Tarceva, Iressa and EGFR screening.

No Duh.

Can't believe I missed this yesterday. In the NEJM there is an article talking about Tarceva therapy (Very Expensive) and that it targets lung cancers that have EGFR mutations. So if you don't have those mutations, why would we expect you to benefit from these expensive drugs first line?

Wha?

Ok let me explain.

Read this first

Iressa and Tarceva are EGFR tyrosine kinase inhibitors, which interfere with cancer cells' ability to multiply. People with certain mutations respond. In fact, I heard Mike Murray talk about the Lazarus response to Iressa which was published back in 2004

We tried a novel treatment and found that in certain tumor types, those with EGFR mutations, deletions in exon 19 and L858R primarily had better response to treatment with these TK EGFR inhibitors.

So, now we have what is a prospective trial assessing the utility of genotyping for therapy. This trial took 3 years to complete.

In addition, there was another study published which showed a head to head trial of toxic IV chemo versus targeted molecular therapy in a group highly likely to have EGFR mutations. Guess what they found? Yup, better outcomes with EGFR TK inhibitors and best outcomes in those with EGFR mutations......

They found:
Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.

The data are stunning. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel.

But the subgroup findings are where this personalized medicine approach had the most teeth with again, a very, very expensive drug.

In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001),> the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001).

This will be music to the comparative effectiveness gurus ears. Have an expensive drug? Test first to see if it works. Then give it........

Brilliant.

The Sherpa Says: We need more studies like this in many, many more fields. They will come, I am certain of that, which is why I am where I am.........

Where from here?

This is the question I am asked so often.

1. We have the steady progress towards cheap genomes.
2. We have the biggest supporter of personalized medicine running the NIH
3. We have "some" clinical awareness of personalized medicine
4. We have the government aware of the shenanigans of some unscrupulous DTC advertising, etc
5. We have several milemarkers under our belts with genome science..... We are moving in the "right" direction, but where do we go from here

There are several areas we need to investigate. I would like to sum a few of them, both basic science and clinical. Basic Science first.

1. We need to understand precisely how gene regulation occurs in the face of certain common environmental exposures. Trans Fat, Tobacco Smoke, Alcohol, Stress. Is it RNA? Is it Methylation? What precisely is it? Maybe it is all of them and more. But the quicker we understand that, the quicker we can look for signs of these ill effects.....and stop them molecularly

2. We need a good CNV/Indel etc database. Toronto sure, I have heard that. But seriously. We need this and we need it now. Give me Normals, Give me abnormals, Give me phenotypes......This is a very key missing piece of the puzzle which neds to be completed in the next 2 years

3. Junk DNA investigation. This will come once we have a database like the one in Iceland......I am certain this will come. I think that next to nuclear fission, the investigation into the "junk dna" will prove to be one of the most fruitful works of governmental science. Yes, you can quote me on that one.

4. Systems biology. This is one of those areas where we will eventually realize the Greeks were right with phlegmatic systems vs bilious systems.......

Now onto the top 3 Clinical Science targets

1. A complete revamping of the current risk stratification system. What do I mean? We need to develop a process for efficiently introducing genotypic risks into current clinical risk stratification. We need to evaluate the with and without and change in AUC......
1b. We need to evaluate the role of integrating family history in some risk stratification models. I know Dr. Khoury/Scheuner et.al are working on these things, but it sure would be nice to have odds ratios and RRs/HRs for adverse drug outcomes, common autoimmune disease risks, COPD, Alcoholism, Suicide, etc. types based on fam hx integrated with current models.

2. Pharmacogenomics......end of story, we need more science here for more drugs. There is not nearly enough clinical study weight on outcomes. I understand why from the Pharma end, but the US government cannot ignore its utility, especially with the pain they feel from Medicare part D
This area has tremendous promise, but has not seen the will from genetics departments, mine looked at my cross eyed when I wanted to do a PGx study. There has to be a will in basic medical science departments like pharmacology and cell biology to understand the processes and polymorphism which really screw up a drug's effect.....or really enhance it. And there has to be a will in clinical departments to study the outcomes with different therapies based on genes.....

3. I want to know what behavioral outcomes are likely with knowledge of one's family history risk versus genome scan risk vs both together vs with no knowledge.

These are some low hanging fruit that could get accomplished and probably already are........

The Sherpa Says: These are not stretch targets, these are do-able things in the next 5 years or so. If we can accomplish most of these, we will be well on our way to evidence based personalized medicine, which is where we need to be........

Family History, State of the Science

The NIH/CDC is hosting a conference next week. I conference I wish I could go to, but alas, I will be DOING family histories on my patients that week.

The conference will be held at the NIH in Bethesda. This is an NIH state of the science conference about Family History and its usefulness.

I for one, am very glad that the government is trying to address this super important issue. It is beyond due for an evaluation.

Why?

With the cost of a genome going to drop to 5000 USD by the late fall (trust me), we will soon see another level of DTC and Clinical lab set offering the genome as a predictive tool.

There are several reasons that Family History beats a Genome (For Now)
1. Phenotypic data of family history represents complex interplay of genes and environment

There is no way that a simple genome will be able to give us the story of how a human will develop. That is predicted by environment and genes, which are successfully covered by..... A family history.

2. 5000 USD is still more than what it costs to obtain a family history.

By the time the software tools are released, we will see that social networking and the internet will transform the costs of family history next to nothing. Which is still a long way to go for the genome scans.

3. We have no clue what most of the genome data means.

Indels or CNVs or SNPs, we have no freaking clue what most mean, we do know what a heart attack at 40 means.......

4. Even if we had everyone's genome scans, we would still need phenotypic data and pedigrees.

What's the one thing we do when we have an intellectually delayed child with an abnormal CMA/CGH? We test the parents. Looking for THEIR phenotypes to make sense of the genome mess.

Look, people always give me reasons why the genome is important and a family history is useless.
I've heard them.

-"We don't speak with that side of the family"
-"My father lived with his uncle, because his father died (secretly running the empire as Darth Vader)"
-"I was adopted by Bail Organa, only to find out I have a lost twin brother"

There is one thing that will always be certain over time, there will be some screwed up family dynamics making it difficult (BUT NOT IMPOSSIBLE) to obtain an accurate family history.

That being said, it is still often useful to capture those who you can. And still less expensive.

I look forward to the briefings from this conference, and Muin, if you are listening, I would love to have the link to the webcasts.... Oh wait, they have that too! Sweet.

If you can't be there, you can get the information you seek!

Once again, we need a state of the science on genome prediction, not a consensus statement a real eval of the state of the science. When placed side by side with the state of the science for a family history, we will soon see why family history is the preferred screening tool and will likely to continue that way, perhaps in conjunction with a genome scan, but genomes will NEVER replace family history.

The Sherpa Says: The press better be at this conference and report on Family History. And to the founders of Geni.com, you missed on this one when Tindall presented to you. Or maybe you just are going to steal the idea.........

Finally Francis!

This is exactly what we have all been waiting for. Someone, one of us, one like us who has now gotten a hold of the National Institutes of Health. Thank the Lord!

For those atheists among you, I want to assuage your fears. Christians can perform great science too. Francis has and will continue to. I am so very happy for this pretty amazing occurrence.

From the WSJ.

Collins, 59 years old, served as director of the NIH’s National Human Genome Research Institute from 1993 to 2008 and oversaw the international collaboration known as the Human Genome Project. That project, completed in 2003, determined the sequence of the three billion base pairs that make up human DNA.

Moreover, it spurred the field of genomics and the dream to personalize medicine for individuals based on their genes. His nomination is being applauded by organizations like the American Heart Association and Personalized Medicine Coalition, who laud his “landmark discoveries of disease genes.”

Tell me, how many winners of the Presidential Medal of Freedom have led the NIH?

Francis had this vision from the very beginning, merge genetics with environment. Nature or Nurture?

Yes, and that is why he is an ideal NIH director. He will bring comparative effectiveness research into the personalized medicine realm and has the insight to understand the answer can often be "Both"

A long time supporter of what we only saw as obvious, yet others not so much, his wisdom and insight only stands to benefit the United States tremendously.
Bravo Francis!

The Sherpa Says: Whatever your opinions on genetics, genomics, medicine, you have to admit Francis is one hell of a great leader.

Something off my chest........Health care will never be fixed by Lawyers

I rant and rave about genomics and about hyping of genetic tests but today I have a bigger issue. That issue is plain and simple.


Healthcare is FCUk3D up.



I run a successful personalized medicine practice, just recently we started taking health insurance. The demands from handling billing and copays from insurers AND medicaid has not been that cumbersome. Why? We only see 10 patients per doctor per day.

When you start seeing more than that it creates all sorts of problems.

Like manpower requirements that start to exceed 100-200k per doctor.......

If you have less doctors for more patients, the equation is simple.

Rationing of physician care.

That is what will happen when you cut 400 million dollars of Medicare money. Oh wait, I mean 500 BILLION dollars......

Do I think that the Lawyer serving in congress will ever solve those problems?
No.
Do I think that the very few doctors in congress will fix this problem?
No.

But trust me, there are way more lawyers than doctors in Congress, so I am extremely doubtful.
No Offense GenomicsLawyer.......

Why?

They are not the people who are experiencing the problems.

Maybe the doctors were, but they aren't now.

The solution will come from doctors/nurses/patients who are involved in the system already...... currently.......

To think otherwise is foolish.
And to drown out the protesters, intimidate them and hide from town halls is also foolish.

Both parties in this argument are dead wrong.

They are having the wrong argument.

The average primary care doctor gets paid about the same as they did 10 years ago. Does that make sense?
Costs go up. Rent Goes up. Medical Supplies cost more. And insurance pays less and less, Including Medicare, who pays routinely 1/2 to 1/3 of what private insurers pay.

As a doctor, Don't like what you get paid? Switch Insurers.
But you won't be able to do that under a universal plan.

As a patient? Don't like what your insurance paid for? Switch insurers. Pretty simple, unless of course you have preexisting conditions.......

The system is a mess, not because of what we pay doctors or hospitals or whoever.

The system is a mess because there are a whole lot of sick people out there......More sick people than healthcare practitioners equals shortage of attention.

Shortage of attention leads to worse care and more labs and more procedures. Shortage of attention leads to increased malpractice costs, risks and fears...... Want to fix the system?

Encourage more doctors to go into primary care, make their liability risks less, create technology so that they can "fire" their overhead this will create increased revenues for doctors without raising pay.

But please, don't ration care because we are too busy and too risk averse to do it on our own.

Enable the professionals to do it by giving them time to think about their patients...... This system will never get fixed by lawyers.......never.

Medicine is a thinking man/woman's game, not a sweatshop.....why ask us to run sweatshops? The American people deserve better than that......

The Sherpa Says: What good is personalized medicine if the doctor can't take the time to personalize it for the patients??? You tell me.

The Doctors are OK with this?

Yesterday in "The Times" a nice article was posted about the revolutionary way in which doctors will receive education about CLINICAL genetics, this time it is from NonClinical Scientists......

At the tune of 4.5 Million British Pounds!

This may work with CGCs, oh wait, they don't do much of anything in the UK system.

What about clinical geneticists?
Who?

Ok, scientists it is......

So I can just see it now.

A busy NHS practice, patients out the door, flu shot here, flu shot there and in rolls the "Scientist"

Clinician-"Oh hi, you must be the genetics guy sent from the government. Have a seat, I'll be right with you"

4 hours later

Scientist-Sitting nicely, waiting

Clinician-"Ok, lets chat over lunch"

Scientist-"Glad to be here, Let's talk about what a chromosome is"

Clinician-Scarfing down a sandwich "Ok, that was great, gotta go. I am double booked. See you in a few"

4 hours later

Scientist-Sitting Nicely, waiting

Clinician-"Sorry about that, I had a sickie and then the crazy lady....G-d where did the time go?"

Scientist-"See you tomorrow?"

Clinician-"You bet, I feel better prepared already"

As nice as this one is, I have already tried it with a clinical geneticist who actually can create billable events and see patients........ I am not so certain that going to the doctors will help as much as being on their iPhone or on a hotline.......

The Sherpa Says: When climbing the mountain for the first time, it is best to chat with someone who has been there before.....Muin and Franics, I hope you are paying attention here.

Pharmacogenetic Indication for a Medication?

That's one way to market the newest medication to prevent stroke, heart attack or stent thrombosis.

Wha? Yes, I mean, Prasugrel otherwise known as Effient is FDA approved for use in these patients.

But one thing I was thinking is that, since the FDA put on the insert of Plavix that 2C19 testing may be useful to identify people who will not respond to Plavix (generic Clopidogrel)

Perhaps, the marketing geniuses over at Eli Lilly could use this as an FDA suggestion that these 2C19 people may be better off with Prasugrel.

Yes, it would be one of the most brilliant ways to market pharmacogenomics. I can only imagine the DTC genomics companies salivating over this "We offer the 2C19, test. Act now, save your life." Technically, It actually could. Yes, all the stops would be pulled out and it could potentially save the DTC genomics companies.

You may be asking yourself, "The DTC companies need saving?"

Yes, they do. Face facts, Research revolution is a flop, nowhere near 1000 people per study. Funny how people don't trust google or anyone without proper research accreditation.

Navi is slashing costs and they have a CEO who is the master of running wastelands (i.e. companies where all the bad assets of a VC firm go)
DeCodeMe.....huh?
Pathway and Tru have no marketing budgets and no real scientific staff.......... Seriously here. WTF?

But, if they could get one big hit from Lilly shoving billions into this PGx marketing campaign, they could be ok. Otherwise, I am afraid, they are lost.

For Lilly it would be a huge win too. Why? Imagine being able to pull a full 1/3rd of all patients taking Plavix off and switching them to Effient/Prasugrel. They could, they really, really could.

So now that I have you attention. The big question is , when will Eli Lilly do this? My guess, in the fall.

Mark my words, they WILL DO THIS and it WILL SAVE companies like 23andSergey and Navi. If of course they offer the test. LabCorp, Genelex and Quest all offer the test now.

But here's the rub, if they offer this and say it is used to make a clinical decision, then they will be a part of the healthcare industry......... Oops, forgot to mention that before. Survive and take regulations or Die..........

The Sherpa Says: This would be the most brilliant marketing campaign in the world, Personalized Medicine awareness would be worldwide, and Pharmacogenomics would hit the stage in a major, major way....Thanks Lilly, call me to orchestrate your campaign.....