The use of genetic tests before a treatment is decided on should help to determine whether the treatment is likely to be successful
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Every patient reacts differently to a given therapy. There is no single “cancer” but 36 different leukemias and 51 different lymphomas. One of the reasons for this diversity is a range of slight genetic variations. Pharmacogenetics investigates these variations and uses its findings to design customized therapies.
Pharmacogenetics pursues an age-old dream of medicine: precisely targeting therapies, saving the patient from side effects, and predicting the effectiveness of a therapy more accurately. In pursuit of these goals, genetic testing and the identification of biomarkers are being included as factors in decisions about therapies and in therapy monitoring.
“There are different strategies in pharmacogenetics,” says Andreas Kovar, Head of Global Exploratory Medicine at EMD. “For instance, one can identify the target molecule. Does the tumor even have the specific target point against which the drug is effective, or is the therapy directed at a void because there is no suitable target molecule to attack?
Genetics also determines how an individual responds to a therapy and how well it is tolerated. Can the patient’s metabolism modify the active ingredient so that it can be discharged after a certain period? A patient who metabolizes the substance too fast or too slowly needs a higher or a lower dose.”
By mid-2012 there were 22 approved drugs in Germany for which a genetic test was either required or recommended prior to a prescription. These drugs include Erbitux® from EMD. This therapeutic antibody is used to treat metastasizing colorectal carcinomas as well as head and neck tumors. Erbitux® blocks a receptor on the surface of tumor cells that receives growth signals and transmits them to the cell’s interior via what is known as the KRAS protein.
In intestinal cancer this blockade is particularly effective if the KRAS-coding gene is not mutated. In case of a mutation the cell is stimulated to divide even without a related growth signal. The outlook for therapy using Erbitux® in intestinal cancer is therefore especially favorable if the patient has no KRAS mutation and this has also been ascertained by a genetic test. “This example shows how important a genetic test can be in therapeutic decisions,” says Kovar.
“In the future, EMD would prefer to include in its clinical development program only those active ingredients for which there is a suitable biomarker or genetic test that can be useful in therapeutic decision-making or in monitoring the patient’s response. Biomarkers and active ingredients should therefore always be developed at the same time,” Kovar emphasizes. “We expect that this will also enable us to differentiate ourselves more clearly from our competitors.”
The right drug in the right dosage and at the right time — pharmacogenetics stands for precisely targeted therapy
Although in many cases the target molecule for a therapy hasn't existed prior to the onset of the disease, the individual’s enzyme system for the conversion or degradation of the active ingredients is congenital. The most important enzymes are members of the cytochrome P450 system. The individual enzymes have names such as CYP2D6 or CYP2C19.
Some may be mutated or duplicated, i.e. doubled in quantity, which makes a difference in whether and how fast specific active ingredients will be discharged. Depending on the individual’s genetic makeup, doctors distinguish between weak, moderate, intensive, and superfast metabolization. Genetic testing can already determine which category a patient belongs in with respect to his or her individual CYP enzymes. The example of tamoxifen shows how important this information can be.
This antihormone is prescribed for many women as a follow-up to breast cancer therapy to prevent a recurrence. But in order to ensure that the women will actually benefit from this drug, they must have a CYP2D6 enzyme that is sufficiently active to be able to convert the tamoxifen into the active ingredient. “One can use this knowledge of the individual patient's enzyme status to predict how he or she will respond to a therapy,” says Kovar. “In a few years, the Patient Package Inserts (PPIs) will include a note about what dose adjustments are required with a fast or slow metabolization of the active ingredient.”
Kovar also expects that software solutions will soon exist to compute such dosage adjustments during routine clinical work. Pharmacometrics is the special field that deals with these issues. EMD is also using pharmacogenetics to select participants for smaller and more specifically targeted clinical study groups. A study group will then only include patients who have the appropriate target molecule for the drug being tested, as well as the enzymes needed to ensure safe degradation of the active ingredient. “We will then be treating fewer patients, but the treatments will be more precisely targeted and will probably have fewer side effects,” Kovar says.
Systems biology aims to record and understand the complexity of cells, tissues, organs, and organisms.