A cancer biomarker refers to a substance or process that is indicative of the presence of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

in the body. A

biomarker 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, p ...

may be a molecule secreted by a

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

or a specific response of the body to the presence of cancer. Genetic,

epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are ...

, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum. Cancer deaths by type, 2, OWID

While numerous challenges exist in translating biomarker research into the clinical space; a number of

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

based biomarkers have already been used at some point in patient care; including, AFP (

liver cancer Liver cancer (also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy) is cancer that starts in the liver. Liver cancer can be primary (starts in liver) or secondary (meaning cancer which has spread from elsewhere to th ...

BCR-ABL The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

( chronic myeloid leukemia),

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...

BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...

(

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...

), BRAF V600E (

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

CA-125 Mucin-16 (MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the ''MUC16'' gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 has found application as a tumor marker or b ...

(ovarian cancer), CA19.9 (

pancreatic cancer Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancr ...

), CEA (colorectal cancer), EGFR ( Non-small-cell lung carcinoma),

HER-2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refe ...

(Breast Cancer),

KIT Kit may refer to: Places *Kitt, Indiana, US, formerly Kit * Kit, Iran, a village in Mazandaran Province * Kit Hill, Cornwall, England People * Kit (given name), a list of people and fictional characters * Kit (surname) Animals * Young animal ...

( gastrointestinal stromal tumor),

PSA PSA, PsA, Psa, or psa may refer to: Biology and medicine * Posterior spinal artery * Primary systemic amyloidosis, a disease caused by the accumulation of abnormal proteins * Prostate-specific antigen, an enzyme used as a blood tracer for pros ...

(prostate specific antigen) (

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

), S100 (melanoma), and many others. Mutant proteins themselves detected by

selected reaction monitoring Selected reaction monitoring (SRM), also called Multiple reaction monitoring, (MRM), is a method used in tandem mass spectrometry in which an ion of a particular mass is selected in the first stage of a tandem mass spectrometer and an ion product ...

(SRM) have been reported to be the most specific biomarkers for cancers because they can only come from an existing tumor. About 40% of cancers can be cured if detected early through examinations.

Definitions of cancer biomarkers

Organizations and publications vary in their definition of

. In many areas of medicine, biomarkers are limited to

s identifiable or measurable in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

. However, the term is often used to cover any molecular, biochemical, physiological, or anatomical property that can be quantified or measured. The

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. T ...

(NCI), in particular, defines biomarker as a: “A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule." In cancer research and medicine, biomarkers are used in three primary ways: # To help diagnose conditions, as in the case of identifying early stage cancers (diagnostic) # To forecast how aggressive a condition is, as in the case of determining a patient's ability to fare in the absence of treatment (prognostic) # To predict how well a patient will respond to treatment (predictive)

Role of biomarkers in cancer research and medicine

Uses of biomarkers in cancer medicine

Risk assessment

Cancer biomarkers, particular those associated with genetic

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

s or

alterations, often offer a quantitative way to determine when individuals are predisposed to particular types of cancers. Notable examples of potentially predictive cancer biomarkers include mutations on genes

KRAS ''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...

, p53, EGFR, erbB2 for

colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being rem ...

, esophageal,

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

, and pancreatic cancer; mutations of genes

and

for

and ovarian cancer; abnormal

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

s p16,

CDKN2B Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the ''CDKN2B'' gene in humans. Function This gene lies adjacent to the tumor suppressor gene CDKN2A in a regi ...

, and p14ARF for

brain cancer A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and second ...

; hypermethylation of MYOD1, CDH1, and CDH13 for

cervical cancer Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...

; and hypermethylation of p16, p14, and RB1, for

oral cancer Oral cancer, also known as mouth cancer, is cancer of the lining of the lips, mouth, or upper throat. In the mouth, it most commonly starts as a painless white patch, that thickens, develops red patches, an ulcer, and continues to grow. When on ...

Diagnosis

Cancer biomarkers can also be useful in establishing a specific diagnosis. This is particularly the case when there is a need to determine whether tumors are of

primary Primary or primaries may refer to: Arts, entertainment, and media Music Groups and labels * Primary (band), from Australia * Primary (musician), hip hop musician and record producer from South Korea * Primary Music, Israeli record label Works ...

or metastatic origin. To make this distinction, researchers can screen the

chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

alterations found on cells located in the primary tumor site against those found in the secondary site. If the alterations match, the secondary tumor can be identified as metastatic; whereas if the alterations differ, the secondary tumor can be identified as a distinct primary tumor. For example, people with tumors have high levels of circulating tumor DNA (ctDNA) due to tumor cells that have gone through apoptosis. This tumor marker can be detected in the blood, saliva, or urine. The possibility of identifying an effective biomarker for early cancer diagnosis has recently been questioned, in light of the high molecular heterogeneity of tumors observed by next-generation sequencing studies.

Prognosis and treatment predictions

Another use of biomarkers in cancer medicine is for disease

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain sta ...

, which take place after an individual has been diagnosed with cancer. Here biomarkers can be useful in determining the aggressiveness of an identified cancer as well as its likelihood of responding to a given treatment. In part, this is because tumors exhibiting particular biomarkers may be responsive to treatments tied to that biomarker's expression or presence. Examples of such prognostic biomarkers include elevated levels of metallopeptidase inhibitor 1 (TIMP1), a marker associated with more aggressive forms of

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...

, elevated estrogen receptor (ER) and/or progesterone receptor (PR) expression, markers associated with better overall survival in patients with breast cancer; HER2/neu gene amplification, a marker indicating a breast cancer will likely respond to

trastuzumab Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wi ...

treatment; a mutation in exon 11 of the proto-oncogene

c-KIT Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...

, a marker indicating a gastrointestinal stromal tumor (GIST) will likely respond to

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...

treatment; and mutations in the

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

domain of EGFR1, a marker indicating a patient's non-small-cell lung carcinoma (NSCLC) will likely respond to gefitinib or erlotinib treatment.

Pharmacodynamics and pharmacokinetics

Cancer biomarkers can also be used to determine the most effective treatment regime for a particular person's cancer. Because of differences in each person's genetic makeup, some people metabolize or change the chemical structure of drugs differently. In some cases, decreased metabolism of certain drugs can create dangerous conditions in which high levels of the drug accumulate in the body. As such, drug dosing decisions in particular cancer treatments can benefit from screening for such biomarkers. An example is the gene encoding the enzyme thiopurine methyl-transferase (TPMPT). Individuals with mutations in the TPMT gene are unable to metabolize large amounts of the

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

drug,

mercaptopurine Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's dis ...

, which potentially causes a fatal drop in white blood count for such patients. Patients with TPMT mutations are thus recommended to be given a lower dose of mercaptopurine for safety considerations.

Monitoring treatment response

Cancer biomarkers have also shown utility in monitoring how well a treatment is working over time. Much research is going into this particular area, since successful biomarkers have the potential of providing significant cost reduction in patient care, as the current image-based tests such as CT and MRI for monitoring tumor status are highly costly. One notable biomarker garnering significant attention is the

biomarker S100-beta in monitoring the response of malignant

. In such melanomas,

melanocytes Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and hear ...

, the cells that make pigment in our skin, produce the protein S100-beta in high concentrations dependent on the number of cancer cells. Response to treatment is thus associated with reduced levels of S100-beta in the blood of such individuals. Similarly, additional laboratory research has shown that tumor cells undergoing

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

can release cellular components such as

cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

nucleosome A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundame ...

s, cleaved cytokeratin-18, and

E-cadherin Cadherin-1 or Epithelial cadherin (E-cadherin), (not to be confused with the APC/C activator protein CDH1) is a protein that in humans is encoded by the ''CDH1'' gene. Mutations are correlated with gastric, breast, colorectal, thyroid, and ovari ...

. Studies have found that these macromolecules and others can be found in circulation during cancer therapy, providing a potential source of clinical metrics for monitoring treatment.

Recurrence

Cancer biomarkers can also offer value in predicting or monitoring cancer recurrence. Th
Oncotype DX®
breast cancer assay is one such test used to predict the likelihood of breast cancer recurrence. This test is intended for women with early-stage (Stage I or II), node-negative, estrogen receptor-positive (ER+) invasive breast cancer who will be treated with

hormone therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic ho ...

. Oncotype DX looks at a panel of 21 genes in cells taken during tumor

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

. The results of the test are given in the form of a recurrence score that indicates likelihood of recurrence at 10 years.

Uses of biomarkers in cancer research

Developing drug targets

In addition to their use in cancer medicine, biomarkers are often used throughout the cancer drug discovery process. For instance, in the 1960s, researchers discovered the majority of patients with

chronic myelogenous leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumul ...

possessed a particular genetic abnormality on

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...

s 9 and 22 dubbed the

Philadelphia chromosome The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

. When these two chromosomes combine they create a cancer-causing gene known as

. In such patients, this gene acts as the principle initial point in all of the physiological manifestations of the leukemia. For many years, the BCR-ABL was simply used as a biomarker to stratify a certain subtype of leukemia. However, drug developers were eventually able to develop

, a powerful drug that effectively inhibited this protein and significantly decreased production of cells containing the Philadelphia chromosome.

Surrogate endpoints

Another promising area of biomarker application is in the area of

surrogate endpoint In clinical trials, a surrogate endpoint (or surrogate marker) is a measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of H ...

s. In this application, biomarkers act as stand-ins for the effects of a drug on cancer progression and survival. Ideally, the use of validated biomarkers would prevent patients from having to undergo tumor

biopsies A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a disea ...

and lengthy

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s to determine if a new drug worked. In the current standard of care, the metric for determining a drug's effectiveness is to check if it has decreased cancer progression in humans and ultimately whether it prolongs survival. However, successful biomarker surrogates could save substantial time, effort, and money if failing drugs could be eliminated from the development pipeline before being brought to clinical trials. Some ideal characteristics of surrogate endpoint biomarkers include: * Biomarker should be involved in process that causes the cancer * Changes in biomarker should correlate with changes in the disease * Levels of biomarkers should be high enough that they can be measured easily and reliably * Levels or presence of biomarker should readily distinguish between normal, cancerous, and precancerous tissue * Effective treatment of the cancer should change the level of the biomarker * Level of the biomarker should not change spontaneously or in response to other factors not related to the successful treatment of the cancer Two areas in particular that are receiving attention as surrogate markers include circulating tumor cells (CTCs) and circulating miRNAs. Both these markers are associated with the number of

cells present in the blood, and as such, are hoped to provide a surrogate for tumor progression and

metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, the ...

. However, significant barriers to their adoption include the difficulty of enriching, identifying, and measuring CTC and miRNA levels in blood. New technologies and research are likely necessary for their translation into clinical care.

Types of cancer biomarkers

Molecular cancer biomarkers

Other examples of biomarkers: *Tumor suppressors lost in cancer **Examples:

*RNA **Examples:

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...

*Proteins found in body fluids or tissue. **Examples: Prostate-specific antigen, and

*Antibodies to cancer antigens **Examples:

Merkel cell polyomavirus Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called ...

*DNA **Examples: Circulating Tumor DNA ( ctDNA)

Cancer biomarkers without specificity

Not all cancer biomarkers have to be specific to types of cancer. Some biomarkers found in the circulatory system can be used to determine an abnormal growth of cells present in the body. All these types of biomarkers can be identified through diagnostic blood tests, which is one of the main reasons to get regularly health tested. By getting regularly tested, many health issues such as cancer can be discovered at an early stage, preventing many deaths. The neutrophil-to-lymphocyte ratio has been shown to be a non-specific determinant for many cancers. This ratio focuses on the activity of two components of the immune system that are involved in inflammatory response which is shown to be higher in presence of malignant tumors. Additionally, basic fibroblast growth factor ( bFGF) is a protein that is involved in the proliferation of cells. Unfortunately, it has been shown that in the presence of tumors it is highly active which has led to the conclusion that it may help malignant cells reproduce at faster rates. Research has shown that anti-bFGF antibodies can be used to help treat tumors from many origins. Moreover,

insulin-like growth factor The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF " ...

(IGF-R) is involved in cell proliferation and growth. It has is possible that it is involved in inhibiting apoptosis, programmed cell death due to some defect. Due to this, the levels of IGF-R can be increased when cancer such as breast, prostate, lung, and colorectum is present.

References

{{reflist, colwidth=30em Oncology Biomarkers