St. Jude study helps transfer genetic knowledge into clinical practice
With the help of the thousands of infinitesimal clues to the origin and treatment of disease that have been excavated since the Human Genome Project was completed in 2003, doctors and researchers at St. Jude Children’s Research Hospital are discovering new information about the genetic variations of medicine in humans.
The St. Jude study is one example of the how the treasury of resulting genetic discoveries is moving the medical community closer to personalized medicine, which the Food and Drug Administration defines as “tailoring medical treatment to the individual characteristics, needs and preferences of a patient in all stages of care, including prevention, diagnosis, treatment and follow-up.”
St. Jude has transferred genetic knowledge into clinical practice through a personalized medicine study initiated in 2011 called PG4KDS. The aim is to eventually enroll all patients in this research protocol focusing on pharmacogenetic tests, which measure genetic differences in how people break down medicine in the body.
“The purpose of the study is to move pharmacogenetic test results from the lab into the patient medical record, so that the test results are available to pre-emptively influence prescribing,” said Mary V. Relling, PharmD, chair, pharmaceutical department, St. Jude. “Only test results for which we have built adequate clinical decision support are moved into each patient’s electronic health care record. Clinical decision rules and alerts provide point-of-care support to clinicians so that they can use pharmacogenetics to guide prescribing.”
Study objectives are:
To test patients for hundreds of genetic variations important for drug use. Strong scientific evidence will move a few genes into the medical record if it shows the result can improve the prescribing of drugs for patients
To estimate how often results are moved from research tests into a patient medical record
To use methods to choose which tests are to be included in the medical record
To use computer-based tools in the electronic medical record to help doctors use gene test results when prescribing
To measure patient and patient family concerns about genetic testing information being included in their medical record.
The direct benefit to the patient is that therapeutic care can be customized to the child’s genetic makeup, avoiding serious adverse effects of some medicines, optimizing the drug response and avoiding ineffective therapies. This medical information can then travel through the patient’s life so that fruitless treatments are not repeated.
Relling said St. Jude uses Clinical Pharmacogenetics Implementation Guidelines (CPIC) as well as the hospital’s Pharmacogenetics Oversight Committee to prioritize which
drugs and genes are put into the medical record. There may be hundreds or thousands of gene variations important to drug use. The priority is to decide which ones are used for patient care. It is a painstaking process.
“We use an array-based approach to test for 230 genes, but only 14 of these are ready to use clinically now," she said. "Thus far we have five genes implemented for our patients."
The five “priority genes” are: Cytochrome P450 2C19 (CYP2C19); Cytochrome P450 2D6 (CYP2D6); Dihydropyrimidine Dehydrogenase (DPYD); SLCO1B1; and Thiopurine Methyltransferase (TPMT).
For example, in the 1990s, St. Jude researchers associated life-threatening complications with the important family of cancer drugs linked to Thiopurine Methyltransferase (TPMT). TPMT is an enzyme metabolizing thiopurines, which include the medications 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) and azathioprine.
The drugs 6-MP and 6-TG are useful in treating leukemia or lymphoma.
Efficacy and adverse effects differ in patients due to variations in the TPMT gene, meaning that as many as one in 10 patients may need a lower dose of the drugs; one in every 400 individuals needs a substantially lower amount to avoid potentially deadly side effects. Everyone can be classified into one of three possible genotype groups. St. Jude uses a different starting dose of 6-MP and 6-TG for these groups. Varying the dose based on a patient’s genotype means there are fewer side effects due to low blood counts.
A more common drug example is the familiar codeine. About 10 percent of the population are genetically “poor metabolizers” who cannot activate codeine into morphine and get no pain relief from it. “Ultra rapid metabolizers” comprise 1 to 2 percent of the population, and they are at risk from toxic effects like respiratory depression.
“Some hospitals have removed codeine from their formulary because, without genetic testing, one doesn’t know which patients will benefit and which will not,” Relling said. “This is a problem, because codeine is one of the few narcotics for which patients can get refills, so many of our clinicians wanted to maintain it on the formulary for the 88-89 percent of the patients who might benefit. By using genetic testing, we were able to keep this valuable medication available to our patients with pain.”
Work continues today to identify which of the estimated 18 million gene variations in the human population play an important role in drug response. One gene can impact the workings of 30 to 40 drugs. More pervasive usage of genetic research and lower costs for the blood tests required mean early treatment testing and less time lost on ineffective or more toxic medications on patients.
“Eventually, we don’t want pharmacogenetics to be delivered in a research protocol; we want it to be incorporated into routine healthcare. It is the future of medicine,” Relling said. “It will depend on healthcare changing so we have a universal electronic healthcare record that follows the patient from birth to death.”
