Tailoring diagnostic and therapeutic strategies
Many have called Sir William Osler (1849-1910) the “Father of Modern Medicine”. He was one of the four founding professors of Johns Hopkins Hospital where he was instrumental in creating the first residency program for the specialty training of physicians. He brought medical students from the classroom to the bedside for clinical training. He shared a very profound insight with us: “Variability is the law of life and as no two faces are the same, so no two bodies are alike and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.”
Clinicians have known for some time that diseases as well as the way they are treated can affect individuals differently. Tailoring diagnostic and therapeutic strategies to a patient’s individual characteristics is the field of precision medicine. Today, we are living in a time that allows to implement precision medicine in certain areas. The question is how far can we push this paradigm?
There are three “key ingredients” for precision medicine:
1. A biomarker associated with diagnosis, progression or response to treatment of a particular disease
2. A test to characterize the biomarker
3. A clinical decision that can be influenced by the outcome of this test; this can be a number of different things such as lifestyle changes, the selection of a drug or dosage
There is a growing number of drugs to treat cancer that fall in the category of personalized medicine. Not surprisingly the National Cancer Institute is one of the key beneficiaries of Obama’s initiative to further study this area. Here are a few examples:
1. Bexxar (tositumomab) is used to treat Lymphompa. The biomarker is the CD20 antigen expression.
2. Herceptin (trastuzumab) is used to treat breast cancer. The biomarker is the human epidermal growth factor receptor 2 (HER2) over expression.
3. Xalkori (crizotinib) is used to treat lung cancer. The biomarker is a mutated anaplastic lymphoma kinase gene (ALK).
Warfarin is an anticoagulant normally used in the prevention of thrombosis and thromboembolism; the formation of blood clots in the blood vessels and their migration elsewhere in the body, respectively. It was approved for use as a medication in 1954, and has remained popular ever since. Genetic factors account for up to 35 percent of the variation in the maintenance dose of warfarin. While at least 30 genes may be involved in the biotransformation and mode of action of warfarin, data published in 2007 found that cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes had the largest effect on the drug’s pharmacokinetics and pharmacodynamics. The product labeling for warfarin now includes a table comparing CYP2C9/VKORC1 genotype and the expected maintenance dose. Clinicians are encouraged to determine a patient’s genotypic profile and use the table,along with clinical factors (e.g., age, race, body weight, sex,concomitant medications, co-morbidities), to make a more informed choice of initial dose that will provide efficacy but reduce the likelihood of bleeding.
Maraviroc is a prescription medicine approved for the treatment of HIV infection in adults. Maraviroc is used in combination with other HIV medicines.It belongs to a class of HIV drugs called entry inhibitors. Entry inhibitors block HIV from getting into and infecting certain cells of the immune system. This prevents HIV from multiplying and can reduce the amount of HIV in the body. Maraviroc works by attaching to one of two proteins on the surface of the immune cells. These proteins are called the CCR5 and CXCR4 coreceptors. Maraviroc attaches to the CCR5 coreceptor, but not to CXCR4. When maraviroc attaches to the CCR5 coreceptor, certain strains of HIV—called CCR5-tropic virus—cannot attach to, enter, or infect the cell. Maraviroc should be used only in people whose strain of HIV uses the CCR5 coreceptor. Maraviroc is not recommended for people whose HIV uses the CXCR4 co-receptor or both the CCR5 and CXCR4 coreceptors. It’s important for clinicians to test for this before prescribing the drug.
These are just a few examples of how the individual genetic make up can change diagnosis, selection of treatment options or dosage. This is a very active field that creates new findings every day. What is ahead of us is more research to understand the genetic causes of diseases, the development of more and better treatment and diagnostic options.