Category Archives: Pharmacogenomics

Clinical Implementation of Pharmacogenomics

Pharmacogenomics has the potential to influence clinically relevant outcomes in drug dosing, efficacy, and toxicity that can result in subsequent recommendations for testing. For many routinely used drugs, pharmacogenomics has provided inconclusive evidence for such testing. A probable reason could be the involvement of both genetic and nongenetic factors and their extent of contribution that determines the clinical relevance of some drugs. Therefore, identification of genetic markers associated with drug responses does not always link to clinically useful predictors of adverse outcomes, and most of the time require independent replication of genotypephenotype association before pursuing clinical implementation.

Lack of readily available resources, feasibility, utility, level of evidence, provider knowledge, cost effectiveness, and ethical, legal, and social issues further adds to the limitations and challenges to implementing pharmacogenomic testing in clinical practice. In order for a genetic marker to be implicated in clinical practice, an association of a genetic marker to a particular trait requires screening of tissues from several individuals, and corresponding functional studies are needed to establish probable association with the trait/phenotype. However, to overcome these challenges there are some pharmacogenomic tests for drugs currently used in clinical practice that have applied value in predicting ADRs and/or drug efficacy. Table 7.2 lists some of these clinically valuable pharmacogenomics tests. These tests are based on distinct genetic variants that have well-validated reproducible and significant impact on the drug therapy. These tests have a strong causal association between genetic polymorphisms and drug responses: a strong indication for clinical utility and high prognostic value. The tests are available both commercially and in academic settings, with many of these tests having clinical guidelines for dose adjustment and alternative medications (Wei et al., 2012). In addition, various international pharmacogenomic consortia have been developed recently to supervise drug response studies.

Table 7.2. Examples of Clinically Valuable Application of Pharmacogenomics Tests in Predicting Drug Response (Efficacy and Toxicity)

A list of current pharmacogenomic guidelines from these consortiums along with a well-annotated pharmacogenomic database has been consolidated into one curated database known as Pharmacogenomics Knowledge Base (PharmGKB) (Thorn et al., 2010). PharmGKB is available via an online portal where users can search on the website by gene, drug, metabolic pathway, and disease. To boost the clinical application of pharmacogenetics and address the barriers to implementation of pharmacogenetic tests into clinical practice CPIC was formed as a shared project between PharmGKB and the Pharmacogenomics Research Network (https://cpicpgx.org). CPIC provides freely available, peer-reviewed, updatable, and detailed gene/drug clinical practice guidelines that enable the translation of genetic laboratory test results into actionable prescribing decisions for specific drugs. The guidelines can focus on genes (e.g., thiopurine methyltransferase and its implications for thiopurines) or around drugs (e.g., warfarin and CYP2C9 and VKORC1). Efforts like PharmGKB and CPIC can help to overcome the confusion created about various pharmacogenetic tests and can help clinical decision making. In addition, the FDA has created a table of Pharmacogenomic Biomarkers in Drug Labeling that lists FDA-approved drugs with pharmacogenomic information in their labeling (http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm). This biomarker table provides up to date information on genomic markers that have been referred in FDA package inserts for different drugs. Various biomarkers are included in this table, e.g., germ-line or somatic gene variants, functional deficiencies, expression changes, and chromosomal abnormalities as well as selected protein biomarkers that need to be tested before starting treatment in a selected subset of patients. Moreover, with continued integration of pharmacogenomics in clinical trials and drug development, novel important genes and variants that can predict drug efficacy and toxicity will be identified and can be implemented in clinical practice.

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Pharmacogenomics - an overview | ScienceDirect Topics

Drugs and Genes Conference

Getting you the right drug at the right dose at the right time is the goal of pharmacogenomics, which involves studying how your specific DNA sequence influences your response to medications.

The drugs available today to treat cancer, heart disease and other conditions are powerful agents that work as intended in most patients. Yet, in some people, a particular drug at the standard dose might not work well enough or may even trigger a serious adverse reaction. The reasons for this lie, at least in part, in your genes.

By using your unique genetic makeup as a factor when prescribing a drug for you, your doctor can maximize treatment effectiveness while avoiding potentially life-threatening side effects.

Pharmacogenomics can help us answer a broad range of questions, such as:

Results from a subset of the 77 "pharmacogenes" will be placed into the electronic health record (EHR) and an interpretive report will be placed into the patient's medical record.

Most electronic medical record systems are not equipped to alert the pharmacist or physician to these drug-gene interactions. The RIGHT10K study is utilizing the infrastructure built together with the RIGHT study at Mayo Clinic, which alerts to physicians in the drug prescription process so that patients get the right drug at the right time in the right amount.

The BEAUTY study performed whole-genome sequencing before and after neoadjuvant therapy (drug therapy before surgery) in women newly diagnosed with breast cancer.

Pharmacogenomics Program researchers are then comparing then compared the tumor genome before and after neoadjuvant therapy against the patient's germline genome the sequence of DNA in normal, noncancerous tissue in order to match the genomic response to therapy.

Read results of the BEAUTY study.

Based on the findings to-date from BEAUTY, clinicians are personalizing therapy to help ensure that women with breast cancer resistant to current therapy receive the right combination of drugs resulting in the highest chance of a cure. BEAUTY 2 participants will experience this approach and seamless health care in the treatment of breast cancer, during the crucial time between diagnosis and prior to surgery.

The PROMISE study will use participants' biopsies of metastatic breast cancer to obtain detailed information regarding the genetic makeup of the tumor as well as the host (germline) genome, with the goal of developing personalized treatment approaches to improve patient outcomes. Endocrine resistance is common in breast cancer patients, and while the drug palbociclib in combination with endocrine therapy has provided substantial improvements in progression free survival in women with metastatic breast cancer, that is not the case for all patients.

The PROMOTE study took an approach similar to the BEAUTY study, but for prostate cancer. The Pharmacogenomics Program hopes to elucidate the DNA sequences associated with response to therapy in order to identify new treatment options for patients with advanced prostate cancer that has resisted all conventional therapies.

This study also included groundbreaking work with mouse avatars, again to identify new and novel treatment options.

Patients with coronary artery disease often come into the emergency room requiring placement of one or more stents. In the TAILOR-PCI study, we are determining the specific DNA variant that might indicate whether the patient should receive the anticoagulant drug clopidogrel or an alternative drug, a question that has vexed cardiologists for years.

Safer and more effective treatment decisions will be systematically based upon genetic information.

Projects in Computational and Genomic Medicine, such as the joint NIH U54 and an NSFcenter grant project, blend the computational analysis, pharmacogenomics, and supercomputing expertise of the University of Illinois at Urbana-Champaign with the medical informatics and clinical practice expertise of Mayo Clinic. Researchers will develop new and innovative processes, such as artificial intelligence, that facilitate the translation of genomics and other high-dimensional data into clinical care.

The University of Illinois at Urbana-Champaign and Mayo Clinic as well as our affiliate, the University of Chicago, which are leading institutions in these areas and already have strong ties to each other, have established the Center for Computational Biotechnology and Genomic Medicine (CCBGM), a collaborative environment that will improve the applicability, timeliness, efficiency, and accuracy of the computational infrastructure that will address pressing genome-based challenges.

The Mayo Clinic and Illinois Strategic Alliance for Technology-Based Healthcare was organized in 2010 to advance research, technology, and clinical treatment options in health care. It's a collaboration of The Interdisciplinary Health Sciences Initiative at Illinois (IHSI).

The Alliance is a framework for collaboration in individualized medicine, and involves innovative educational programs, integrated research activities and projects, and entrepreneurial modes to deploy and commercialize outcomes.

BD2K funds research and training activities that support the use of Big Data to advance biomedical research and discovery. This includes efforts in enhancing training, resource indexing, methods and tools development, and other data science-related areas. As part of this NIH award, Mayo Clinic is developing tools for standardizing research metadata.

Richard Weinshilboum, M.D., director, Pharmacogenomics Program

Pharmacogenomic testing helps patient and her family members find answers to health-related questions.

The Pharmacogenomics Program investigates how variations in genes affect response to medications, thereby using a patient's genetic profile to predict a drug's efficacy, guide dosage and improve patient safety.

Sequencing uncovers genetic makeup of aggressive tumor.

The Center for Individualized Medicine is a strategic priority for the Campaign for Mayo Clinic.

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Pharmacogenomics Program - mayo.edu

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One study will recruit 1800 adults of African ancestry with hypertension to evaluate the impact of returning high-risk APOL1 genetic test results to patients

ISR will undergo continued pharmacogenomic and product sales training. Communicate with healthcare providers and their staff about pharmacogenomic testing and

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Pharmacogenomics Jobs, Employment | Indeed.com

The right drug, at the right dose, at the right time. This is the power of pharmacogenomics.

When it comes to medications, a drug that works well for one person may not work well for another. A standard dosage may achieve the desired treatment outcome in most patients yet could result in side effects or no therapeutic benefit at all in others.

We know that 98% of patients who take the MedClueRx test have at least one result that may impact their care. Pharmacogenomics testing is particularly valuable before you have tried several medications for a condition. It is also useful if you feel your medications are not working or have experienced adverse side effects.

*Do not change or stop taking any medicine based on a genetic test report without consulting your healthcare provider. This test is not intended to inform you about your current state of health, including whether or not you should take a medication or how much you should take. This test does not diagnose any health conditions and is not a substitute for visiting your health care provider. Discuss the results of the genetic test with your healthcare provider, including whether the medication label includes information on how to use genetic information to determine dosage. Medicine should always be taken as prescribed by your healthcare provider.

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Pharmacogenomics and Personalized Medicine | NorthShore

Pharmacogenomics studies how medicine interacts with inherited genes. This includes how inherited genes affect the way medications work for each person. Genetic differences mean that a drug can be safe for 1 person but harmful for another. One person may experience severe side effects from it. Another may not, even when given a similar dose.

Standard genetic testing. Standard genetic testing searches for specific genes. For example, BRCA1 and BRCA2 genes. These genes are linked with a higher risk of breast and ovarian cancer. Standard genetic test results may prompt preventive steps.

Preventive steps include:

Pharmacogenomics. Pharmacogenomics is a kind of genetic testing. It looks for small variations within genes. These variations may affect whether genes activate or deactivate specific drugs. Test results help the doctor choose the safest and most effective drug and dose.

Pharmacogenomics is constantly changing. Researchers continue to identify gene variations that affect how a drug works. As personalized medicine grows, testing for gene variations may become more common.

Drug activation. Many drugs that treat cancer need activation to work. Activation is the process of turning on. Proteins called enzymes speed up chemical reactions in the body. This activates a drug so that it can do its job.

Each person inherits variations in enzymes. The variations affect how fast a drug changes into its active form. For example, some people break down drugs slowly. This means standard doses of treatment may not work as well.

Drug deactivation. Drugs also need deactivation to limit the drugs exposure to healthy tissues. Deactivation is the process of turning off.

Some people may have slower enzymes. As a result, high levels of the drug may remain in their bodies for a long time. This means that they may have more side effects from the drug.

Besides pharmacogenomics, other factors may influence a persons reaction to a drug:

Here are some of the benefits of pharmacogenomics:

It may improve patient safety. Severe drug reactions cause more than an estimated 120,000 hospitalizations each year. Pharmacogenomics may prevent these by identifying patients at risk.

It may improve health care costs and efficiency. Pharmacogenomics may help find appropriate medications and doses more quickly.

Here are some challenges in the development and practical use of pharmacogenomics:

It is expensive, particularly if insurance does not cover the costs.

Access to certain tests may be limited in some places.

Privacy issues remain, despite federal antidiscrimination laws. These laws prohibit discrimination based on genetic information.

Here are some examples of pharmacogenomic testing in cancer care:

Colorectal cancer. Irinotecan (Camptosar) is a type of chemotherapy. Doctors commonly use it to treat colon cancer. In some people, genetic variations cause a shortage of the UGT1A1 enzyme. This enzyme is responsible for metabolizing irinotecan. Metabolism is the chemical reaction that helps the body process the drug.

With a UGT1A1 shortage, higher levels of irinotecan remain in the body. This may lead to severe and potentially life-threatening side effects. The risk is greater with higher doses of the drug.

Doctors may use a pharmacogenomic test called the UGT1A1 test. It shows which people have this genetic variation. Then, the doctor may prescribe a lower dose of irinotecan. Often, the lower dose is just as effective for these people.

Acute lymphoblastic leukemia (ALL). Doctors use pharmacogenomic testing for children with ALL. About 10% of people have genetic variations in an enzyme called thiopurine methyltransferase (TPMT). TPMT is responsible for metabolizing chemotherapy for ALL.

Children with lower TPMT levels receive lower chemotherapy doses. This prevents severe side effects.

Other cancer types. Fluorouracil (5-FU) is a type of chemotherapy. Its used to treat several types of cancer including colorectal, breast, stomach, and pancreatic cancers.

A genetic variation in some people causes lower levels of the enzyme called dihydropyrimidine dehydrogenase (DPD). DPD helps the body metabolize fluorouracil.

Doctors may use a pharmacogenomic test to find this variation. If found, a lower fluorouracil dose helps prevent serious side effects.

Talk with your health care team about your treatment options and consider asking the questions below:

What are my treatment options?

Which treatment or combination of treatments do you recommend? Why?

Do these treatments work differently in different people? If so, are there tests to find these differences?

What are the possible side effects of this treatment?

Could my genetic makeup affect my bodys response to treatment?

Is there a way to predict how my body will respond to this drug? To predict whether I might experience severe side effects?

What are my options if the cancer does not respond to the drug? Or if I experience severe side effects?

Whom should I call with questions or problems?

Genetics

National Institutes of Health: Frequently Asked Questions About Pharmacogenomics

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Understanding Pharmacogenomics | Cancer.Net

Drugs and Genes Conference

The right drug at the right dose at the right time

Drug-gene testing is also called pharmacogenomics, or pharmacogenetics. All terms characterize the study of how your genes affect your body's response to medications. The word "pharmacogenomics" is combined from the words pharmacology (the study of the uses and effects of medications) and genomics (the study of genes and their functions).

Your body has thousands of genes that you inherited from your parents. Genes determine which characteristics you have, such as eye color and blood type. Some genes are responsible for how your body processes medications. Pharmacogenomic tests look for changes or variants in these genes that may determine whether a medication could be an effective treatment for you or whether you could have side effects to a specific medication.

Patient Information: Pharmacogenomics Finding the Right Medication for You

Pharmacogenomic testing is one tool that can help your health care provider determine the best medication for you. Your health care provider also considers other factors such as your age, lifestyle, other medications you are taking and your overall health when choosing the right treatment for you.

The Pharmacogenomics Program investigates how variations in genes affect response to medications, thereby using a patient's genetic profile to predict a drug's efficacy, guide dosage and improve patient safety.

The purpose of pharmacogenomic testing is to find out if a medication is right for you. A small blood or saliva sample can help determine:

The laboratory looks for changes or variants in one or more genes that can affect your response to certain medications.

Each person would need to have the same specific pharmacogenomic test only once because your genetic makeup does not change over time. However, you may need other pharmacogenomics tests if you take another medication. Each medication is associated with a different pharmacogenomics test. Keep track of all your test results and share them with your health care providers.

The need for pharmacogenomics testing is determined on an individual basis. If your pharmacogenomic test results suggest you may not have a good response to a medication, your family members may have a similar response. Mayo Clinic recommends you share this information with your family members. Your health care provider can also provide recommendations for family members who may benefit from having testing.

Genomic sequencing is a process for analyzing a sample of DNA taken from your blood. In the lab, technicians extract DNA and prepare it for sequencing.

Applied pharmacogenomics resolves patient's lifelong anxiety and depression.

Current limitations of pharmacogenomics testing include:

The cost of pharmacogenomics testing varies depending on which test is ordered and your health insurance coverage. To help you determine test costs and coverage:

A federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance companies to discriminate against you based on your genetic information. This federal law does not protect you against genetic discrimination by life insurance, disability insurance or long-term care insurance companies. Some states have laws in this area.

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Drug-Gene Testing - Center for Individualized Medicine ...