Question

What are the three ways that pharmacogenetics (individualized medicine) can be used to make treatment decisions? How/why are they used?

Answer 1

In pharmacogenomics, genomic information is used to study individual responses to drugs. When a gene variant is associated with a particular drug response in a patient, there is the potential for making clinical decisions based on genetics by adjusting the dosage or choosing a different drug, for example. Scientists assess gene variants affecting an individual's drug response the same way they assess gene variants associated with diseases: by identifying genetic loci associated with known drug responses, and then testing individuals whose response is unknown. Modern approaches include multigene analysis or whole-genome single nucleotide polymorphism (SNP) profiles, and these approaches are just coming into clinical use for drug discovery and development.

Pharmacogenetics and pharmacogenomics have been widely recognized as fundamental steps toward personalized/individualized medicine. They deal with genetically determined variants in how individuals respond to drugs, and hold the promise to revolutionize drug therapy by tailoring it according to individual genotypes.

Within the United States, serious side effects from pharmaceutical drugs occur in 2 million people each year and may cause as many as 100,000 deaths, according to the Food and Drug Administration. Costs associated with adverse drug reactions (ADRs) are estimated at $136 billion annually. ADRs come in two forms. One form results from misuse, such as taking too much of a medication or taking the medication too often or for too long. The second form involves the mysterious, idiosyncratic effects of various drugs. The term "idiosyncratic" is used because these (often serious) side effects are not related to drug dose and are thought to be unpredictable. Scientists believe many idiosyncratic effects result from individual variation that is encoded in the genome. Thus, genetic variation in genes for drug-metabolizing enzymes, drug receptors, and drug transporters have been associated with individual variability in the efficacy and toxicity of drugs. Genetics also underlies hypersensitivity reactions in patients who are allergic to certain drugs, such as penicillin, wherein the body mounts a rapid, aggressive immune response that can cause not only a rash, but can also hinder breathing and cause edema to the point of cardiovascular collapse.

Predicting serious ADRs is a priority for pharmacogenomic research. For example, the enzyme CYP2D6, one of a class of drug-metabolizing enzymes found in the liver, breaks down and terminates the action of certain antidepressant, antiarrhythmic, and antipsychotic drugs. Molecular cloning and characterization studies of the gene that codes for this enzyme have described more than 70 variant alleles. These alleles contain one or more point mutations, only some of which affect enzyme activity; however, some of these alleles involve gene deletions and duplications that can lead to increased enzyme activity. Individuals who are homozygous or heterozygous for the wild-type or normal activity enzymes (75%–85% of the population) are called extensive metabolizers; intermediate (10%–15%) or poor (5%–10%) metabolizers are carriers of two alleles that decrease enzyme activity (Ingelman-Sundberg, 1999); and ultrarapid metabolizers (1%–10%) are carriers of duplicated genes. The most common alleles can be detected by DNA chip microarrays, allowing most patients to be assigned to a particular phenotype group.

Every person has a unique variation of the human genome. Although most of the variation between individuals has no effect on health, an individual's health stems from genetic variation with behaviors and influences from the environment.

Modern advances in personalized medicine rely on technology that confirms a patient's fundamental biology, DNA, RNA, or protein, which ultimately leads to confirming disease. For example, personalised techniques such as genome sequencing can reveal mutations in DNA that influence diseases ranging from cystic fibrosis to cancer. Another method, called RNA-seq, can show which RNA molecules are involved with specific diseases. Unlike DNA, levels of RNA can change in response to the environment. Therefore, sequencing RNA can provide a broader understanding of a person's state of health. Recent studies have linked genetic differences between individuals to RNA expression, translation and protein levels.

The concepts of personalised medicine can be applied to new and transformative approaches to health care. Personalised health care is based on the dynamics of systems biology and uses predictive tools to evaluate health risks and to design personalised health plans to help patients mitigate risks, prevent disease and to treat it with precision when it occurs. The concepts of personalised health care are receiving increasing acceptance with the Veterans Administration committing to personalised, proactive patient driven care for all veterans. In some instances personalised health care can be tailored to the markup of the disease causing agent instead of the patient's genetic markup; examples are drug resistant bacteria or viruses.

Pharmacogenetics and perrsonalised/individualized medicine may provide better diagnoses with earlier intervention, and more efficient drug development and therapiesThe three ways that pharmacogenetics (individualized medicine) can be used to make treatment decisions in:

1. Improving Cancer Outcomes

Both drugs and chemotherapy are used for the treatment of breast cancer, and diagnostic tests have allowed some limited degree of disease typing. For patients with estrogen receptor-sensitive cancer that has not yet spread to the lymph nodes, for example, tamoxifen is the drug of choice, but chemotherapy is frequently offered as an adjunct. However, chemotherapy is known to help only a small number of patients. In fact, a long-term study called the National Surgical Adjuvant Breast and Bowel Project (NSABP) found that only 4% of patients who received chemotherapy had improved outcomes.

Could patients receive individualized treatment based on their specific type of cancer? It appears that the answer to this question is "yes." For instance, using real-time PCR methods to study gene expression in breast cancer and taking advantage of a large collection of paraffin-preserved tissue samples, a team of NSABP researchers developed a diagnostic kit that assays 21 genes. This project has resulted in a diagnostic tool that identifies key genetic components of particular patients' breast cancer and can improve outcomes. This diagnostic kit predicts the likelihood of cancer recurring for patients who are categorized into one of three risk groups: low, intermediate, and high. In a clinical validation study, the diagnostic data did indeed predict long-term recurrence. Moreover, in studies to determine treatment benefit, the researchers analyzed tissue samples from the original NSABP study. There was no benefit to adding chemotherapy to tamoxifen in low-risk patients, and only a tiny benefit (2%) in intermediate-risk patients. In high-risk patients, though, the benefit of chemotherapy was clear, with a 28% decrease in recurrence of cancer.

2. Genotype, Phenotype, and ADRs

If there are multiple mutations that can lead to similar susceptibilities to ADRs, diagnostic tests that directly assess the phenotype rather than a genetic mutation may be more reliable (and may remain necessary even if genetic diagnostic tests do become available). Although DNA-based technology is potentially faster and requires only a single blood sample from a patient, for many genetic variants, the correlation between genotype and phenotype has not been well described.

The phenotype is what the physician wants to know and, unfortunately, present DNA-based tests can fail to reflect the full range of phenotypic variation. As a result, a major challenge for companies designing DNA-based tests is to develop dependable, economical, high-throughput genotyping platforms, and a major challenge for pharmacogenomic science is to determine comprehensive, clinically useful genotype-phenotype correlations.

Differential responses to thiopurine drugs provide a concrete example of why this is true. Thiopurine drugs are used to treat acute lymphoblastic leukemia, inflammatory bowel disease, and organ transplant recipients. These drugs are useful, but they are also toxic, and the window for dosing to induce the desired therapeutic effect before causing toxicity is very narrow. The major toxicity related to thiopurines is life-threatening bone-marrow suppression.

Thiopurines are inactivated by the metabolic enzyme thiopurine S-methyltransferase (TPMT), which is encoded by a polymorphic gene. In Asian populations, TPMT*3C is a common gene variant with a cytosine at position 3, but in Caucasians, TPMT*3A is more common. TPMT*3A has two different SNPs that result in alterations in the encoded amino acids. The gene product encoded by TPMT*3A is degraded rapidly, such that individuals homozygous for this allele have little or no detectable TPMT protein in their tissues. Thus, individuals homozygous for TPMT*3A are at greatly increased risk for life-threatening myelosuppression when treated with standard doses of thiopurine drugs. However, such people can be treated with these drugs at approximately one-tenth the standard dose, but only with careful monitoring

3. Therapeutic Human Genome Project

With the completion of the Human Genome Project, anticipation was high that genetic information would radically improve medicine, that side effects would be more predictable, and that patients could be screened for likely drug responses. But thus far, progress has been much slower than what the initial excitement suggested.

A great deal of this delay relates to the fact that an individual's response to drugs is multifactorial, resulting from multiple gene and environmental interaction. Scientists also recognize that even as the knowledge base continues to expand, the clinical translation of that knowledge still requires empirical evidence, generated for a particular disease and drug combination, before treatment can be customized to a patient's genotype. Thus, much work remains to be done before personalized medicine can reach its fullest potential.