Biomarkers
Developments in research have paved the way to unlocking messages coded in our genes, gut microbiome, and other biological processes. Although researchers have been studying biomarkers for decades, recognizing the many advancements in care they provide, it is still a complex field of study for many reasons. One of the main barriers is that many healthcare professionals, along with the public, continue to have different interpretations of biomarkers, leading to confusion over definitions and applications. To promote a consistent understanding and awareness on this subject, this article provides an overview of biomarkers, including types and categories.
Definition
Biomarkers, or biological markers, is a broad subcategory of objective indications of medical state observed from outside the patient, which can be measured accurately and reproducibly.1 They allow us to pinpoint, quantify, and determine the right tools and therapies for individuals and their biological makeup throughout the continuum of care.
In 2008, Health Canada developed a Guidance Document on genomic biomarkers defining it as a characteristic in deoxyribonucleic acid (DNA) and/or ribonucleic acid (RNA) that we can measure and use to identify biologic processes in the body, disease mechanisms, and/or a body’s response to treatments and care.2 The US Food and Drug Administration (FDA) holds similar views but generalizes this to a characteristic that is an indication of certain biologic processes and responses.3 With gaps in awareness and education on this topic, the FDA developed a living document to promote harmonization of definitions and classifications, called the BEST (biomarkers, endpoints, and other tools) Resource. However, these definitions and understandings of biomarkers continue to evolve as we make advancements in research.
Biomarkers Video
Precision Medicine
To fully understand the value of biomarkers and their role in an individual’s care, we must first explain precision medicine (also known as personalized medicine). Precision medicine focuses on providing recommendations that are based on a person’s genes, additional biomarkers, lifestyle, environmental factors, and more.4 Medicine traditionally focuses on standardized approaches to treatment, and while this works well for the majority, others will need customized treatment, as we now know that even the same disease among a group of individuals may have different biological compositions, which affect how a disease presents and responds to treatment uniquely in each person.
Types of Biomarkers
Currently, there are five types of biomarkers, defined by their characteristics.3 These are molecular, radiographic, histologic, physiologic, and digital. Blood glucose is an example of a molecular biomarker. With imaging tests, the size of a tumour is a radiographic biomarker. The diagnosis of cancer, particularly its grading (what the cancer cells look like) and staging (where, how many, and if it has spread), is an example of a histologic biomarker. Blood pressure is an example of a physiologic biomarker. Of interest, scientists are evaluating if data from personal health tracking apps and devices, such as smartphones and wearable electronic devices, can be digital biomarkers.5
Biomarker Categories
We categorize biomarkers based on their use and applications in research and treatment. These are:
- diagnostic,
- monitoring,
- pharmacodynamic or response,
- predictive,
- prognostic,
- safety, and
- susceptibility and risk.
Diagnostic
These biomarkers confirm whether a person has a particular disease or condition.5 Diagnostic biomarkers will play a significant role in detecting rare diseases and disorders and specific subtypes of conditions as evidence grows in personalized medicine. It can revolutionize the way we classify health conditions from a broad approach to one that is based on genetics and biological characteristics. This is already happening in cancer, as researchers are increasingly looking at tumours from a molecular basis instead of the tissue or organ from which it originates. This helps determine if the cancer is a particular subtype, which can lead to the use of targeted therapies.
Monitoring
We measure these biomarkers repeatedly to determine how a disease or condition develops and responds to treatments or environmental factors that can cause adverse events (environmental agents). This includes looking for new disease effects, changes in severity and/or abnormalities of the disease, or any complications that might come from the treatment or the disease itself.3 An example of this is recording blood pressure.
Pharmacodynamic or Response
These biomarkers allow us to know if a person responded to a drug or environmental agent.5 A response can be a change in blood sugar, heart rate, and other biological and physiological indications that are relevant to a specific outcome in clinical trials. It also helps with establishing the dosing recommendations for a drug, how long a person should be on this treatment, and when they should discontinue and move on to other therapies instead.3 The use of molecular response biomarkers is established for those who take biologics for Crohn’s disease and ulcerative colitis by way of therapeutic drug monitoring.6
Predictive
Predictive biomarkers identify the likelihood that an individual, or a group of similar individuals, will respond positively or negatively to a therapy or an environmental agent.5 Responses could be an improvement in survival rates, symptom relief, or an adverse event. In personalized medicine, these biomarkers can help with finding the right treatments for a disease subtype.
One well-known predictive biomarker is the human epidermal growth factor receptor 2 (HER2), which is a protein that encourages abnormal growth outside breast cells.7 Overexpression of this protein can also present in other cancers, such as stomach cancer. People with this biomarker are more likely to respond well to therapies that target this protein, such as trastuzumab (Herceptin®).
Prognostic
We use prognostic biomarkers to identify the possibility, or risk, of a disease progressing or recurring, or a particular outcome for an individual, regardless of the treatments they are receiving.3 However, this biomarker does not predict how an individual responds after treatment. A 2019 UK study8 developed and validated the first blood-based prognostic biomarker for inflammatory bowel disease (Crohn’s disease and ulcerative colitis). This biomarker test determines whether individuals with active IBD will have a more aggressive disease and thus require appropriate and early treatment escalation.
Safety
Safety biomarkers assist with measuring the possibility, and the extent of, a toxic or adverse event from treatments and environmental agents.3 High levels of liver enzymes called aminotransferases and bilirubin, which is a yellow compound that forms due to the liver’s degradation of old red blood cells, are safety biomarkers that predict serious liver damage.
Susceptibility and Risk
These biomarkers can indicate the level of risk a person has for a disease or condition before diagnosis.3 For instance, certain genetic biomarkers are associated with the development of specific types of cancer. However, this biomarker is distinct from prognostic biomarkers in that the latter identifies the likelihood of an outcome among individuals who already have a diagnosis of a disease or condition.
GI Diseases and Disorders
Your genome can affect your susceptibility to celiac disease. Scientists have identified three gene variants so far with a linking haplotype (the genes you inherit from your biological parents) associated with celiac disease.9 While these genes are potentially a prognostic biomarker, scientists do know that there are many other factors that affect the expression of the genes, so it is only a correlation, not an absolute indicator of disease.
There is growing research on biomarker-based screening tools for irritable bowel syndrome (IBS). In previous issues of the Inside Tract® newsletter, we wrote about a study from McMaster University on urine testing for early detection10 and a blood test (ibs-smartTM) to detect diarrhea-predominant IBS.11 The ibs-smartTM test uses two validated diagnostic biomarkers, anti-vinculin and anti-cytolethal distending toxin B.
Scientists have also found that a panel of blood-based biomarkers from our gut microbiota, associated with inflammation, could indicate major depressive disorder.12
In cancer research, biomarkers are biological molecules that a tumour or an individual’s body creates. They can be DNA, RNA, protein, or small molecules from cancer.13 There are several studies on the use of predictive, prognostic, and diagnostic biomarkers in gastrointestinal cancers. Many are in development or undergoing testing in clinical trials.
- colorectal cancer: EGFR, HER2, KRAS/NRAS, VEGF/VEGFR, BRAF V600E7,14
- pancreatic cancer: BRCA1 or PALB2, SMAD4, KRAS7
- esophageal cancer: PD-L115
- gastric cancer: HER2, C-Met, PD-1 and PD-L17
- gastroesophageal junction adenocarcinoma cancer: HER27 and PD-L115
biomarkers for any type of cancer (tumour agnostic): deficient mismatch repair (dMMR), microsatellite instability (MSI-H), and NTRK fusions *not an exhaustive list
Data Collection and Rights
Precision medicine and biomarkers inevitably require the collection of our health data to identify the appropriate treatment for us as individuals, based on our genes. If you are concerned with the protection of your data, there are some legal mechanisms available. In 2017, the Genetic Non-Discrimination Act came into force, and it prohibits discrimination by any organization or individual based on a person’s genetic testing results. It also prevents mandatory genetic testing and disclosure of results. This ensures that Canadians will have equal access to care and services, such as life insurance, regardless of their genetic data.16
Outlook
This article only scratches the surface on the complexity of biomarkers and several barriers prevent us from fully realizing their benefits in healthcare, such as lack of equitable access to biomarker testing and the awareness that these are available in Canada. However, developing a common understanding and raising awareness are crucial first steps to their development and uptake. The GI Society is committed to increasing education on biomarkers and promoting access to these therapies so that all individuals in Canada can receive the right treatment at the right time.