2D6 Rears its ugly head.....

Ok, I have been to hell and back......but I am back.......

I am working on a video you all may soon love to hate, I am also working on a poster for GAPPNet which you too may also soon love to hate......

Well, for all you Amplichip fans, the data from a recent retrospective analysis of German and US cohorts reveals that null function 2D6 may actually portend a worse prognosis for those taking adjuvant (after surgery) chemotherapy for breast cancer. These are women who had hormone receptor positive breast cancer stages I-III, without metastases and without chermotherapy.

At 9 years of follow up, patients who had null 2D6 CYP 450 enzymes ended up with a 29% recurrence rate instead of those who had active 2D6 enzymes. This compared to 14.9% for extensive metabolizers.

Why does this matter?
1. Tamoxifen is used a lot
2. Aromatase inhibitor therapy (Another Drug) is another option for this type of cancer
3. This test is easy to do
4. This follows the Plavix model......

My guess, Roche is about to make a lot of money on the Amplichip shortly.......

Why is this study important? It is the first sufficiently powered study to assess 2D6 genotypes and outcomes.....

Even more importantly, Tamoxifen is a Pro-Drug.....just like Plavix. This time it requires conversion to Endoxifen which is the active drug derived from Tamoxifen.......

The hazard ration for recurrence with poor metabolizers is 2.12. That is a useful thing, which may prompt refined endocrine therapy for these postmenopausal breast cancers......

The Sherpa Says: I am back!!!

Muscle Pain from Statins? Time for a genetic evalutaion!

In a wonderful demonstration of how successful genetic research on pharmacogenomics needs to be done. The SEARCH Collaborative Group successfully demonstrated the power of GWAS nested in other studies. This will be the hallmark of all great medication studies for the next 50 years. Do I mean GWAS? No!

I mean genetic analysis of the outliers in response to the medication being studied. I only ask myself, why in the hell hasn't pharma been doing this for the last 10 years????? I have my suspicions, but I'll never mention them in public.

So why am I so excited? Well......you know how the DTC companies test you for SNPs that give you odds ratios of 1.3 or less??? Imagine an Odds Ratio of 16 for developing statin induced myopathy!!! I was just talking to the founder of one of those sequencing companies worth billions of dollars about this the other day!!! Odds ratio of 16.9

Uhhhhh...Yeahhhh....that is a pretty good chance of getting the myopathies associated with this super common medication. How is that for immediately clinically relevant. Have the polymorphism?.....Don't take statins...instead take Fenofibrates.

This study was signed sealed and delivered to the door of the makers of Zocor(Merck). I sure hope they license that test!!!! Oh wait...this will likely be sold by deCode. Caraiso just told me that this SNP is on all of the big 3's chips! So who will contact their patients...sorry/customers? If the MD ordered the test....it would be the MD's duty........This is why the government is trying to regulate this testing.....for this type of follow up. This is a great study it needs follow up!

How was it done? From NEJM...

Methods: We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants.

At first, I balked.....80 mg of Zocor. That's a whopping dose! Who the hell uses that much Zocor? So I tried to dismiss this study....but it was the replication in the 40mg Group that got me.....

So what did they find?

The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r2=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy.

Why am I salivating over these results????

1. 16.9 is a huge Odds Ratio in a region where we know there has been lots of literature reporting the issues with Organic Anion Transporters and the bad effects of statins.

2. The replication in a clinically useful cohort.....40 mg of Zocor....there are tons of people on that dose.

3. Statin Myopathy can cause kidney failure from rhabdomyolysis(muscle breakdown). It is a dangerous side effect! Another clinically useful point!

4. There were NO OTHER SNPs associated with anything!!! The odds of that are preposterous! That IMHO means this is a very valid SNP. With everything, I suggest replication and then the marketing of this test to the physician. With the OTC Zocor in the UK....maybe they have an interest in DTC????? Or maybe not

The Sherpa Says:

Pharma are you listening? This is the way to save your medications and save you from lawsuits. The way to stay alive is by developing diagnostics that protect your patients and doctors.....If you don't follow this model, you will perish. When this study is replicated and the test available through a CLIA certified lab, Helix Health of Connecticut will test their patients for this very important genetic polymorphism.....As for the big 3 screens changing medications......Dr Agus should stick to Heme-Onc. The SNPs associated with heart attack in the SNP scan are separate from cholesterol....and statins have not been proven to lower risk via any mechanism other than lipid lowering....Either way, he would be better served testing the organic anion transporter.

FDA Warnings, Breast Feeding and Codeine

This is something I have been following for over a year now. There were several published reports of mothers taking codeine and their babies having problems.

First, let me explain how that could happen. Codeine is something called a pro-drug. That means Codeine essentially does nothing when taken. It only works by being converted to another substance in the body. In codeine's case, that substance is morphine. That's correct, codeine is really morphine.

So what happens in these new babies is due to the metabolizer status of their mothers. If dear old mom is an ultra-rapid metabolizer of codeine, then there will be higher than usual amounts of morphine in the blood, and in the breast milk.

Recently the FDA issued a warning regarding codeine consumption during breastfeeding.

"Codeine frequently is prescribed to women after giving birth for pain associated with episiotomies or caesarean sections, the Washington Post reports. In addition, codeine is a common ingredient in some forms of Tylenol and nonprescription cough syrups, the Los Angeles Times reports" from medical news today..."According to FDA, about 16% to 28% of people with North African, Ethiopian and Saudi dissent are ultra-rapid metabolizers. Labs usually charge between $500 and $1,000 for a Roche Diagnostics test that can determine how people metabolize several drugs, including codeine"

The Sherpa Says: So does this mean all nursing mothers should be genotyped for polymorphisms in their metabolizing enzymes? Not really. What should be done is 1. Less convoluted pain medications should be given 2. If mothers are taking this drug, then they need to monitor their child for signs of intoxication (slow breathing, sleepiness, failure to feed) 3. Watch the news, you are bound to find more out about personalized medicine there rather than from your MD.