Respiragene Test and CT Screening for Lung Cancer?

I love personalized medicine.

I absolutely think it is beyond fantastic to be able to say to a patient "This is the drug for you"

Or, we need to screen for disease X because of Gene Y and your family history

But what I don't love is companies purporting the import of their special home brew test to do personalized medicine without any sort of data backing them up.

A news report and "AACR Feature" highlighted precisely that. A test with no data......

From the article:

Researchers administered a gene-based predisposition test that incorporates 20 genetic markers associated with smoking-related lung damage and propensity to lung cancer along with clinical factors including age, family history and diagnosis of chronic obstructive pulmonary disease to derive a risk score on a 1 to 12 scale with higher scores correlating with higher risk.

Ok, new score with 20 markers, family history and age and clinical data....sounds reasonable. Has anyone else validated this tool????

Ahem. Crickets.....

“At scores of 6 or more … only 25 percent of otherwise eligible smokers would be screened but over half of lung cancers would potentially be detected, many in a treatable stage,” concluded Young and colleagues, who suggested that increasing the detection rate of lung cancer per number of patients screened could improve the cost-effectiveness of CT screening.

Ok, so did you get the jump? Did you catch it? "Who Suggested"

This guy who designed a genetic panel AND NEVER TESTED IT IN CONJUNCTION WITH CT CHEST SCREENING, is suggesting that using the test could increase the cost effectiveness of CT Screening, without one single solitary IOTA or shred of evidence of this.

This would be the same Dr. Young who found that genetic testing for a smoking cessation program likely doesn't have cost effectiveness or at best is uncertain.

Last year they were still researching this panel

Yet Respiragene is being held up as a great test!

One word that makes me suspicious is the word "Testamonials"

That word alone reminds me of the time I was bamboozled into going to multi level marketing events for proton pills and the like. You know, they all had lots of "Research" behind them.

Put simply, we do not know if gene screening PRIOR to CT Chest screening for lung cancer does any of the following things

1. Make CT Screening more cost effective

2. Personalizes medicine, targeting radiation to only those who need the test

3. Improves outcomes and detection rates of lung cancer.

That research is not available today. Nor will it be in one year.

My Advice, hold off on this one for now.

The Sherpa Says: Parroting an esteemed researchers OPINION as if it were scientific fact is a great way to get yourself in trouble and an even greater way to confuse the community! But it is the best way to get a test sold.

Carrier State IS Disease State. Pre-Disease IS Disease.

In my ever-lasting challenge to Mendel, I submit my thesis. "There is no such thing as a carrier, nor is there such a thing as a single gene disorder."

Why? I have a treatise on the subject. But suffice it to say one thing. "No Gene Is An Island"

In the most recent argument I offer a study recently published in the Archives of Internal Medicine. Did you see the issue? It is a freakin' Gene Fest I tell ya. Too often we tell people you need 2 bad copies of Gene X to be affected by disease Y. But what if Gene X also caused Disease Z? Do the same rules apply? No wait a second, I thought Gene X only caused Disease Y? Well, we now know that many genes are invloved in diseases other than the traditional "Monogenic Disease" Which was reported ages ago, when we were limited to what we could taste, touch, smell, hear, see or feel.

This is the case with Marfan's disease. It is also the case in Cystic Fibrosis. Now a study from the Archives.

Researchers found that the genetic disorder, alpha-1 antitrypsin deficiency (α1ATD), could explain up to about 12 percent of lung cancer patients in this study and likely represents the same widespread risk in the general population. "This is a seriously underdiagnosed disorder and suggests that people who have lung cancer and chronic obstructive pulmonary diseases (COPD) in their families should be screened for these gene carriers," says Ping Yang, M.D., Ph.D., a Mayo Clinic epidemiologist and lead investigator on the study.

Don't you just love widespread, sweeping statements like the one from Dr Yang?

While true, yes the Sherpa did diagnose a 74 year old non-smoking white woman "COPD'er" with A delta 508 Cystic Fibrosis. It is not true that we should screen every 74 year old white woman with COPD for CF or α1ATD. But a careful detailed family history, should be sought out. Including environmental exposures...

In the case of Alpha 1 Antitrypsin Deficiency (α1ATD) much like CF, you need 2 defective genes to have "the Disease"....for now....

So what does this study say? From Medical News Today.

The α1ATD carrier rate among 1,443 genotyped patients with lung cancer was 13.4 percent, compared to 7.8 percent among unrelated control participants.All α1ATD gene carriers were at a similarly greater risk of developing lung cancer, regardless of smoking status. Those who had never smoked were at a 2.2-fold higher risk; light smokers had a twofold greater risk; and moderate to heavy smokers had a 2.3-fold increased risk.

Did they control for other environment or other genes? Yes.
This study actually paired cancer-free siblings with their α1ATD carrier brethern. Guess what? 2 fold increased risk of lung cancer. In CARRIERS!!!!
This serves as a modest control for environment and some modicum of epigenetic regulations.

So what we are saying is, that a previously "benign" carrier state...Is not so Benign! This is the same with CF carriers, Sickle Cell carriers, I could go on and on.

Ladies and Gentleman, I submit to you Exhibit C. Further proof that Mendel has been screwing up genetics and medicine for over a century. We must be careful in how we consult and counsel patients.

The Sherpa Says:
I have been called a blasphemer. But I do maintain, teaching Mendelian Genetics is a disservice to the medical community and to our undergraduate communities. It leads to be rigid in interpretation of things that are very much not black and white.

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.......

Harvard Honoring the Sherpa!

Today I was asked to be on the faculty of Harvard's famous Continuing Medical Education conference in the Genetic Basis of Adult Disease. I am extremely honored to be a part of this distinguished faculty. This year's conference will be held October 12-14th. The last conference topics and website are still up and I am certain the new one will be shortly. I highly recommend it for all physicians looking to become Sherpas or at least to stay up with the breakneck pace of genetic discovery in medicine. Several topics include:

• Genetic Causes of Heart Failure
• Genetics of Lipid Disorders
• Genetics of Cardiovascular Disease
• Genetics of Common Psychiatric Diagnoses
• Genetics, Lung Cancer and Treatment Responses
• Genetics of Gastro-Intestinal Diseases
• Barriers to the collection and use of the Family Health History in Primary Care

So who should attend this great conference?

Internal Medicine Docs
Family Physicians
Genetic Counselors
Registered Nurses
Nurse Practitioners
Physician Assistants

I was at the conference last year and am excited to be behind the podium this year. Please mark your calendars!!!!

Not all drugs benefit all man!

While Bertalan Mesko at ScienceRoll is introducing us to the best medicine 2.0 tools, i am reviewing some results from the American Society of Clinical Oncology meeting last week.

In another example of how we need to examine patients pharmacogenomics prior to instituting therapy the SWOG (South Western Oncology Group) in the U.S. releases results of a collaborative effort with two clinical groups in Japan (Japan Multinational Trial Organization).

The researchers were interested in how these different groups metabolized certain chemotherapeutic agents Paclitaxel and Carboplatin. Now what is interesting about this study presented at the ASCO conference is the fact that they were able to isolate two gene polymorphisms responsible for these effects.

In patients with certain variations in the CYP3A4 gene, it took 2.75 times longer for their lung cancer to progress than in patients without the variations. A variation in another gene, ERCC2, appeared to interfere with how well patients responded to treatment.

The problems with this type of analysis are threefold.

1. The study was too small a size to not need replication


2. The study did not involve the genome of the tumors (Perhaps the DNA repair mechanisms in the Caucasian tumors were better. This would like to decreased cell death i.e. response to chemo. As with the tumors and ERCC1)


3. The dose of chemo was not controlled (although the lower dose worked better in the Japanese)

The Sherpa Says: In order to make useful sense of Personalized Oncology we must look at genomes of both the cancer and the person. I feel that we are introducing erroneous data to confuse us. I hope The Cancer Genome Atlas will show us some better data!

African Americans, Family History and Lung Cancer

A pre-publication release of the Journal Chest includes a study assessing family history of lung cancer and likelihood of acquiring a tobacco related malignancy.
From the study:

"In 2006.....estimated that 174,470 new lung cancer diagnoses and 162,460 deaths from lung cancer will occur. Lung cancer remains the leading cause of cancer related death, regardless of gender."

I just saw 2 new cases yesterday myself :(

"Among case relatives, African Americans were 2.44 fold more likely to have head and neck cancers and 1.86 fold more likely to have any tobacco-related cancer compared to white case relatives"

This is where we have to wonder what role detoxifying genes such as GST polymorphisms. It has been show that they do play a role in risk of disease. If only DNA was collected from the participants in this study..........

Most scary for African Americans with a first degree relative diagnosed with Lung Cancer in this study

1. They are 13 times more likely to have head and neck cancer


2. Almost 4 fold more likely to have any tobacco related cancer


3. 4 times more likely to have any tobacco related cancer other than lung

For the Caucasian analysis it appears that African Americans are at 2 fold increased risk compared to their White counterparts when it comes to Lung Cancer.

The Gene Sherpa Says:

We all know smoking causes cancer. But those who continue to play Russian roulette with Marlboros would like to know how hard they should try to quit. This study was limited by only studying early onset lung cancers (less than 60) Kick the Habit Now!

Genes predict metastases

Today in the Journal Nature it is reported that there is a panel of four genes that when expressed enable breast cancer cells to metastasize to the lungs. Those genes EREG, MMP1, MMP2 and Cox2 when shut off have dramatic effect. These results make us question the utility of pulling drug like Vioxx (a COX2 inhibitor) off the market. Perhaps we can find a way to give this drug to those who need it and will not have adverse drug reactions. I am betting Vioxx will see the light of day again.
What do you think?