Pharmacogenetics is the study of the variability in patients’ responses to drugs due to the differences in genetic sequences that govern the drug responses. Some of these genes include genes corresponding to metabolic enzymes and cellular targets for drugs.
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Mutations in the genome can occur either spontaneously during replication or due to endogenous and exogenous deoxyribonucleic acid (DNA) damaging agents. However, mutations accumulate at an increased rate in cancer cells as compared to healthy cells.
Acquiring pharmacogenetic data
The mutations that occur in certain genes can have an impact on drug transport, metabolism, cellular targets, signaling pathways, and responses to xenobiotics. Microarray analysis of messenger ribonucleic acid (mRNA) can identify patterns of the gene expression profiles. Using mathematical techniques, these patterns can then be characterized to generate pharmacogenetic data.
Pharmacogenomics and personalized medicine
Pharmacogenomics encompasses the study of complex multi-gene patterns within the genome. Of the estimated 1.4 million single nucleotide polymorphisms (SNPs) identified in the human genome, a major fraction of them contribute to variability in drug responses among various individuals.
Knowledge of this complex relationship between the differences in genotypes due to polymorphism or mutations, with associated gene expression profiles and resulting phenotype, plays a key role in the success of personalized medicine.
Significance of pharmacogenetics
Personalized medicine, which involves the prescription of drugs based on the individual’s genetic and biological profile, could be a new norm in the future. Harnessing the power of pharmacogenetics can help clinicians to prescribe drugs both safely and effectively, especially in the case of drugs with a narrow therapeutic index.
For example, chemotherapeutic drugs used in cancer treatment cause life-threatening adverse effects and can have a narrow therapeutic index. In such cases, pharmacogenetic and pharmacogenomic knowledge of the patient will significantly improve the ability of clinicians to treat their patients with a safe and effective dose of chemotherapeutic drugs.
Physicians can also use a patient’s genetic data to guide drug therapy decisions. During the past few years, clinicians are beginning to gain more insight into this approach of personalized medicine. However, more widespread application and use of patients’ genetic data to make treatment decisions must happen to better serve these patients.
For example, the genetic variability of the metabolic enzyme cytochrome P450 2D6 can cause patients to show variable responses to opioid analgesics. Comparatively, genetic variability in the CYP2C19 enzyme can also affect the patient’s response to some anti-platelet drugs.
Pharmacogenetics and pharmacogenomics in oncology
Pharmacogenetics and pharmacogenomics have been used in oncology to predict patients’ susceptibility to cancer, tumor progression, cancer relapse, and survival. Additionally, pharmacogenetic data is also utilized to make decisions regarding the patient’s treatment regimen based on their response to and toxicity associated with cancer chemotherapeutic drugs, as well as monoclonal antibodies (mAbs) that are increasingly used to treat these patients.
Role of genetic polymorphism on therapeutic efficacy and drug toxicity
The clinical outcomes of cancer patients in relation to various polymorphisms such as FcgR are being extensively studied. SNPs in cancer patients leading to even a single amino acid switch at a particular residue can show a differential response rate to immunotherapy mAbs.
In addition to the differences in drug efficacy, genetic polymorphisms can also result in variability in drug toxicity among different patients. A recent study has shown that Her2 polymorphism at 655 Val/Ile in breast cancer patients receiving certain mAbs resulted in cardiotoxicity, whereas individuals without this mutation tolerated this mAb relatively well.
Additionally, the therapeutic efficacy of other mAbs can also be affected by the variability in the expression of other elements of the signaling pathway, including tumor suppressor genes such as phosphatase and tensin homolog (PTEN).
Challenges in the clinical application of pharmacogenetics and pharmacogenomics for assessing mAb therapies
The expression status of specific genes can be analyzed using various methods. It is necessary to use the appropriate methodology to detect the amplification status to obtain reliable pharmacokinetic data to prescribe the medications for the best outcome for the patients.
For example, HER2 amplification status can be assessed by both florescences in situ hybridization (FISH) or by using immunohistochemistry (IHC) techniques. The use of FISH will provide the most accurate representation of the amplification status of a particular gene, like HER2.
On the other hand, IHC may provide inconsistent results as a result of fixation, antigen retrieval, and visualization methods. Other challenges associated with the clinical application of pharmacogenetics include sample procurement and validation of surrogate biomarkers.
Sources:
- Miteva-Marcheva, N. N., Ivanov, H. Y., Dimitrov, D. K., & Stoyanova, V. K. (2020). Application of pharmacogenetics in oncology. Biomarker Research 8(32). doi:10.1186/s40364-020-00213-4.
- Yan, L., & Beckman, R. A. (2018). Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development. BioTechniques 39(4S). doi:10.2144/000112043.
- Chang, K., Weitzel, K., & Schmidt, S. (2015). Pharmacogenetics: Using Genetic Information to Guide Drug Therapy. American Family Physician 92(7); 588-595. https://www.aafp.org/afp/2015/1001/p588.html.
Further Reading