer patients to treat the hot flashes associated with tamoxifen therapy, might reduce the effectiveness of the drug, a researcher said here.

In a multicenter prospective study, venlafaxine inhibited the metabolism of adjuvant tamoxifen by lowering the concentration of the drug's active metabolite, endoxifen, according to Matthew Goetz, MD, of the Mayo Clinic in Rochester, Minn.

The effect – caused by an inhibition of cytochrome P450 2D6 (CYP2D6) -- is small but statistically significant, Goetz reported in a poster at the San Antonio Breast Cancer Symposium (SABCS) here.

The drug, which has long been regarded as having no interaction with tamoxifen, "should be used with caution, especially in women with endoxifen concentrations that are known to be low," he said.

The issue of drug interactions with CYP2D6 has been controversial, commented Hiltrud Brauch, DPhil, of the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology in Stuttgart, Germany, who was not part of the study, but who moderated the SABCS poster discussion session.

Brauch was the leader of a study that reported in 2009 that variations in CYP2D6 have an effect on disease-free and event-free survival in patients taking tamoxifen.

"Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers," she said. "The long and the short of it is that this matters to women."

But as well as natural variation, several drugs -- including many of the antidepressants -- are known to either block CYP2D6 permanently or interfere with it while they are being taken, she noted.

For that reason, Brauch said, the study by Goetz and colleagues is important, suggesting that clinicians should be careful when they prescribe venlafaxine to women taking tamoxifen.

The study itself looked at paired blood samples from 30 women, taken before starting venlafaxine and 8 to 16 weeks afterward.

Across all genetic subgroups, Goetz reported, the drug depressed levels of endoxifen over time by a median of about 1.6 ng/ml (P=0.04).

On the other hand, it's still not known how much endoxifen is needed to provide a benefit, so that the effect of venlafaxine on breast cancer outcomes remains an open question.

Goetz said limited evidence suggests that at least 6 ng/ml is needed, and in the study, three women with low CYP2D6 activity saw their levels drop below that.

"The bottom line is that there is a decrease – it's small but it's statistically significant," he said. "The question really is: Are there subgroups of patients in which this is important?"

He and colleagues are currently conducting a phase I study to examine the question of optimal endoxifen levels and a phase II study will begin next year, he reported.

Susan , that's the way I read it. Which supports what I'm saying about our understanding of the work of the pathway. Poor Metabolizer is a "slow metabolizer?". Getting our language down re: the Paths is work i.e intense study.

Susan, we will see a change in reimbursement for genetic testing , but it will take awhile. That's why I included a short letter suggesting language for the letter to the insurer. The more people do this over time, the more the insurer is likely to move toward covering it. Everyday research is showing the importance of CYP usuage with drugs as the articles that Jelson and kayb have sited. We are at the advent of an avalanche of gentic tests being available. Insurers will eventually see the cost effectiveness of making sure drugs work and that no untoward effects occur b/c of incorrect prescribing b/c someones path wasn't present or being altered b/c of another drug.

It was hoped some day that Genomic Analyses of cancer tumors would be able to identify in advance which patients will benefit from use of cancer drugs (clinical responders). The Agency for Healthcare Research and Quality (AHRQ) suggests that day is still a ways off.

A study looked at whether the presence of specific mutations in people who had breast and colon cancer and chronic myeloid leukemia determined if patients would respond to expensive new drugs commonly used to fight the diseases. Only in colon cancer did the mutation matter and in that case, while it ruled out the effectiveness of drug therapy, the relevant mutation only appears in a small percentage of cases.

In the finding, the AHRQ report 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. 

Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective.

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

SAS

In regards to drug interactions, an editorial in the Journal of Clinical Oncology by University of Chicago researchers ruffled some industry feathers a couple years ago by arguing that taking Tykerb with fatty meals (the label says not to) is synergistic, greatly improved absorption and could lead to reduced doses (by 60%) which means less cost for the $2,900-a-month price tag, and reduced side effects, particularly diarrhea.

A company-sponsored study showed that Tykerb blood levels increased by 167% when taken with a low-fat meal, compared with taking the drug on an empty stomach -- and by 325% after a high-fat meal. Researchers, Drs. Mark Ratain and Ezra Cohen, argued that these kinds of food-drug interactions should be explored to lower drug costs.

And if taken with grapefruit juice, the potential cost savings could be about 80%, since Tykerb interacts with CYP3A4. Powerful compounds in the grapefruit called furanocoumarins obliterate the CYP3A4 enzyme in the intestines and liver. The result is that more of the drug gets into the bloodstream.

Individuals have different levels of CYP3A4 that breaks down drugs before they even have the chance to get into the bloodstream. Patients with very active CYP3A4 get lower amounts of drugs into their systems than those with low levels of the enzyme. Some patients may have naturally low levels of the CYP3A4 enzyme and thus wouldn't need it, 

Certain drugs have a hard time reaching optimal blood levels at prescribed doses. Some doctors are interested in intentionally boosting the effects with grapefruit.

http://jco.ascopubs.org/content/25/23/3397.full.pdf

This is but one of several similar findings. In addition to Tykerb, Zytiga (abiraterone) is also better absorbed with food, though the label says "empty stomach." One Laboratory Oncologist I know has actually been able to reverse Zytiga resistance by having his patients take it with a fatty meal.

Greg

SAS

What little I know of the cytochrome (CYP) system comes from keeping tabs with laboratory oncologists who are into cell function analysis. The challenge of identifying which specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors and monoclonal antibodies).

In the early part of the 20th century, a German biochemist name Otto Warburg observed that tumor tissues and normal tissues metabolize glucose differently. Instead of relying on the citric acid cycle to extract maximal energy from a molecule of glucose, tumor cells rapidly convert glucose to lactate through glycolysis even when oxygen is abundant.

His discovery became known as the Warburg effect and this observation sits at the core of the field now known as cancer metabolomics. But for many years after Warburg's observation, scientists focused on separate mechanisms of oncogenesis without considering that these metabolic differences could drive the formation of new cancers or could speed their growth.

More recently, cancer researchers have recognized that these metabolic changes help cancer cells build the macromolecules that support the rapid growth and proliferation of tumors.

These laboratory oncologists, utilizing the primary culture platform, have been able to unravel the complexities and redundancies of these processes. It enables them to examine the end result of signal inhibition and dissect disease specific profiles. 

Biological complexity is the hallmark of life, and the hallmark of cancer. For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues and bodily fluids.

Laboratory Oncology: http://cancerfocus.org/forum/showthread.php?t=3734

In regards to writing in layperson language, someone had told me, "people who want to teach themselves, teach themselves" and that's what I've tried to do. By educating myself on what happened to my wife and why, I've been hoping to help others understand more about the consequences of medical treatments and not fall through the same cracks.

Although I sometimes post in a narrative writing style, my information generally gets too technically involved and at times, controversial. I'm not very good at putting things in layperson's language. After 17 years at this, the geekness of it has gotten to me.

Greg

Nice article Heidi

Metabolomics is a newly emerging field of "omics" research concerned with the comprehensive characterization of the small molecule metabolites in biological systems. It can provide an overview of the metabolic status and global biochemical events associated with a cellular or biological system.

An increasing focus in metabolomics research is now evident in academia, industry and government, with more than 500 papers a year being published on this subject. Indeed, metabolomics is now part of the vision of the NIH road map initiative (E. Zerhouni (2003) Science 302, 63-64&72).

Many other government bodies are also supporting metabolomics activities internationally. Studying the metabolome (along with other "omes") will highlight changes in networks and pathways and provide insights into physiological and pathological states.

The concept of Systems Biology and the prospect of integrating transcriptomics, proteomics, and metabolomics data is exciting and the integration of these fields continues to evolve at a rapid pace. Developments in informatics, flux analysis and biochemical modeling are adding new dimensions to the field of metabolomics.

To be able to walk from genetic or environmental perturbations to a phenotype to a specific biochemical event is exciting. Metabolomics has the promise to enable detection of disease states and their progression, monitor response to therapy, stratify patients based on biochemical profiles, and highlight targets for drug design.

The metabolomics field builds on a wealth of biochemical information that was established over many years.

The Metabolomics Society

From everything I have read and from the most recent tests done by Mayo Clinic (which I have a lot of faith in) I am getting the blood test for Tamoxifen efficacy. I could not believe that my Onc did not tell me about this. Also, my Onc's office said I would have to have the blood draw done at their office and have it sent to a specialty lab. This is incorrect. I called Quest which is in my network and they do perform this test. They did not know of this without a little work but they found it in their system. Don't just assume you have to pay out of network. I had the blood drawn today and they send it to there California lab. Mon - Thurs only.

Greg you were talking up there about grapefruit juice. I truelly dont understand a lot of what you talk about. Just goes way over my head. But do you know why they say us tamoxifen users cant drink grapefruit juice anymore? Is it that it will make my tamoxifen be absorbed more or better? I know the occasional glass wont kill me, but I love grapefruit.

http://www.sciencedaily.com/releases/2012/12/121226153030.htm

According to this collaborative study, poor metabolizers should go on AIs instead. At least until they can develop endoxifen, the active part of tamoxifen, as an alternative.  I am an ultrarapid metabolizer and taking half a dose (10mg) only.

repost from Insomnia thread. sassy

Post a reply

2 hours ago, edited 3 minutes ago by sas-schatzi

Tamoxifen(active metabolite endoxifen), ALl AI's go through the 3a4 enzyme path. Anyone with an abnormality of the path or on a drug that majorly affected the path would have an effect of how the drug works.

EDIT: lol ---I READ THE COMMENTS, ALL YOU NEED TO READ IS THE BOLDED STUFF. THE OTHER STUFF IS THE GENETIC EXPLANATION. YOU DON'T NEED TO KNOW THAT ---BUT YOUR DOC SURE AS HELL SHOULD. IS THAT BETTER?????????

tamoxifen through the 3A4 path ----

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.

Tamoxifen through the 2d6 path----

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.

Arimedex, Femara, Aromasin. " I failed all three". The info was available in 2011. I went on Aromasin as a last try in 2011. Had this testing been done. The dose would have been changed or gone to every other day dose.

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.

----------------------------------------------------

2 hours ago, edited 38 minutes ago by sas-schatzi

I know this all sounds very technical. But there are only seven major players--2d6, 2c9, 2c19, 3a4, 3a5, VKORC1

Polymorphic means there are variations----in this case of these genetics, it means the path can be absent, intermediate, normal, rapid, ultra rapid.

All the two's ----2d6, 2c9, 2c19----have a greater numbers in the population with abnormalities. That's why Genelex offered them in a package b/c abnormalities are that common.

Then when the test for coumadin/ warfarin became available, they packaged it with the "2's". It made the package panel very attractive. The gene is VKORC1(subset of 2c9) 1of 15 hospital admission in the USA are due to complications caused by coumadin/warfarin. We are talking likely millions and millions of dollars. That's why insurance companies are now VERY likely to cover this test b/c it's cheaper than one day in the hospital. Medicare covers the cost, but must be pre-approved. Plus, adverse drug interactions have become to be recognized as a major source of complications for patients resulting in added medical problems and costs.

The complete conversation with Daugherty was "only 5% of the population has variations in 3a4 &3a5, statistically that is very small, they felt that it was taking money for a test that was likely for most normal" I've told you the pitch I made.

25% of all drugs take a first pass through 2d6

50% of all drugs go through 3a4 and 3a5

The way the Genelex system is set up: the genetics are entered into the system & patients drug list. The computer does an interaction check and uses the genetics to show whether the drugs are interfering with each other at a PARTICULAR path. If there is a conflict the computer offers a suggestion of alternate drugs. As in cases where a path is abnormal a similar thing occurs. There is a pharmacist on duty to answer questions and help.

Story time: Gary my counselor after I told him about the above, had a patient that was on Prozac. Trying to get her on a maintenance dose was impossible b/c she continued with mood fluctuation. In frustration, he decided to have her tested. Prozac is 100% metabolized by 2D6. Her pathway was absent. He had spent time trying to regulate her on a drug that had no chance of working.

When he told me this story, he initiated it with a Thank You. Once he got her genetic tests back, the Genelex pharmacist worked with him to figure out the best alternative. They got her regulated on a med. He from that time forward will not recommend any drugs without genetic testing. The case was actually publishable, but couldn't talk him into it.

I pay under 25.00$ a year to have my own subscription. YouScript.

It's time to shake our Docs up. Technically, my doc did not meet the standard of care. He should have been aware that a test was available. 

Spookiesmom…FloridaJoined: Dec 2012Posts: 1,298

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9 hours ago Spookiesmom wrote:

Sas, the clots were about 4 years ago. Installed a vena cava filter ASAP at hospital. Heparin(gotta love rat poison) then lovenox, then Coumadin. Doc said I was very lucky.

Taxotere was a year ago. They told me it would be easier than A/C. Somebody didn't get the memo. I did a little digging, what I found pointed to polysorbate 80 in the solution as the cause. No one ever mentioned the Coumadin as a cause.

I was supposed to get 4 cycles of T. MO said no more chemo and stopped it. So the little black cloud we all have hanging around, mine feels a bit bigger. The what ifs a tad more frequent. And WTF happens to me if it comes back?

I've spammed this around the boards, hopefully, the mods will get that now is the time to get our MO's and PCP's to take our care seriously by protecting us from injury by drugs and or drugs that aren't working for us because of our genetics.

----------------------------------------------------------

Hi Folks, I haven't posted here before, but recently found out some info that has pissed me off in re: the drugs given to me during treatment for BC. I was almost killed with my one and only chemo. Taxotere was the culprit. I "failed" all three AI's b/c of s.e.'s. All of this could have been avoided had my MO paid attention to the Cytochrome450 genetic testing. Of the six genes tested, I have abnormalities in three. All are major players in the drugs I was given. Had I been tested, it would have been known. The drug choice and /or dosage modifications could have been made

Rather than rewrite the details here The link below will take you to a thread that has the posts that I have written in the last few days.

I'm not trying to sell Genelex. Other laboratories are doing genetic testing. But Genelex is the only company right now that provides the application of the genetic results to the drugs we are taking. Other companies, I'm sure are trying to build the same business model. It's the future of drug administration.

Why? Patients will no longer except being experimented upon with drugs that can harm them. If the docs won't do this because it's the right thing to do it. Then we have to PUSH them into doing the right thing.

http://community.breastcancer.org/forum/73/topic/7...