Medicines Tailored to Your Genetic Quirks

The audience seemed a little put out when I told them that, the way things are at the moment, their doctors are really experimenting when they prescribe for them.

This is why it’s called the practice of medicine, I told the patients and staff at a presentation I was giving to a local self-help group and the National Alliance on Mental Illness. But the brave new world of pharmacogenomics and personalized medicine is going to change all that I assured them.

We are currently living in a “one-size-fits-all” world when it comes to medicines especially. Also in a system that dogmatically imposes treatment algorithms insisting that everyone should be given the one “correct” treatment.

But depending on your bodies individual quirks of metabolism the same dose of the same drug may work great for one person, but be totally inadequate for another, and an overdose for a third. Or it may have some awful toxic effect to those susceptible individuals.

Depression for example, which was of particular interest to this audience, and which we are told doesn’t respond 38% of the time to the first medicine. Which means I just have to try my favorite first line antidepressant and wait for 2-3 months to see if you are in the 38% non-responders – and members of the audience told anguished stories of just such trial, and all too often error, before hitting on the right antidepressant or psych’ medicines of all kinds (if ever).

Pharmacogenomics is changing all this however. This is the art of using genome analysis to know how a persons body will respond to a given medicine - a trick made possible by The Human Genome Project, when the entire human DNA was analyzed for the first time.

It is all part of this clever new era of “personalized medicine” - or “precision” medicine as president Obama is calling it in announcing a new precision medicine initiative in February of this year.



A Heartfelt Benefit


It has allowed identification of heart patients with a genetic quirk that makes them unable to activate the platelet inhibitor clopidogrel (Plavix) for example, so they can be known before the disaster of clotting off their stent and having a heart attack.

Similarly it has allowed the identification of breast cancer survivors who are among the 65% of women who developed resistance to main-stay anti-estrogen drug Tamoxifen - who previously only found out when their cancer came back.

Personalizing medicine has also led to a whole array of new products that interfere with cancer growth on a cellular level, with far less toxic effects than conventional   “ blunderbuss” chemotherapy, that is so toxic it makes your hair fall out, suppresses your bone marrow so you become anemic and susceptible to infections, not to mention sick as a dog so your cancer sometimes seems preferable.

It’s worked wonders for melanoma by the ability to identify and target the gene mutation that leads to overstimulation of cell growth by the B-Raf protein in metastatic malignant melanoma. The drug vemurafenab (marketed as Zelboraf), blocks the B-Raf protein. Which has improved odds of survival, from less than 12% to 53%.

An interesting consequence of mapping the genetic quirks of cancers is the realization that cancer is a gene specific rather than organ specific diseases so it’s not “colon cancer” or “lung cancer”. The BRAC1 gene mutation (which Angelina Jolie has) for example causes not only breast, but ovarian cancer.

Though pharmacogenomics has not seemed to have hit small-town USA (none in the audience had personal experience) it is rapidly achieving prime time – for the psychiatric community with GeneSight for example, which will “analyze how your genes affect the way your body may respond to FDA-approved medicines commonly prescribed to treat depression, anxiety, bipolar disease, schizophrenia or other behavioral health conditions” notes the manufacturer.

It can help with the notoriously difficult business of getting the right dose of the blood thinner, Coumadin. It can also tell who is at risk of adverse effects, as in determining who has a variant in the SLCO1B1 gene, and will get muscle inflammation from cholesterol lowering statins, like Zocor and Lipitor.

As in the Vanderbilt University Medical Center PREDICT program that allows a “doctor to use the results from the test to make better decisions about the drugs that are right for you” or the “StatinSmart” test which is “known to impact the risk of statin induced myopathy.”

Knowing how people will react to drugs has huge implications for drug trials also. Experimental medicines could be given to only those whose genetic make up makes you expect will respond – and not to tens of thousands of untested subjects, in the hope it works on some, and doesn’t kill too many.



Illness Surveillance Through Genomics


Personalized medicine can also tell you who’s prone to what illness – allowing progression from traditional “diagnose and treat” to preferable “predict and prevent.”Sometimes it’s a fairly circumscribed genetic aberration, like having a mutation of the BRCA gene greatly increasing a woman’s risk of breast cancer. Sometimes it’s a mess of genes, as in type II diabetes.Also there is great hope that population wide studies - so called “gene wide association studies” (GWAS) where the genetic makeup of people with the same illness - will hopefully allow the identification of offending genes (as was found to be the case in 2005 when the first common defect was identified in people with age related macular degeneration). Such studies are being correlated by the production of a “HapMap” to catalogue common variants in European, East Asian and African genomes.

Identification of dangerous gene mutations has the potential to allow prevention - Angelina Jolie, for example, when found to have BRCA mutations giving her a high risk of breast cancer, opted for prophylactic bilateral mastectomy.



The Foibles of Human Nature and Other Problems


The bad news is, when prevention calls for behavior modification, we are up against the foibles of human behavior. Eric Topol MD Cardiologist and Director

of the Scripps Translational Science Institute notes that in 3,600 subjects, at increased risk of various illnesses, especially different kinds of cancers, there was “no clear evidence of lifestyle improvement.”

Nor do we know exactly how to interpret the data. A report in JAMA of February 2010 of a team from Brigham and Women’s Hospital that found 101 genetic variants that appear to be linked to heart problems showed no ability to predict who was going to actually get heart disease.

One hope in identifying more usable information is to analysis of RNA, which is influenced by environmental factors and in turn influences the expression of genes. This may give more useful information than DNA alone.

Other issues cramping the style of pharmacogenomics and personalized medicine are; attempts to patent genes and genomic tests; maintaining confidentiality of this highly sensitive, personal, information; fear of discrimination if you have some bum gene that may disable you or increase your healthcare costs; regulation of the whole business and claimed overreach by the FDA (the FDA has regulatory power here, as in dinging genomics company 23andMe for, in their view, inappropriately providing medical interpretation). There are accusations they are stifling progress.

This is causing not unreasonable skepticism and causing people – like the audience I was talking to – to ask “well who should get their genome tested?”

Current recommendations seem to be anyone with a particularly bad family history of some kind of cancer; anyone taking a medicine where a test has been developed – especially if having trouble finding the right one, or if you are having side effects; people from at risk ethnic groups like Ashkenazi Jews, or people of African origin having an increased risk of Sickle Cell Anemia.

Genome analysis, and pharmacogenomics is rapidly becoming faster, cheaper and prime time. But there are not yet enough products on the market that have penetrated the consciousness of the average patient,” says Edward Abrahams, president of the Washington, D.C.-based Personalized Medicine Coalition. He looks forward to the day when we are beyond the one-size-fits-all and patients are asking “Is this therapy going to work for me?”

No Comments Yet.

Leave a comment