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Toxgnostics is part of personalized medicine as it describes the guiding principles for the discovery of pharmacogenomic biomarker tests, also referred to as companion diagnostic tests, which identify if an individual patient is likely to suffer severe drug toxicity from treatment with a specific therapeutic agent. Once at-risk individuals are identified, drug toxicity can be prevented using elective dose reduction or prescription of a different medication. [1] [2] [3]
The majority of toxgnostic studies have been candidate gene studies restricted to the known Absorption, Distribution, Metabolism, and Excretion genes (ADME) of drug treated patients. The PharmaADME consortium [4] identified 32 core genes containing 184 variants within common pathways that should be included in ADME candidate gene studies of toxicity biomarkers. Toxicity biomarkers that have been clinically validated using this restricted panel of genes include the P450 cytochrome assay that is currently recommended for routine clinical use of the oral anticoagulant warfarin. Using next-generation sequencing methods and genome-wide association studies a more comprehensive toxgnostic approach can be utilized through unbiased analysis of several million variants across the whole human genome, including introns and exons, for pharmacogenomic markers of drug induced toxicity. [1]
Cancer drugs have been highlighted as particularly appropriate candidates for toxgnostic studies due to the significant toxicity profiles associated with both targeted therapies [5] and chemotherapy. [6] Most cancer patients obtain only modest benefit from treatment, whereas toxicity is common and often associated with severe side effects which include considerable morbidity and mortality. One of the most commonly used chemotherapy drugs 5-fluorouracil (5FU) prescribed as adjuvant therapy following surgical resection of early stage colorectal cancer benefits only approx. 4% of patients, whereas 30–40% of those treated will suffer severe toxicity such as neutropenia, mucositis, hand-foot syndrome, diarrhoea, and stomatitis, fatal toxicities will kill 0.5-1% of people treated. [7] Through the use of toxgnostic screens a number of genetic variants have now been identified that can be used to predict 5FU toxicity prior to treatment. [8] These genetic variants can be used to identify the individuals predisposed to severe drug toxicity and the dose of 5FU chemotherapy can be reduced to prevent severe toxic side effects. Toxgnostic biomarker tests currently available for use in clinical practice include markers for irinotecan, thioguanine, warfarin and 5FU.
Toxgnostic studies are defined by four key elements: [1]
Appropriate analytical approaches for toxgnostic studies include candidate gene studies, GWAS and whole genome sequencing. GWAS and whole genome sequencing are the most comprehensive approaches though careful considerations must be applied to the relevance, analysis and interpretation of the results to prevent over-fitting, which produces false-positive results, a proposed GWAS workflow is shown below. [1]
Toxicity biomarkers can be co-developed and co-approved with the respective drug as a companion diagnostic test, this requires premarket approval (PMA). The Food and Drug Administration (FDA) IVD Companion Diagnostic Device guidance issued in draft 14 July 2011 states that a companion diagnostic test can be used to “Identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic product”. [9] Additionally there are guidelines for the submission of pharmacogenomic studies from the FDA [10] and draft guidance from the European Medicines Agency (EMA). [11]
In genetics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently large fraction of the population, many publications do not apply such a frequency threshold.
Pharmacogenomics is the study of the role of the genome in drug response. Its name reflects its combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects their response to drugs. It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with pharmacokinetics and pharmacodynamics. The term pharmacogenomics is often used interchangeably with pharmacogenetics. Although both terms relate to drug response based on genetic influences, pharmacogenetics focuses on single drug-gene interactions, while pharmacogenomics encompasses a more genome-wide association approach, incorporating genomics and epigenetics while dealing with the effects of multiple genes on drug response.
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.
Personalized medicine, also referred to as precision medicine, is a medical model that separates people into different groups—with medical decisions, practices, interventions and/or products being tailored to the individual patient based on their predicted response or risk of disease. The terms personalized medicine, precision medicine, stratified medicine and P4 medicine are used interchangeably to describe this concept though some authors and organisations use these expressions separately to indicate particular nuances.
MammaPrint is a prognostic and predictive diagnostic test for early stage breast cancer patients that assess the risk that a tumor will metastasize to other parts of the body. It gives a binary result, high-risk or low-risk classification, and helps physicians determine whether or not a patient will benefit from chemotherapy. Women with a low risk result can safely forego chemotherapy without decreasing likelihood of disease free survival. MammaPrint is part of the personalized medicine portfolio marketed by Agendia.
Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.
In biomedical contexts, a biomarker, or biological marker is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers are used in many scientific fields.
Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.
Panitumumab (INN), formerly ABX-EGF, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.
The Cancer Genome Project is part of the cancer, aging, and somatic mutation research based at the Wellcome Trust Sanger Institute in The United Kingdom. It aims to identify sequence variants/mutations critical in the development of human cancers. Like The Cancer Genome Atlas project within the United States, the Cancer Genome Project represents an effort in the War on Cancer to improve cancer diagnosis, treatment, and prevention through a better understanding of the molecular basis of the disease. The Cancer Genome Project was launched by Michael Stratton in 2000, and Peter Campbell is now the group leader of the project. The project works to combine knowledge of the human genome sequence with high throughput mutation detection techniques.
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction
Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.
Molecular diagnostics is a collection of techniques used to analyze biological markers in the genome and proteome, and how their cells express their genes as proteins, applying molecular biology to medical testing. In medicine the technique is used to diagnose and monitor disease, detect risk, and decide which therapies will work best for individual patients, and in agricultural biosecurity similarly to monitor crop- and livestock disease, estimate risk, and decide what quarantine measures must be taken.
The Pharmacogenomics Knowledge Base (PharmGKB) is a publicly available, online knowledge base responsible for the aggregation, curation, integration and dissemination of knowledge regarding the impact of human genetic variation on drug response. It is funded by the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS), and is a partner of the NIH Pharmacogenomics Research Network (PGRN). It has been managed at Stanford University since its inception in 2000.
The genotype-first approach is a type of strategy used in genetic epidemiological studies to associate specific genotypes to apparent clinical phenotypes of a complex disease or trait. As opposed to “phenotype-first”, the traditional strategy that has been guiding genome-wide association studies (GWAS) so far, this approach characterizes individuals first by a statistically common genotype based on molecular tests prior to clinical phenotypic classification. This method of grouping leads to patient evaluations based on a shared genetic etiology for the observed phenotypes, regardless of their suspected diagnosis. Thus, this approach can prevent initial phenotypic bias and allow for identification of genes that pose a significant contribution to the disease etiology.
A variant of uncertainsignificance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely. When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic.
Personalized onco-genomics is a growing area of interest in the field of oncology and genomics that is focused on utilizing whole genome analysis to make rational clinical treatment decisions for each individual patient. The idea for this program was devised at Canada's Michael Smith Genome Sciences Centre and is currently being led by Dr. Marco Marra and Dr. Janessa Laskin. Genome instability has been identified as one of the underlying hallmarks of cancer. The genetic diversity of cancer cells promotes multiple other cancer hallmark functions that help them survive in their microenvironment and eventually metastasise. The pronounced genomic heterogeneity of tumours has led researchers to develop an approach that assesses each individual's cancer to identify targeted therapies that can halt cancer growth. Identification of these “drivers” and corresponding medications used to possibly halt these pathways are becoming increasingly important in the treatment of cancer.
Cancer pharmacogenomics is the study of how variances in the genome influences an individual’s response to different cancer drug treatments. It is a subset of the broader field of pharmacogenomics, which is the area of study aimed at understanding how genetic variants influence drug efficacy and toxicity.
Tumour mutational burden is a genetic characteristic of tumorous tissue that can be informative to cancer research and treatment. It is defined as the number of non-inherited mutations per million bases (Mb) of investigated genomic sequence, and its measurement has been enabled by next generation sequencing. TMB has shown potential as a predictive biomarker with several applications, including associations reported between different TMB levels and patient response to immune checkpoint inhibitor (ICI) therapy in a variety of cancers.
Mary Violet Relling is an American pharmacogeneticist. Relling's research focuses on pharmacokinetics and pharmacodynamics in children and how genome variability influences a child's response to cancer chemotherapy.