deCode Versus Arthur Caplan PhD.

To attempt to sort out the hype from the hope, Sherpa Style. I will review each and every SNP that deCode is using for it's Breast Cancer Test. This weekend I will cover the first 2. But first some hype from both sides.

Dr Caplan from MSNBC

Genetic testing for all sorts of conditions is all the rage these days. Everywhere you turn, some company is urging you to spit in a cup, take some blood or swab your cheek so your DNA can reveal your health risks, know who your long-dead ancestors are, pick the right mate or help you design a diet that is perfect for your genetic makeup. But, "spitomics" has gotten way ahead of genomics.

Sadly, the tests Decode and other companies are offering are more likely to empty family pocketbooks and leave women with a false sense of security than they are to prevent breast cancer.

Dr Gulcher from deCode

Arthur Caplan stresses caution in the application of the new genetic risk tests for common diseases and I certainly agree that genetic testing should be applied with care. However, he goes too far when he says that the new deCODE BreastCancer genetic risk test is only useful for women who have two or more close relatives with breast cancer, is not based on large enough studies to be accurate, and is not regulated........Each of the genetic markers in this risk test have been replicated in between 5 and 30 different populations in studies by deCODE genetics, the National Cancer Institute, and UK Cancer Research.

These studies have been published in the most prestigious, peer-reviewed journals, including Nature Genetics and the New England Journal of Medicine. Altogether almost 100,000 patients and controls have been studied to define the marker risks. We made this test available for physicians to order for their patients through our reference laboratory which is regulated under CLIA by the US Federal government.

There are two major types of breast cancer: the rare, early onset form that occurs in certain families and for the detection (for which the Myriad Genetic test is well suited), and the common form which accounts for 95 percent of breast cancer.

Well, Dr. Jeff, you are making the case for BRCA smaller than the data shows.....So right off the bat I am a little suspect.....The number for familial breast cancer is 10-12% and BRCA has the majority of that......Oh and you do read the economist don't you? Famous is not always better buddy.

Ok, so who is right. The chances are high that they both are. But let's go to the tape!

What are the SNPs they test for? On limited weekend hours I will review 2 SNPs.

1. rs13387042 when looked up in a pubmed search only shows one article in Nature, by guess who? deCode.....still waiting for this "Well replicated SNP"

What does this SNP reveal and for whom?

Population: Icelanders, replicated on Northern Europeans (Sweden, Spain, Holland, US MEC)

Prevalence: 25% of Europeans, widely varied in other ethnicities

Function: Unknown, no genes known in this linkage disequilibrium block.

Penetrance: Unknown, OR is 1.2 for ER positive and 1.06 for ER negative

This study isolated 10 SNPs and only 2 SNPs replicated, I don't see the unreplicated ones in the paper. Importantly, this SNP did not replicate perfectly in the Swedes.... The SNP varied widely between ethnicities in the Multi-Ethnic Cohort in the US.......They observed no interaction between the 2 SNPs that replicated in Caucasians.....The effect seems that it could be recessive.....

The study even acknowledges that this was a limited effort in finding risk SNPs....."However as the relative risks remain low, they (these SNPs) can only account for a small fraction of the familial clustering of this disease.

2. rs4415084 guess what, the same thing happened with this SNP. Only one article, by guess who? deCode. This time in the Brief Communications of Nature Genetics......I look forward to the Independant Replication...

Population: Iceland first, then replication in (Sweden, Spain, Holland, US MEC). It flopped in Nigerians!

Prevalence: Not reported in this one and only paper on this SNP

Function: Unknown, but maybe linked to FGF10 which is amplified in 10% of breast cancers. Also MRPS30 is in this area....but really, we have no freakin' clue.

Penetrance: Unknown, but the OR for ER positive breast cancer is 1.27, for total breast cancer is OR of 1.14

So let me translate. These are 2 of the seven SNPs DeCode claims will help show risk of common (Read as not BRCA related) breast cancer. If this is any indication of the rest, I am sad to say that they are out on a limb here.

Several clinical questions come up when I want to order this test.

1. Who do I test? In the case of these SNPs, I would guess white women.

2. How common is this risk? Not very common in the case of Asians or Africans. In fact in one of these papers, a SNP being tested for didn't show increased risk, it actually showed protection from breast cancer.

3. How do I counsel a positive test? Tough to say. We don't know the penetrance, we know an odds ratio for a certain group.

4. Can I see deCode's data on their magical risk calculator thingy that includes these SNPs? Or is that a trade secret?

5. How reliable is this science? Not very, the studies were replicated by deCode and not by other groups.....

6. Is this "test" validated? I would love to review the seven panel test publication....oh wait, I couldn't find it.....

Not all of these SNPs are that thoroughly validated or as "replicated" as Dr Gulcher said. So this is the case of rushing to market with a test.

The Sherpa Says:

This test is Hype until proven otherwise. I await the future studies on these SNPs. Dr Jeff does a good job on deCode's blog of promoting it though. I know early detection is key and pre-disease is the new disease, but a clinician has to have confidence in their tools. This one is a little primitive for me.......and at worse could give patients a false sense of security. So guess what......Jeff and Art, you are both correct.

Heavy Heart

I vowed I would never post when family took precedence. I have to break that vow today. I wish I didn't but there is something so vitally important that I must share with you. Why is this important? Because it might save more lives than have been previously lost.

The scourge of Ovarian and Breast cancer has ravaged several populations. With very few cases of early detection in Ovarian cancer, many women present with spread of the cancer and very poor prognosis. Even more importantly, women who have ovarian cancer and BRCA mutations still are at risk for other cancers including breast cancer.

Despite this I have heard comments from Oncologists like "Why do we need testing?" This is why I have pulled myself away from my grief stricken family.


To fight this lack of knowledge I have dedicated and arm of Helix Health of Connecticut to educate and promote genomic medicine. This arm will host at minimum monthly podcasts on very important topics. The first of these is Hereditary Breast and Ovarian Cancers and the BRCA genes.


The panel will include a patient with BRCA1. She not only happens to be afflicted, she has written about her experiences. Jessica is gifted with the pen and is a very successful writer. Her book "Pretty is What Changes" raises significant issues and serves as a wake up call to clinicians and patients. It serves to empower us all.


Jessica will join David Ewing Duncan, bestselling author of Masterminds: Genius, DNA and the Quest to Rewrite Life, and a panel of distinguished medical and legal professionals to discuss how the doctor-patient relationship is changing and what the potential liability is for physicians in this new era of breast & ovarian cancer and genomic medicine.


The Sherpa Says:
The Helix Health of Connecticut webcast series is dedicated to my grandmother who died at 35 years of age from metastatic breast cancer. Too young for me to ever know. Please sign up for this conference. The information may just save a life......If Helix Health of Connecticut can save just one life then all the hard work is worth it. Please sign up now. Seats are limited, but you can also sign up for the podcast.

Jessica Queller and BRCA1

First I would like to apologize to Spiegel and Grau. I missed you gracious letter. Please give me a call.


Second.....I am catching some serious heat about the deCode rant! I never knew so many smokers were hoping to escape cancer and angrily flaming me with emails. Here's a hint ladies and Gentlemen........Quit Smoking and maybe you will avoid cancer. To all of those who decided to fill my gmail yesterday....thanks for reading this blog. I appreciate your interest.


I don't know how many of you picked up the USA Today on March 31st, but in it was a profile on Jessica Queller. She has written a book called:

Pretty Is What Changes-Impossible Choices, The Breast Cancer Gene, and How I Defied My Destiny

About the Book....
Eleven months after her mother succumbs to cancer, Jessica Queller has herself tested for the BRCA “breast cancer” gene mutation. The results come back positive, putting her at a terrifyingly elevated risk of developing breast cancer before the age of fifty and ovarian cancer in her lifetime.
Thirty-four, unattached, and yearning for marriage and a family of her own, Queller faces an agonizing choice: a lifetime of vigilant screenings and a commitment to fight the disease when caught, or its radical alternative—a prophylactic double mastectomy that would effectively restore life to her, even as it would challenge her most closely held beliefs about body image, identity, and sexuality.

The Sherpa Says:
To understand the human issues surrouding genetics we need to experience or read others' experiences. I think many of you already know of my family's history.....very similar.
I am hoping to invite Jessica to the blog. Wish me luck.....

Having a Breast Augmentation? Get tested for BRCA?

I never thought I would be reading the Aesthetic Surgery Journal.....but when the word BRCA pops up, I have to take notice.

From Medical News Today

"Plastic surgeons must play a part in monitoring women who come in for cosmetic breast procedures. These patients should be assessed for potential breast cancer risk by a physical examination as well as a family history evaluation," said Foad Nahai, MD, President of ASAPS and Associate Editor of ASJ. "It is imperative that these patients understand their potential risk, if any, as well as the implications breast surgery may have on future screening, in order for them to make the best possible decision regarding their own care."

I never thought I could tell the guys from Nip Tuck to do a 3 generation pedigree.....Well, Now I can. There is a problem though...I don't think plastic surgeons are the most astute genetic counselors out there.....

So what does this article say?

"Before every elective breast surgery, special attention should be paid to any family history of breast or ovarian cancer."

The reason? Since you are working with young women, this is the ideal group to identify these risks.... They demonstrated the PAT model and also show the gail model.......Both are not the best choices and can underestimate risk. Still with the BRCAPRO model, physicians need to know that limited family structure can play a role...something most physicians miss.

From Medical News Today:

Some key considerations for patients at high risk for breast cancer include:

- BRCA1 and BRCA2 related breast cancers generally occur in younger women, making detection by mammography difficult because of the denser breasts.

- The current screening recommendations for patients who test positive for BRCA1 and BRCA2 mutations include monthly self breast exams starting at age 18, semiannual clinical breast exams starting at age 25, and annual mammography and breast MRI starting at age 30.

- All breast reconstruction methods are available to patients with genetic predisposition for developing breast cancer; however, every high-risk patient must be counseled carefully and thoroughly to enable her to arrive at a decision suitable for her.

- For patients with BRCA mutation, it is important to note that bilateral reconstructions can be very lengthy and a staged approach may be advisable, and must be coordinated with the oncologic and gynecologic surgeons during combined procedures.



"Close cooperation between oncologists and plastic surgeons will improve patients' psychosocial outcomes and decrease the psychological burden for patients who have been diagnosed with a genetic predisposition for breast cancer," added Dr. Soltanian.



The Sherpa Says:
How sad is it that the only time a woman may get her family history evaluated is when she is seeing a plastic surgeon for breast augmentation......BTW did you notice that Dr Soltanian did not mention Medical Geneticists....I wonder if they know medical genetics exists????

Flu and Personalized Vaccines

As I sit here shivering, febrile and with myalgias, I had a thought. "Hey wait a second....I got the flu shot this year". Yes, it is true. For the first time EVER in my adult life I had received the flu vaccine. It's funny, becuase if you think about it, Flu Vaccine IS personalized medicine/Genomic Healthcare.

You may be saying, HUH? But it is the truth. The flu vaccine is a combination of two genes...well the protein products of those genes. Yes, much like humans there are several different types of the "flu" Influenza virus. They are classified according to these genes Hemagluttinin and Neuraminidase.

Hemagglutinin also called H and then subtyped by number, is useful for the little influenza to stick to the cells it wishes to invade.

Neuraminidase also called N and then subtyped by number is used for the "little bastard" (sorry, it is just the cytokines in my body speaking) to escape from infected cells and spread to other cells.

So when a vaccine is made they actually put components of these subtypes together with their "Best Estimate" of which viruses are likely to infect during a given year. Hence "Personalized Vaccine Medicine"

Well this year guess what. Our best guess was.....WRONG and now I sit here with the flu. This is not the only thing wrong in personalized medicine land. We have long known that sometimes we make a mistake in subtyping a woman's breast cancer for the Her-2 protein. Now we are finding a better way....through chickens. So how's that Chicken Soup for the Genomic Soul. Her-2 is used to direct therapy of a Her-2 Monoclonal antibody. For more, see the Personalized Medicine article.

The Sherpa Says: The best laid guess is as good as anybody's This is why we need to always view these technologies very carefully. Imagine getting a flu shot thinking you will have better protection, only to get the flu for the first time in years. Now imagine taking herceptin only to find out it doesn't work for you. We have to be careful and double check what we are given and what our results are. Too many people take printed reports AND clinicians at face value. While usually a good thing (Only if we understand the language) it can have some bad outcomes. Including my own illness ;)

Polls Closed, Myriad Tallies Up and We await Navigenics!

First I would like to thank everyone who voted on this very non-scientific poll. I extended the voting over a month, thousands of visitors later, we have our results.

What Personal Genomics Company is most Likely to be sued 1st?

23 and Me - 70%

Navigenics - 15%

DeCode - 10%

Knome - 3%

You may be saying "Hey That's Only 98%" I say, "exactly" That's why it's not scientific. For all who may be reading, including my daily friends from Mountain View (that's right, everday)
Who exactly will be doing the suing? Maybe an Attorney General? If you are Myriad then that is the case. I prevously posted about this dangerous predicament these genomic companies could be in and the reposted last week about it.

As for Myriad, expect more BRACAnalysis ads to be coming. The WSJ reports that the Myriad ad campaign in the NY metro/NE area has increased sales of their test. from medical news today:

According to the Journal, sales of BRCAnalysis, which identifies the BRCA1 and BRCA2 genetic mutations, have increased by about 55% from $34.2 million to $53.1 million in its second quarter that ended Dec. 31, 2007.

Does this mean more patients at risk are getting identified? Most Definitely. Does this mean that their opponents are saying that more people are getting tested inappropriately? Most definitely. How did this campaign succeed where the one in 2003 fizzled? Primary Care Providers including OB/Gyns. Ask your local rep how many more tests came through these avenues and I think you will be surprised.

Now back to the wait. Navigenics is slated to open early this year. With GenomeBoy receiving an invite to the ball, I am certain to see this launch very soon. Will they follow Myriad's suit? I imagine a 3 million dollar ad campaign would work very nicely in the tri-state area. But then we have to warn them of the DTC testing laws in these states. Lest they end up like Myriad.

I guess anyone can file a suit these days. So here's a word to the Genomics Companies....."Be prepared".

As for the other companies not so well capitalized....."Be Afraid"

The Sherpa Says:
If I had a law degree, like the millions of lawyers out there who can do this work for free. I would bone up on genetics legal precedent, corporate protections and genetic discrimination. If you think a certain ex-candidate for president made a bundle suing OB/Gyns, you haven't seen the beginning of the legal fortune to be made in genomics.

Failed the Test? Blame Homocysteine!

Recently there was an article which raised some red flags for me. It explains why we can't be jumping to all sorts of conclusions about genes and their effects.
From Medical News Today:

"UMaine psychology professors Merrill F. "Pete" Elias, Michael A. Robbins and Penelope K. Elias, in collaboration with colleagues in Syracuse, N.Y., England and Australia, studied the relationships among the gene ApoE, homocysteine concentrations, and cognitive performance"

This prompts me to ask what variants did they study and what do they mean by cognitive performance?

Nine hundred eleven dementia-free and stroke-free subjects (59% women) from the Maine-Syracuse study (26–98 years old) were stratified into no-ApoE-4 (n = 667) and ApoE-4 carrier (n = 244) cohorts

The clinical diagnosis of dementia was determined from cognitive data, self-report, and medical records, using the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria

This is quite a few people, but they do not eliminate those patients who may have had a TIA or separated them by IQ. Which is probably a better way to assess this. In addition, Self report is a notoriously poor way for dementia patients to identify themselves. Remember these people who have dementia frequently deny that they have dementia.

Participants completed the Center for Epidemiological Studies Depression Scale (CES-D [34]) within one week prior to neuropsychological testing. Following a fast from midnight, a blood sample was drawn and a light breakfast was served. A physical examination and neuropsychological testing followed.

Probably some of the best testing so far....

What did they find?

With adjustment for the Expanded model (Basic +CVD+ B-vitamin covariates), we found that persons with high, as versus low, plasma tHcy in the presence of an ApoE-4 allele performed 0.30S.D. and 0.40S.D. lower on the Global composite and the MMSE, respectively. Deficits of this magnitude are of considerable importance at the population level and constitute a risk factor for dementia

Here's where the researchers make a huge error! They state "But there is hope for prevention and reversal of cognitive deficit related to elevated homocysteine by reducing homocysteine levels."

Great! If you have Apo-E4 you should take folate? No!

Hope? Listen, this same old story was thought to be true for cardiovascular disease. "We'll give you folate to lower your risk for heart attack" What happened? Nothing. In fact recently there is literature hinting that folate may actually increase your risk of colon cancer growth!

The Sherpa Says:
So where does this leave us? Is Folate good for those with APO-E4? Don't starting taking it yet. Nutrigenomics is coming, but the data, much like in Personalized Genomic testing, is not there yet. In Folate's case, what you don't know might actually kill you. Or At least give you colon cancer. That's why you need the Sherpas, to guide you through the study trail!

Highest Breast Cancer Risk! Hispanic women.......and Men!

In the December 26th issue of the Journal of the American Medical Association an article caught my eye. It turns out that Hispanic women(and men) have the highest carrier rate for BRCA1 mutations aside from the Ashkenazi Jewish population.

The study sought to identify carrier rates among several different ethnicities. This is important because traditionally we have had little data on women of color as well a worse outcomes in African American and Hispanic women with breast cancer. There have been several hypotheses for this.

This study performed by the Northern California Cancer Center had methods of design where they sought "patients younger than 65 years with newly diagnosed breast cancer and meeting defined eligibility criteria, and their family members, were enrolled

This analysis is based on women diagnosed with invasive breast cancer between January 1, 1995, and December 31, 2003. Patients were identified through the population-based Greater San Francisco Bay Area Cancer Registry, which ascertains all incident cancers as part of the SEER (Surveillance, Epidemiology, and End Results) program and the California Cancer Registry.

We recruited patients with oversampling of patients having characteristics suggesting an inherited basis for their cancers.

In stage 1 of sampling, we administered a brief telephone interview to all patients and assessed self-identified race/ethnicity and family history of breast and ovarian cancer.

In stage 2, we invited all patients in category A and a random sample of patients in category B (2.5% of non-Hispanic whites and 33% of all other races/ethnicities) to enroll in the family registry.

Participants completed questionnaires on family history of cancer and breast cancer risk factors and provided a biospecimen sample.

This 2-stage sampling design provides unbiased estimates of mutation carrier prevalence having greater precision than those obtained from a simple random sample of the same size.

What did they find?

Among African American, Asian American, and Hispanic patients in the Northern California Breast Cancer Family Registry, the prevalence of BRCA1 mutation carriers was highest in Hispanics and lowest in Asian Americans. The higher carrier prevalence in Hispanics may reflect the presence of unrecognized Jewish ancestry in this population.

In the editorial after it states a similar quandary

What are the reasons women are not offered genetic counseling and testing as part of a comprehensive risk assessment program? Are minority patients less likely to accept genetic counseling, or are there barriers to physicians offering the test to minority women? A recent case-control study found that African American women were 78% less likely to use genetic counseling and BRCA genetic testing than white women. Data on BRCA testing from Myriad Genetics Laboratories showed that less than 10% of individuals tested were from minority populations, such as Hispanics, African Americans, Asian Americans, and Native Americans.

Given that most literature on genetic testing has focused on Ashkenazi Jewish and non-Hispanic white women, it is conceivable that clinicians are not aware of the clinical usefulness of BRCA testing among US minority populations. To compound the problem, most of the available risk assessment tools were developed using empirical data collected mainly in non-Hispanic white populations. Their applicability in other populations is uncertain. Other models were developed based on mendelian principles and the Bayes theorem. Of these, the BRCAPRO model has been widely used in the genetic counseling setting, and its performance has been evaluated mostly in white populations. However, as an essential parameter of the BRCAPRO model, the prevalence of mutation carriers is available only for the Ashkenazi Jewish and non-Hispanic white populations.

The Sherpa Says:

If you are using the Gail model.....you are putting yourself at risk for missing cases. In addition, not all BRCA carriers are Ashkenazi. Maybe insurers need to wise up and start covering testing for other ethnicities as easily as they do for the Ashkenazim. However, these data must be interpreted with caution as they assume the penetrance of the BRCA1 to be the same in minority patients as they are in Caucasians. In addition, there is no analysis of BRCA2 carriers. But this is a great starting point.

Algorithms and Validation

A friend of mine asked me "If the framingham risk assessment fails to take family history into account, then why do we use it to guide anti-cholesterol therapy?" My answer was "It is scientifically validated."

In medicine we like to do things based on evidence. It is true that we do many things that do not have solid evidence behind them. But we always try to acquire data and then make a rational conclusion, leading to a treatment. When it comes to risk prognostication, validation studies are extremely helpful. And often keep us from getting sued.

So what did the Framingham do to be validated?

The Framingham Heart Study and the Framingham Offspring Study were the first epidemiological studies that prospectively collected population based data on the association between risk factors and the occurrence of fatal and non-fatal coronary and other cardiovascular events in a systematic and sustained fashion. It has been dissected for it's validity over the years.

So can we use the Framingham for everyone? Well, in Europe they tried. Several articles like this one show that the risk tool must be validated in the population you plan to use it for. The Framingham doesn't work so well on the Dutch. However when modified by the REGICOR, Spain's NHLBI, it seemed to perform well for the Spanish. The same with the Chinese modification.

You may now be asking what the heck does this have to do with Personalized Medicine. My answer....Everything. You see part of personalized medicine is prediction. That's why Helix Health of Connecticut trademarked "Prediction, Prevention, Privacy" These are the pillars of genomic medicine.

How can you predict the likelihood of Alzheimers in 5 years? Well, there are some corporate genomic companies doing it without having ever submitted articles for peer reviewed publication. They have "Trade Secret" algorithms that calculate risk. What the hell? How can you trust the accuracy of an algorithm without validation?

This is why we advise against using the Gail model for breast cancer risk. It can only work for certain populations, absolutely not for African Americans. There are new attempts at this type of risk stratification, and several attempts to defend the Gail model. But what has evolved is even more important. New algorithms...that were put to the test and peer reviewed.

Which brings me to my last point. What good is a tool if you don't know how to use it, or who it works for? A recent post on Wingedpig points this out. Confusion as to the tools. But what I wonder is what tools they used to create the tools. Would they publish their algorithm? Should they have to? Should other companies who will foray into medicine have to? As for SNPedia...a great resource, but the results are just like a wikipedia....not exactly peer reviewed.

The Sherpa Says:

The votes are in. I am surprised of the results. 23 and Me is the big winner. Why? Well, they specifically state that they do not intend their tools to be used for medicine. Yet all the posts I read have authors who mistakenly are using it as a medical tool. (See the genealogists post "when will they learn") I would have thought the readers would have chosen Navigenics. Navigenics WILL use their tool as a medical device! So I have to ask them. Where are your data on algorithms? Where did you publish and validate them? Which algorithms are you using? I guess we will find out soon enough. 2008 is right around the corner.

Interesting Readers

Over the last week I have been working on a little personal genome search project. I was contacted by one of my readers to help her find someone to "donate" her genome to. Initially I was surprised to receive such a request. Especially because I have railed against using the genome for a crystal ball.

But she was vehement that she wanted to donate her genome. Now I Have to tell you that I was then convinced of her altruism. She didn't know where to turn so we began with the usual suspects Dr Church, Dr Collins, Dr Rothberg, Hodosh. But when we were turned away a window opened.

I turns out Dr Venter's Institute is looking to turn out 10k genomes in 10 years. The perfect project.....provided these subjects have appropriate care providers to help out......

Since Helix Health of Connecticut is taking patients now, it seems only natural that we take her on as a patient.

I wouldn't have it any other way.

On another interesting note Dr Robison at OmicsOmics posts on yet another whole genome player who is entering the Archon X Prize.

Base4 (Real Cute) Innovations is pretty young and Keith covers it nicely.

Formed in 2007 with support from the University of Warwick and Warwick Ventures, base4 innovation is a group of highly talented and innovative biologists and physicists from the University of Warwick and Oxford and Cambridge Universities specialising in molecular biology, single photon detection, and nanotechnology.We are developing a new high-speed, low-cost method of DNA sequencing which combines well-known techniques such as photon detection and fluorescent labelling with nanostructures and cutting-edge methods of nanofabrication.

X Prize team leader and base4innovation founder Cameron Alexander Frayling is a researcher at the University of Warwick and the inventor of the innovative method behind this sequencing technology.

The Sherpa Says: This wonderful woman wanted to donate her genome and was turned away. I wonder who would have bit if she was willing to pay. What a shame!

Just saw the BRACanalysis Ad on ABC 7

First off, please vote on my site. "How Much Would You Pay For Your Genome!

For those of you who live in the Greater New York Metropolitan Area. You are in for a treat! I just saw the confusing, puzzle like ad for BRACanalysis (The BRCA tests by Myriad)

Do you remember those tile shifting puzzles where you have to move all the pieces the right way to get a clear picture. This is actually a perfect metaphor for this ad. It shows women of every race and age all in blocks. The boxes look exactly like the aforementioned puzzle.

Each woman says a different thing and they all blend together. From "My mother has breast cancer" to "my father's sister has breast cancer" they make it seem that all breast cancer can be detected by this test. The commercial states BRACanalysis B. R. A. C. "Be Ready Against Cancer" Too bad they don't give their aunt's age, and no one says "everyone in my family has breast cancer" This ad portrays sporadic breast cancer as an indication for BRCA screening.

This paper describes the past ad campaign. My gut says this is the same as before. Guerrilla marketing does state that you do have to be consistent and have commitment to be successful. SO IF AT FIRST YOU DON"T SUCCEED.......

This type of advertising creates an opt-in, directing you to the website BRACnow which is actually a pretty useful site. The problem I have is when you are searching for a provider. They list several physicians who have not had cancer genetics training. Which is ok.....if you have a NEGATIVE test. But what if you have a Variant? Also my question is....... why are there so few genetics providers in the Tri-State Area? I know my group at Helix Health of Connecticut can do these services, but where are the other providers?????

The Sherpa Says: Here it comes New York.....I hope you are ready. Too bad most NYC genetics providers are booked for 6 months in advance......

NYT and WSJ cover Myriad's campaign

I have been silent on this for too long. Why? I was awaiting the review by my attorneys. The last thing I need is another threat of litigation. Why litigate? Because, critics like myself and the esteemed Ellen Matloff from Yale :) have been telling physicians that testing for BRCA ain't like checking a sodium.....or even better a pregnancy test.

Why can you get a pregnancy test over the counter? Because its results are crystal clear. The FDA has requirements for OTC testing. This whole issue was raised with at home HIV testing. The issues were portrayed here.

The interesting questions poses include these.

What test characteristics favor possible approval of an OTC home-use HIV test?

• The test is simple to use compared to other types of HIV tests and earlier versions of rapid HIV tests, suggesting that untrained persons will be able to perform the test properly.
• The test does not require special storage conditions.

The most interesting one was......

• Informational materials supplied with the test are sufficient to provide adequate information to potential users on performing the test and to substitute for live counseling.

Now my question is....has it even been proven that written materials substitute for adequate face to face counseling? Never for BRCA testing. So why does it take evidenced based medicine to prove a drugs efficacy? Well, partially because the FDA's evaluation is not about efficacy. It is about danger to the patient. Is there danger in not getting cancer screening if your BRCA test is negative? (Which BTW is not an appropriate counseling answer to the patient)

Yes, I do agree with Hsien. Direct to consumer advertising is a great way to introduce new products. Like the iPOD.

"Advertising serves to bring new products to our attention and to stimulate interest as well as the desire for more information. In the case of genetics and genetic testing, I would venture to say that all of us need to learn more, not less."

But the best way to learn about breast cancer risk is by being able to ask question to a knowledgeable, trained, health professional. How do we learn more about genetics? Take a freaking class, don't try to do self counseling for G-d Sake. Has anyone seen the Edward Jones commercial where the surgeon is telling a guy sitting at his kitchen table how to do surgery? Over the phone the surgeon asks "Did you sterilize the field?.....Good now with your kitchen knife make a 3 inch incision.........."

This is the type of thing that DTC testing is trying to get you to do. Patient empowerment aside, I don't let my patients prescribe their own meds. I even guide them on vitamins that they take. Did anyone see the expose on the Vitamin Shoppe's vitamins containing abnormally high amounts of lead. It was on Good Morning America a couple month's ago.

Well as the post was entitled the NYT and the WSJ had article on this yesterday. The ad campaign is telling you to go see you internist, OB/Gyn, or family practitioner. Guess what none of them have had training regarding this topic. There are less than 100 internist/geneticists in the country and even fewer OB's and FP's. According to the WSJ

Myriad says it is developing a program to school primary-care doctors about the test. Dr. Critchfield said the company is focusing on primary-care doctors, oncology specialists and tertiary-care centers, along with genetic counselors, "to get the message out."

What struck me was the benevolence of Dr Critchfield, who in the NYT article

Dr. Critchfield said Myriad waited nearly five years to start the new campaign to give more time for health care providers to learn to handle genetic testing. “We are in a far different place today than we were then,” he said.

The Sherpa Says: Well Dr Critchfield, you are incorrect. Clearly he has no clue or doesn't want to sour the internists' palate. OB's regularly fail to recognize at risk and not at risk groups, so do internists. As for the newest batch? I just tested primary care residents at a major academic center and only 30% recognized that a BRCA test was NOT indicated. Maybe that's what Myriad is looking for? If you want the literature I have quoted, send me an email and I will be more than happy to forward it on. As for the 8 month wait, Helix Health of Connecticut is open for business and seeing patients in less than a month!!!

Tip60 tips off breast cancer aggresiveness

According to a study published today in the journal Nature shows that a gene called Tip60 is involved in the development of breast cancer. But more importantly.........reduced expression of Tip60 protein leads to more aggressive tumors. Tip60 is a tumor suppressor gene unlike others.....

Let me explain. Usually you are required to have both copies of a tumor suppressor gene affected to start developing tumors. I feel that this theory along with all things mendelian will start to fade away. Why? Because we are much more complicated that punnet squares. The field of systems biology is growing and we will soon realize that we are a complex interactome, not just autosomal/Xlinked/Ylinked dominant/recessive genes.

So where were we? Well it turns out that this tumor suppressor gene only needs one copy malfunctioning to start enhancing tumor growth

From the Primary Investigator Dr Tim Crook "More aggressive types of breast cancers tend to recur after treatment, spread to other parts of the body and respond less well to chemotherapy. The identification of Tip60's role in breast cancer is a step towards predicting the aggressiveness of the disease and then individualising chemotherapy for women. If we can transfer this knowledge to the clinic, it could have dramatic effects."

From the Study

* Activity of the Tip60 gene was found to be lower in nearly half of all ductal breast cancers studied (21 of 52 cases) and in 17 out of 20 of tumours classed as 'high grade'

* The amount of TIP60 protein was studied in an additional 179 breast cancer samples. In almost three quarters of these (129/179), there was no TIP60 protein present in the cells' nucleus - in healthy cells this is where most of it is located. The proportion of cancers lacking nuclear TIP60 was even higher when they singled-out aggressive cancers and early cancers - suggesting that this is an early event in breast cancer development.

The Sherpa Says: Personalized medicine is coming and in many cases it is already here. This is an example of tumor tissue sampling to analyze outcomes. What is truly needed is a tissue bank that can put phenotype with genotype. Then we can have an excellent expression array analysis combined with phenotypic markers. This is the best way to put together personalized oncology. Trust me it is coming. Soon.....

This week in NEJM

So I have been reading about how the new article in the New England Journal of Medicine shows that BRCA gene mutations are not worse than sporadic breast cancers due to non-BRCA mutations.

If you look at the article you will see that there are many reasons why this is flawed thinking. But more importnatly it flies in the face of another study which actually showed and increased risk in worse outcomes with BRCA1 mutations.

So on closer inspection what was the NEJM article about?

They took all breast cancer specimens available in Israel's National Healthcare repository and looked for 3 I repeat 3 FOUNDER MUTATIONS....... This immediately makes the study invalid to comparison on women who have non ashkenazi mutations, especially if they are not founder mutations.

Secondly they analyzed outcomes retrospectively. This is a notorious way to get confounding results as well.

Thirdly this study did not have interpretable data regarding estrogen or progesterone receptor status.......This is a big deal!!!

And Lastly,
"We had 16-year follow-up data on mortality and incident cancers, but information on the cause of death was available from the Central Bureau of Statistics only for deaths that occurred before 2000." None from after 2000........

The Gene Sherpa Says: Before bloggers and press go off half cocked in this interpretation we need to be careful in how we evaluate this study. This ONLY means if you are an ashkenazi jew from Israeli heritage and have one of 3 founder mutations, then you are not more likely to have adverse outcomes than ANYONE else who is Israeli and Ashkenazi with non founder mutation breast cancer....That's IT. Nothing else can be extrapolated here. To those who are.....tread carefully...Because you are misleading the public!

Taking Appointments For August

After Much Ado, Legal Wrangling and Getting the Practice up, we are now accepting patients!!!! We have dates available in August. I have to tell you how very excited I am about this revolutionary style of medical practice. Heck, even when I talked with Dr Collins he was excited.

The biggest problem with genetic care as well as primary care is its true lack of continuity. Helix Health of Connecticut of CT will fix that problem and more. Yes, I know you may be thinking "Gosh, this is a shameless plug for his personalized medical practice"

You are correct it is completely shameless. It is a revolution. The future of health care is about to change in a big way.................

Which came first? The cancer or its chromosomes?

Every now and again I like to throw out the old paradigms and put in some new. Geneticists love this......The So Called "Paradigm Shift"

Back in 2005 this was done with Marfan's disease. It is an example I use to teach my students that what they may have learned is wrong. It is wrong because medical teaching is only built on science that has a very limited set of knowns and an immense set of unknowns.

This paradigm shift is already in the making.

The classical model of how a cancer develops is called the "two-hit" hypothesis. It states that in order to have uncontrolled growth of cells i.e. cancer, you need two hits to genes. Mostly you have to have at least 2 mutations. Sometimes you activate a gene by mutation and other times you may silence the genes. For the last 30 years the view of cancer is a very geno-centric. Just look at our so called targeted therapies. They block single gene proteins. Guess what. Even when these elegantly designed therapies are administered some cancers develop resistance. Why? I thought that the genes mutated were what caused the cancer. Shouldn't this wonderfully targeted therapy work for all cancers with this gene mutation? The answer is the same as for this question...

Shouldn't all persons with sickle cell have the exact same disease prognosis and complications? NO....no gene or genes are an island!

This new paradigm states just that. It says cancer is the result of 1000s of genes and the chromosome is really the master here. Screw up enough chromosomes and you get cancer. Let's face it. It is now known that gene expression arrays predict the response to chemo better than a single gene or even a microscopic cell type. This indicates that massive gene expression changes similar to those you may get from a chromosomal anomaly could be at play. Is this true? And what role will it play in the personalized therapy for cancers?

The Sherpa Says: This is very likely to be true. That is not to diminish the role of those rare cancers that are uniquely mono/bi-genic. This will lead to better therapies and earlier detection. It could eventually mean that every single case of cancer will truly be personalized and will require personalized medicine in the truest sense.......

The Confusing Thing About Association Studies.

Today is a moderately slow day for genetics in medicine (I can't believe I just said that). But if you want, you can sell your genome to some stranger for 5 grand USD (I can only imagine the identity theft issues) you do it at your own risk. Listen, if you are hard up for cash please do not sell your DNA sample!! Who knows what they will use it for..........Perhaps to frame you for a crime.

But what I want to really talk about is how confusing association studies can be. So lets examine some of these.

1. Long Term Aspirin use prevents cancer incidence in colon 32%, prostate 19%, and breast cancer 17%* (statistically non-significant). There is some molecular evidence of this in colon cancer. But not the others....... The catch is that you have to use aspirin adult dose for >5 years. Why? Like most association studies.....No one knows. What good is that?


2. Hormone replacement therapy increases Ovarian cancer incidence This study called the Million Women Study is a large cohort of British women. 948,576 postmenopausal women were assessed for ovarian cancer incidence. Users were 20% more likely to develop Ovarian Cancer. 1 in 5, that seems small, but in a million women (well......just 52k shy) that's alot of cancer!!! Especially such a nasty killer. But here's the kicker....


3. Oral Contraceptive hormones Reduce Colorectal Cancer risk! Wait a second.....Aren't these female hormones too? This study shows an almost 40% reduced incidence of colon cancer in these women from the Women's Health Study. Perhaps this has to do with dosage? But Who Knows....It's an association study!!!


4. Smoking Cuts Risk of Parkinson's Disease So that is what the media says about this study. Ok so now you have got me flipping out. No mechanism, No pathogenesis, No explanation.... Smoking kills, but at least it reduces your likelihood of ALSO having Parkinson's. Almost a 40% reduction in the likelihood of having Parkinson's. How? Who Cares....It's an association study! This kills me. The people could have predisposition genes for nicotine addiction/taste/etc which also have some salutatory effects. I do not think that smoking is what saves these patients brain cells!!!! But that's not what the press will tell you.

The Sherpa Says: What is sold as a good piece of science is quite often a piece of something else! Just because it was toiled over and hard work to develop it was done does not make it true, correct or even appropriate. I am here to say.....If it sounds fishy it probably smells fishy too. Throw out association studies until you have a reason for the association!!!

Forbes and Genetics

Way back in 2004 Forbes published an excellent article on inflammation and heart disease. That article introduced me to deCODE. In fact, I was so impressed with their model I began to read about their founder voraciously. More importantly I began to see the wonderful role the media has to play in this new revolution. They can influence the demand just as much as Myriad spending 1 million in Denver to market to consumers. Granted these publications don't have the Oprah Effect (Did I mention that Dr Oz is going to meet the Sherpa?), but they do have some teeth!

But I was also distressed when Forbes published an article that I had a tough time swallowing. In fact it brought me to tears. How can this publication blindly validate and promote these tests without any medical guidance, or suspect guidance at best. I am certain you have all read this article, but you can read it here. The wonderfully hyped name 12 Gene Tests That Could Change Your Life says it all. But before I get into the article, which is misleading and not factual enough to guide decision making, I will investigate the authors via my favorite little spy...uh I mean Search Engine Google ;)

Robert Langreth. He has written many articles some good, some bad. He has been writing about deCODE since 2003 prior to the Big Forbes cover story in 2004. He has been writing about personalized medicine since 1999 as Staff Reporter of THE WALL STREET JOURNAL. He also has written many scathing reports about drug companies, which is why I find it ironic that he endorses deCODE's diabetes test. Which does not tell you as much about your risk as if you had a first degree relative with diabetes. Mr. Langreth was a Staff Reporter at the Wall Street Journal from 1995 to 2000 and an Associate Editor at Popular Science from 1992 to 1994. It was at this time in my search when I figured it out

From a chat in 2002
mherper: What's Kari Stefannson like in person?
LANGRETH: Kari is a charming and very emotional person. He literally had to sell his radical database to an entire country. He did it by a grass-roots campaign, going and speaking to anyone who would listen. He eventually by weight of personal charm won the day over his opponents.
mherper: How can you write about DeCode Genetics when their stock is at $2?
LANGRETH: I wasn't recommending them necessarily as an investment, although I'd argue that it is not a terrible deal right now. I chose them because Kari is doing something that will very likely change the course of science and lead to fundamental discoveries. Whether it leads to a successful business is another question entirely. But since you ask, I figure that unlike many tiny biotechs, DeCode has something unique--the genetic access to an entire country. It doesn't mean they won't go out of business someday. But in the meantime, they are almost certain to have a big impact on science.

Does he have stock in DeCODE??????? It did track up on the day of publication.

We have to be careful to fully investigate our sources. Whom do you trust when giving you information about genetic testing? The company spokesman? The company that sells the tests? What about the middle man? We are entering nebulous waters where the lines of relation can still be hidden. Even from google. When you publish for a peer reviewed journal you have conflict of interest disclosures required. How come we don't have the same for a well read and respected magazine/website?

The Sherpa Says:
Mr Langreth has done some crack reporting on several topics, but to include the DeCODE TCF7L2 test as one that will change your life is a HUGE LIE!!! This test is a party trick at best, a distraction that could lead you to not getting your fasting blood sugar tested (The standard of care for early diagnosis). At best he just boosted deCODE stock. At worst he led you down the wrong trail. Be careful, some who play sherpas actually have stock in the pack the tell you to carry.

Coumadin and Cancer!

There are two things I would like to post today. There have been a lot of posts regarding the new findings in FGFR2 and risk for breast cancer. I said yesterday that the population attributable risk was less than family history. This is correct if you are talking about pre-menopausal breast cancer.


I have taken some time to review the article with a fine tooth comb and here are my summary hot points.

1. The study only analyzed post-menopausal, non first degree relative, "sporadic" breast cancer. Thus these findings may not apply to you if you have a first degree relative with breast cancer.
2. The risk for having cancer is increased even if you are wildtype ("normal") for this FGFR2 gene. Therefore the O.R. of 1.64 should be compared with 1.20 for the wildtype Odds Ratio.
3. The authors note that in a pre-menopausal population these findings were NOT associated with increased risk

Second Item. At the American College of Cardiology meeting in New Orleans an announcement was made that there is a 1-hour rapid genotype analysis for coumadin metabolism genes VKORC1 and CYP 2C9. Interestingly enough a physician Dr Jeffrey Anderson found that 72% of his patients on coumadin had a variation affecting metabolism of this blood thinner.

The Gene Sherpa Says: You must always use a guide to identify whether a test is useful or a study is useful. Unless you are already a Sherpa. This breast cancer finding in a subsegment does not represent all breast cancers! And We are well on the way to personalized medicine if we can genotype in less than an hour! Coumadin is a dangerous medication that can cause severe bleeding. I am certain that this point of care testing will find its way into the primary care physicians office. Now who's going to do the counseling??????

So Whaddya Think? Rick from My Biotech Life put together this little guy. He seems motivated, excited and ready to hit the trail. But I need to know....Should he stay or should he go? Oh and about this weekend's posts regarding "major breast cancer genes" The media seems to think they are the best thing since BRCAs.

The Sherpa Says: Hogwash. Those genes have so little penetrance that a family history will tell you more. And to Hsien and EyeOnDNA, if you don't have a family history, then an environmental history will indicate even more risk than these genes. One things for sure, I am glad I don't live in Canada. But as for the Diet Coke....I threw mine out yesterday :)