Journal Club - Tamoxifen and CYP2D6 polymorphisms

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Journal Club - Tamoxifen and CYP2D6 polymorphisms

#1  Postby MedGen » Jun 14, 2010 11:39 am

For those who are interested in joining in with the this discussion the article in question can be found at this link: Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen

Feel free to ask any questions about the paper if you have read, or are in the process of reading, it, and require clarification of any parts.

There are still a few days left until the discussion starts proper, but some people may want to start a little early. I shant be available until after Wednesday (my degree results come out tomorrow so I'll be a little...indisposed for a while).
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#2  Postby Mantisdreamz » Jun 14, 2010 9:30 pm

Bookmarking. Just scanned the article, looks tricky for me - I imagine I'll be researching a lot of various words.

Good luck with your results, MedGen!
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#3  Postby Mazille » Jun 14, 2010 9:40 pm

Bookmarking. Haven't been able to read it yet. I'll get back here once I did so.

And good luck, mate! I know you won't need it, though. :cheers:
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#4  Postby twistor59 » Jun 15, 2010 9:05 am

OK, so my understanding (roughly) of what the paper is saying is:

Tamoxifen works as a breast cancer treatment due to the substances it produces when it's metabolized. The useful (for breast cancer treatment) metabolism products are enhanced by the presence of a specific enzyme CYP2D6. Women have different levels of CYP2D6 activity, so the study aims to see if there's a correlation between increased activity and success in treatment using Tamoxifen.

The "success" was measured by a Kaplan Meier survival curve - never heard of that before, but it looks like a pretty universal way of analysing clinical trials ? From what I can glean, you basically compute the proportion meeting some criterion at each follow-up check. Depending on the data you want that criterion may be simple survival, or not having the symptoms recur etc. If people disappear from the study, these are called censored observations and are treated specially.

Women were placed into 3 groups according to genetic(?) criteria which characterise their CYP2D6 activity (or effectivness or whatever !) :

EM, hetEM/IM and PM

The Kaplan Meier curves were produced for the whole study population ("unstratified") and for each of these subtypes individually. If I look at the first graph in figure 1, I read it as follows:

If I take, say, the 9 year point, then for PM the survival proportion is about 75%, for EM it's about 85% (I can't read the graphs very accurately). Since this first graph is the "time to recurrence" graph, am I right in saying that " the term "survival" in this context means that, for example, in the EM case at the 9 year point 85% of the population have not had a recurrence ?

I didn't understand the term "breast event" in their definition of event free survival. Does that have a precise definition ?

I have still to look up the definition of long rank testing and Cox proportional hazard modelling - not familiar with that at all !
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#5  Postby natselrox » Jun 15, 2010 9:41 am

I didn't get the time to read the article. But from what I read, CYP2D6 polymorphism is associated with varying clinical outcomes of various drugs. An individual with a variant of the enzyme used to be hypotensive after administration of Debrisoquine. Other drugs like Sparteine, Amitriptyline, Dextromethorphan etc. also have different outcomes based on CYP2D6 polymorphism. The most common example is perhaps Codeine which requires its metabolism to morphine for producing its effects which is impossible in some patients who possess a specific variant of the enzyme.

When I first read the heading of the article and the abstract, I thought of going to the Oncology dept. of our college and asking for the data to link the varying outcomes of Tamoxifen with these drugs. Although none of these drugs are frontline clinical drugs of choice, at least in India.

The other thought that came to my mind, was to commercialise this idea, Nanosphere-warfarin style! (Remember, medgen? :grin: )

Btw, the whole Cytochrome P450 system is very interesting from an evolutionary perspective. Interested persons might like to look them up.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#6  Postby natselrox » Jun 15, 2010 10:15 am

twistor59 wrote: Women have different levels of CYP2D6 activity


Not really. Women have different versions of the enzyme. CYP2D6 (and other CYP) polymorphism is a very common topic in Pharma texts as it metabolises quite a few drugs. My Pharma exams ended just a few months ago and I've already forgot the details. :scratch:
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#7  Postby natselrox » Jun 15, 2010 10:21 am

And Tamoxifen is a shit-drug for students. Apparently, it works as a steroid-receptor antagonist in the Breast tissue and agonist in the liver, bone, endometrium. Hence known as Selective Estrogen Receptor Modulator and has been associated with a lot of paraneoplastic disorders.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#8  Postby MedGen » Jun 15, 2010 10:27 am

Nats - The nanosphere was the inspiration for doing a pharmacogenetics PhD (starting in October), but I don't think it would be applicable here. Warfarin response is the gold standard in pharmacogenomics at the moment, but it's still not completely there (I swear they are dragging their feet wrt to developing inclusive dosing algorithms despite the number of papers published in this area!).

Twistor - you've got a good grasp already. The different CYP2D6 phenotypes are very broad classifications based upon the cytochrome P450 nomenclature commission which classifies each variant. This study didn't cover all of them, there are over 100! They only included the following:

Poor metabolisers (phenotype) - variants *3, *4, *5 (genotypes)
Intermediate (phenotype) - variants *10 and *41 (genotypes)
Extensive (phenotype) - non-intermediate and low activity variants (genotypes)
Ultra-metabolisers (phenotype) - Gene duplications of extensive metaboliser variants (genotype)

This is actually one of the flaws of the study, which the authors point out, they lack complete coverage of all the different variants and their activites.

A breast event, from what I can tell, is essentially a clinical diagnosis of a neoplastic growth in mammary tissue following treatment.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#9  Postby natselrox » Jun 15, 2010 10:37 am

MedGen wrote:Nats - The nanosphere was the inspiration for doing a pharmacogenetics PhD (starting in October), but I don't think it would be applicable here. Warfarin response is the gold standard in pharmacogenomics at the moment, but it's still not completely there (I swear they are dragging their feet wrt to developing inclusive dosing algorithms despite the number of papers published in this area!).


Boy! I'm impatient! :grin:

Great to hear about your pharmacogenetics PhD! That's THE future of Medical Science! :thumbup:
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#10  Postby kiki5711 » Jun 15, 2010 10:50 am

Is this the same tomixifen given after breast cancer surgery?
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#11  Postby twistor59 » Jun 15, 2010 11:19 am

@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#12  Postby twistor59 » Jun 15, 2010 11:31 am

natselrox wrote:
twistor59 wrote: Women have different levels of CYP2D6 activity


Not really. Women have different versions of the enzyme. CYP2D6 (and other CYP) polymorphism is a very common topic in Pharma texts as it metabolises quite a few drugs. My Pharma exams ended just a few months ago and I've already forgot the details. :scratch:


Ah right thanks, I guess the term polymorphism gives it away !
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#13  Postby kiki5711 » Jun 15, 2010 11:38 am

twistor59 wrote:@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?


I take Arimidex instead of Tamoxifen. The doctor told me the side effects are not as bad and since I was post menop. I could take Arimidex.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#14  Postby natselrox » Jun 15, 2010 11:48 am

kiki5711 wrote:
twistor59 wrote:@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?


I take Arimidex instead of Tamoxifen. The doctor told me the side effects are not as bad and since I was post menop. I could take Arimidex.


From the article,

Data from clinical trials comparing the efficacy of aromatase inhibitors (AIs) and tamoxifen showed an advantage of AIs in the adjuvant endocrine treatment of early stage breast cancer. However, because the absolute difference in recurrence rates comparing tamoxifen and AIs is less than 5%, it has been hypothesized that treatment outcomes following tamoxifen in patients with normal CYP2D6 enzyme function would be similar to treatment outcomes following an AI.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#15  Postby MedGen » Jun 15, 2010 12:36 pm

twistor59 wrote:@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?


Our university have turned out to be incompetent in the biggest fucking sense. Our results have been delayed because the fucking shitty-ass new system they put in can't even handle the load of people logging on, WHAT THE FUCK?! Stupid retarded fucking nob-shit of a university and their incompetent fucking computer system.

Edit: Sorry, I got a first, and the highest grade in the year. :grin:
Last edited by MedGen on Jun 15, 2010 3:55 pm, edited 1 time in total.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#16  Postby MathieuT » Jun 15, 2010 2:57 pm

kiki5711 wrote:
twistor59 wrote:@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?


I take Arimidex instead of Tamoxifen. The doctor told me the side effects are not as bad and since I was post menop. I could take Arimidex.


I don't get it, why not giving both?
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#17  Postby kiki5711 » Jun 15, 2010 3:18 pm

MathieuT wrote:
kiki5711 wrote:
twistor59 wrote:@kiki - yes I think so.

@MedGen hope results are good. do you know yet ?


I take Arimidex instead of Tamoxifen. The doctor told me the side effects are not as bad and since I was post menop. I could take Arimidex.


I don't get it, why not giving both?


Because it's either or kind of thing. They both do the same thing except Arimidex can be taken by women past menaupasaul stage and according to my doctor has less side effects.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#18  Postby MathieuT » Jun 15, 2010 3:27 pm

Arimidex inhibit the production of estrogen while Tamoxifen act as a specific antagonist for estrogen receptor.

They both result in the same effect, but from different strategy.
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#19  Postby natselrox » Jun 15, 2010 3:59 pm

Maybe kiki is ER negative. Simple, Mathieu!
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Re: Journal Club - Tamoxifen and CYP2D6 polymorphisms

#20  Postby MathieuT » Jun 15, 2010 4:12 pm

natselrox wrote:Maybe kiki is ER negative. Simple, Mathieu!


I'm lost there. What's the point of inhibiting her ER pathway IF she is ER negative.
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