Biomarkers can be defined as a matter/substance/characteristic that is used in a biological system and acts as an indicator of – levels of exposure, as a system effect, likeability, or susceptibility, or as an indicator of clinical disease. The full form of biomarkers is biological markers. There has been a heightened interest in formalizing the operations of biomarkers and they have always been integral to the biomedical field. Historically, there has been a focus on using biomarkers for diseases. During World War II, antibiotics for several infections were introduced and the concept may have gained worldwide momentum from here. Infections were cultured and biomarkers were used to increase the rate of therapy. The broadest definition of biomarkers is ‘symptoms or indicators of a disease that are typically associated with it.’
Around the 2000s, there have been significant molecular and biochemical advancements making biomarkers – specific, measurable, and concurrent. These molecular biomarkers can now be characterized. For example; Cholesterol and levels of LDL & HDL are good indicators of cardiovascular health. Biomarkers that are useful in identifying diseases and have clinical stability can be used for drug testing and thereby drug improvements. Their role in increasing our understanding of how a disease progresses, its biological implications, and also their ability to affect drug discovery and development has received a lot of attention in the current medical environment. In the area of cancer treatment, there has been increasing emphasis on targeting specific molecular therapeutics. There are many applications that can lead to target characterization and a wholesome understanding of drug effects.
Cancer biomarkers are molecular and are produced by the tumor-causing cells or by other cells as a response to the growing tumor. They can help in the early detection of cancer and can be identified through genes, cells, molecules, hormones, etc. Around the 1800s the Bence-Jones protein was the first cancer biomarker that was discovered in myeloma patients. It was a light chain antibody of Immunoglobulin G and was found in the urine in excess. In 1980, the FDA approved tests to help in the diagnosis of leukemia, lymphoma, and myeloma. With the development of monoclonal antibodies and with important research on hormones such as hCG, advancements in genome studies, proteomics there have been rapid advancements in biomarker usage.
Classification of biomarkers
There are different ways of classifying biomarkers and they can be grouped based on their uses. These include:
Based on their function – diagnostic, prognostic, or predictive?
Type of molecule – RNA, DNA, protein, or cellular
Type of pathogens – bacterial or viral
Tumour or cancer biomarkers can be described as biological molecules that indicate the presence of cancer in a patient. They can also be used to classify different characteristics of tumors. Calcitonin is one of the recently identified tumor markers that can help detect early cancer. It is a hormone produced in the thyroid gland and its functioning regulates blood calcium levels. Elevated levels lead to medullary carcinoma of the thyroid. Since it is a hereditary disease, early detection in the blood calcitonin can help people lower their risk. In several cases, where there is a chance of recurrence post-surgery or for chemotherapy patients these biomarkers can be used as indicators of recurrent diseases. The best example is PSA levels where the increase in the levels could be an indicator of recurrence of prostate cancer. Also, additional biomarkers have been discovered which move beyond just relying on PSA levels for prostate cancer.
Biomarkers are either produced by the reaction of the tumor or by the body in response to the tumor. In the process of carcinogenesis, genetic and epigenetic modification, altered genes changes in the molecular pathway can be used to study biomarkers. There are many types of biomarkers and some of them include:
Diagnostic: This can help understand the type of cancer and the way it is present.
Prognostic: It can give information on the overall outcome of the patient’s cancer. This includes standard treatment and non-standard treatment methods.
Predictive: The pathway or route to the treatment that can help in the drug discovery process and also ascertain which treatment will enable the best response for the patient.
There are certain biomarkers that can be all three – diagnostic, prognostic, and predictive. Biomarkers are evaluated through body fluids – stool, urine, or blood; tissues (DNA/RNA analysis) and imaging. Classification of tumors using biomarkers creates a universal prognosis and treatment plan for a similar molecular profile.
There are many other popular cancer biomarkers which include the PSA (prostate-specific antigen) which is used to detect prostate cancer. The Philadelphia chromosome can be found in patients with chronic myeloid leukemia. Sometimes biomarkers have low sensitivity and specificity making them less capable of reducing the tumor load.
How biomarkers are identified for cancer
A biomarker has specific biological functions that are present in many forms. They can be used to identify the existence of cancer or the activity of the cancer cells. The processes and characteristics can be used to identify the presence of cancer cells, risk and progression, course of treatment among other factors. Recent research has indicated that there are new biomarkers for special cancers that have different clinical applications. There are a large number of biomarkers and a variety of them that can be used to detect cancer. Some can be used to identify specific cancer types or general cancer types. Although there is not one comprehensive biomarker that can treat any or all types of cancers.
The most commonly used biomarkers are proteins of non-cancerous cells that are higher in number compared to cancerous cells. An assay can be defined as the presence of a substance and its amount. For example; assays can be done through non-invasive methods that include a collection of biofluids. These include blood, serum, urine, stool, etc. These can be done via biopsies of tumors or through tissue extraction. Biomarkers can play an important role at various stages such as – initial screening, prognosis, diagnosis, predicting the outcome of the treatment, monitoring the progress of the disease.
A very important role that biomarkers play is in that of preventive treatment thereby screening asymptomatic people but helping those with higher risks of developing cancer. Any mutations that happen in the genes, chromosomes, or proteins that are related to cancer can be detected through genetic testing. There are a wide variety of genetic tests that are available – breast, ovarian, thyroid, prostate, melanoma, sarcoma, and more. Genetic testing is only a screening method and can’t determine if someone will develop cancer in the long run but it can only project the risks. Therefore, early warning signs can be detected and through active surveillance or other preventative measures, a good medical care plan can be devised.
Use of biomarkers for cancer treatment
There are many ways in which cancer biomarkers work – differently in the body or respond to different kinds of treatments. One type of biomarker triggers cells causing them to grow into abnormal cell proliferation. In breast cancer and other cancers, the HER-2 protein is found to control abnormal cell growth. When proteins or cells are overexpressed i.e. there has been more than necessary target protein growth, the cells are considered HER-2 positive. This may cause the cells to expand quickly or even metastasize to other parts. Here treatments can be drawn to block the signaling pathway of the HER 2 protein, thus stopping the spread of cancer.
Biomarkers that support treatments at a cellular or molecular level such as the SPARC gene are a perfect example of this usage. It stands for secreted protein, acidic, cysteine-rich gene (SPARC), and helps the flow of albumin into the cells. Certain Chemo drugs attach themselves to the albumin and prevent them from getting to their target cells. Therefore, the biomarker can be used to help albumin-attached treatments to reach their target cells.
There are also biomarkers that can stop the cell or molecule action of the treatment. Chemo drugs that contain platinum can disrupt tumor DNA. ERCC1 is responsible for repairing this and if found on higher levels than platinum-based drugs, the treatment will not be effective.
Certain genes that can be identified in people’s DNA can also point to an increased risk of cancers. Those with BRCA1 and BRCA2 gene mutation may be at higher risk of prostate, breast, ovarian cancer, etc. Genetic biomarkers are not used to detect any hereditary gene effects. In fact, the DNA of cancer cells is different from healthy cells. These include unique genes of the tumor and their molecular structure where cancer biomarkers have been used for treatments.
Apart from genetic biomarkers that determine the increased risk, there are a number of biomarkers that are used in the diagnosis and prognosis of cancer. There are many biomarkers that have also been identified through research but only a few have been approved by the FDA.
FDA approved cancer biomarkers list
The FDA has approved current and potential biomarkers in the detection, management, and treatment of the most common forms of cancer. Biomarkers have a great perspective of being developed for personalized medicine with combined therapeutics and diagnostics. Here is the list of approved biomarkers by the FDA:
Biomarker
Type of cancer
Clinical application
α- Fetoprotein
Liver
Diagnosis, staging, detecting recurrence & monitoring therapy
Prostate-Specific Antigen (PSA)
Prostate
Screening, ruling out benign disease
Cancer Antigen 125
Ovarian
Detecting recurrence & monitoring therapy
HE4 (WFDC2)
Ovarian
Detecting recurrence & monitoring therapy
OVA 1 test
(multiple proteins)
Ovarian
Prediction
ROMA Test
Ovarian
Prediction
Cancer Antigen 15-3
Breast
Monitoring therapy
Cancer Antigen 27-29
Breast
Monitoring therapy
Carbohydrate Antigen 19-9
Pancreatic, ovarian
Monitoring therapy
Carcinoembryonic Antigen
Colon, gastric, pancreatic, lung, and breast
Monitoring therapy and detecting recurrence
HER2/neu
Breast
Therapy choice
Tg
Thyroid
Monitoring therapy
hCG
Testicular, Ovarian
Diagnosis, staging, detecting recurrence & monitoring therapy
Future of cancer biomarkers
A way forward for clinically managing cancer is through the increased use of prognostic and predictive biomarkers. These markers can play a vital role in making clinical decisions that can save millions of lives. They can arm medical professionals to provide critical and timely decision-making skills to manage cancer better. By predicting the true outcome of a specific disease, patients can determine their quality of treatment and their lives.
The traditional approach to treating cancer involved treating early signs or symptoms followed by surgical intervention. The tumor would be removed and prevented from spreading to other parts of the body. There are a few effective screening techniques such as DREs, physical exams, mammograms, etc. that have been helpful for treating breast cancer. Non-invasive biomarkers such as urine and serum samples may be used to predict the outcome of cancer. This will improve the quality of life for patients. When patients are diagnosed too late, their tumours might have spread to different parts of the body. Thus biomarkers can cause a timely intervention.
In the coming years, biomarkers will play a very important role. They would be helpful in screening, detecting, diagnosing, monitoring treatments, and predicting recurrences. The recent advancements in genomic and proteomic technologies have been very promising. There is considerable technological support that is needed to support the demands of developing new biomarkers. New developments like tissue microarrays, gene expression profiling to mass spectrometry, as well as machine learning, and other bioinformatics-based methods have boosted the drug discovery efforts.
Some challenges include the fact that there are still many diseases that have not been assessed sufficiently. There is a need for stronger drug development tools that can maximize trial efficiency. Developing a biomarker is a long-term task and needs intensive resource management. There are many stages – such as biomarker discovery, translational models, clinical observational studies, the accuracy of analysis and validation, and studies with benchmark endpoints for submitted candidates. The link between the biomarker working for various treatments and across different drug classes must be proven. Another challenge is to manage various stakeholders efficiently. Academic societies, companies, and organizations that have patient priority data must be integrated. A conceptual framework must be decoded to identify gaps in the drug development process, tools, and technological endpoints.
