Cancer biomarkers

By Jason Wasserman MD PhD FRCPC
September 2, 2024

---

A cancer biomarker is a substance in a person’s body that provides information about cancer. It can be a gene, protein, or another type of molecule, and it can be produced by either cancer cells or normal cells in response to cancer. These biomarkers can be found in various body parts, including the blood, normal tissue, or within a tumour itself. Cancer biomarkers offer valuable insights into the characteristics of a cancer that a person already has or indicate their risk of developing cancer in the future. Doctors use these biomarkers to identify the most effective treatments, tailor therapies to individual patients, and sometimes take preventive measures to reduce cancer risk.

How are cancer biomarkers used?

Cancer biomarkers can play a critical role in your medical journey, from the initial risk assessment to diagnosis, treatment planning, and monitoring for recurrence. These tests can provide valuable insights at different stages of your care, helping you and your doctors make informed decisions tailored to your specific condition. Understanding how these biomarkers are used can help you better navigate your treatment and your healthcare team’s steps to manage your cancer.

Estimating the risk of cancer

Biomarker tests that estimate the risk of developing cancer are often performed in individuals with a family history of cancer or known genetic conditions that increase cancer risk. For example, a test for BRCA1 or BRCA2 mutations might be performed on someone with a family history of breast or ovarian cancer. If a mutation is found, this information could lead to increased surveillance, such as more frequent mammograms or MRI scans, or preventive measures like prophylactic surgery to remove breast or ovarian tissue. The goal is to reduce the risk of developing cancer or to catch it at an early, more treatable stage.

Screening

Biomarker screening tests detect cancer in its early stages before symptoms appear. A typical example is the PSA (prostate-specific antigen) test used to screen for prostate cancer in men. This test might be performed regularly in men over a certain age or in those with risk factors for prostate cancer. Elevated PSA levels might lead to further testing, such as a biopsy, to determine if cancer is present. Early detection through screening can lead to earlier treatment, which may improve outcomes.

Differential diagnosis

When a patient has a tumour, biomarker tests can help determine the exact type of cancer, especially when cancers look similar under the microscope. For example, if a patient has a lymphoma, immunohistochemistry might be performed to test for CD20, a protein found on the surface of specific lymphoma cells. The results can help distinguish between different types of lymphoma, which is crucial because different types may require different treatments. Accurate diagnosis ensures that the patient receives the most appropriate therapy.

Determining prognosis of a disease

Biomarker tests can provide information about how aggressive a cancer is and the likely outcome. For example, a test for Ki-67, a protein associated with cell proliferation, might be performed on a tumor sample. High levels of Ki-67 indicate that the cancer cells are dividing rapidly, which may suggest a more aggressive tumor with a higher risk of spreading. This information can help doctors determine how intensively the cancer should be treated, such as whether the patient might benefit from more aggressive chemotherapy.

Predicting response to specific treatments

Certain biomarker tests predict how well a cancer might respond to specific treatments. For example, testing for mutations in the EGFR gene might be done in a patient with lung cancer. If an EGFR mutation is found, the patient may be treated with targeted therapies like erlotinib, specifically designed to inhibit the activity of the mutated protein. This approach can be more effective and less toxic than traditional chemotherapy because it targets the cancer cells more precisely.

Monitoring for disease recurrence

After a patient has completed treatment, biomarker tests can be used to monitor for signs that the cancer might be returning. For example, a patient treated for ovarian cancer might have regular blood tests to measure levels of CA-125, a protein that can be elevated when cancer is present. If CA-125 levels start to rise, this could indicate a recurrence of the cancer, prompting further testing or a change in treatment strategy.

Monitoring for metastatic disease

In patients with known cancer, biomarker tests can help track the spread of the disease to other parts of the body. For example, CEA (carcinoembryonic antigen) levels might be monitored over time in colorectal cancer. If CEA levels rise, it could suggest that the cancer has spread to other organs, such as the liver or lungs. This information can guide decisions about performing additional imaging tests or changing the treatment plan to address metastatic disease.

Risk stratification

Biomarker tests can also help classify patients into risk groups, guiding treatment decisions. For example, a test for PD-L1 expression might be performed in lung cancer. Patients with high PD-L1 expression might be more likely to respond to immunotherapy drugs like pembrolizumab. Knowing a patient’s PD-L1 status can help doctors decide whether to include immunotherapy in the treatment plan, potentially improving the patient’s chances of a successful outcome.

Are cancer biomarkers the same as precision medicine?

Cancer biomarkers and precision medicine are closely related but not the same. Precision medicine is a way of tailoring treatment based on the individual characteristics of each patient, which often includes using cancer biomarkers. While biomarkers provide specific information about the cancer, precision medicine uses this information to create a treatment plan that is more likely to work for that specific patient.

Do all cancer reports include biomarkers?

Not all cancer reports will include information about biomarkers. Whether biomarkers are included in your report depends on several factors, including the type of cancer you have, the stage of the disease, and the specific treatment plan being considered. In some cases, especially for early-stage cancers or cancers treated with surgery alone, biomarker testing may not be necessary. However, biomarker testing can be crucial in guiding treatment decisions for other cancers, particularly those that are more advanced or have specific characteristics. Your doctor will determine whether biomarker testing is appropriate based on your case.

How is cancer biomarker testing performed?

Several tests are available to identify cancer biomarkers, each suited to specific types of cancer and the particular biomarkers being assessed. The choice of test in your case will depend on the type of cancer you have and the information your doctor needs to guide your treatment. Understanding the various testing methods can help you better appreciate how your healthcare team is working to provide the most accurate diagnosis and effective treatment plan.

Immunohistochemistry (IHC)

Immunohistochemistry is a technique that uses antibodies to detect specific proteins in tissue samples. A small tumour sample is treated with antibodies that bind to the target protein, and a color change indicates the presence of the protein. This test is often chosen because it allows doctors to see exactly where the protein is located within the tissue, which can be important for diagnosing certain types of cancer. For example, IHC might be used to detect estrogen receptor (ER) expression in breast cancer, helping to determine whether the tumor is ER-positive and likely to respond to hormone therapy. In a pathology report, the results of IHC tests are usually described as positive or negative, sometimes with a percentage indicating the proportion of cells that show the protein.

Fluorescence in situ hybridization (FISH)

FISH is a technique that detects specific DNA sequences within cells using fluorescent probes that bind to those sequences. This test is often performed when there is a need to detect genetic abnormalities, such as gene amplifications, deletions, or rearrangements. For example, FISH might be used to detect ALK gene rearrangements in lung cancer, which can identify patients who may benefit from targeted therapies like crizotinib. FISH is selected over other tests when precise localization of genetic changes within the cells is important. Pathology reports often describe FISH results as positive or negative for the specific genetic change being tested.

Next-generation sequencing (NGS)

Next-generation sequencing (NGS) is a powerful technique that analyzes multiple genes simultaneously, identifying mutations, deletions, insertions, and other genetic changes across the genome. NGS is often chosen when a comprehensive genetic profile of a tumour is needed, especially in cancers where multiple genes may be involved. For example, NGS might be performed on a lung cancer sample to simultaneously identify mutations in EGFR, KRAS, and other genes. This comprehensive approach can guide treatment decisions by identifying all potential targets for therapy. In pathology reports, NGS results may include a list of the mutations found, with information about their possible impact on the cancer and treatment options.

Polymerase chain reaction (PCR)

Polymerase chain reaction (PCR) is a technique that amplifies specific DNA sequences, making it easier to detect mutations or other genetic changes. PCR is often used when testing for specific, known mutations, such as the BRAF V600E mutation in melanoma. PCR is chosen for its sensitivity and ability to detect small amounts of mutated DNA in a sample. In pathology reports, PCR results are usually positive or negative for the specific mutation being tested.

Cytogenetics/Karyotyping

Cytogenetics, including karyotyping, is the study of chromosomes in cells. Karyotyping involves staining chromosomes and examining them under a microscope to identify large changes, such as missing or extra chromosomes or structural abnormalities like translocations. This test is often used in blood cancers, such as leukemia, where chromosomal changes can have significant prognostic and therapeutic implications. For example, the presence of the Philadelphia chromosome in chronic myeloid leukemia (CML) can indicate the need for targeted therapy with drugs like imatinib. In pathology reports, cytogenetics results are typically described in terms of the specific chromosomal abnormalities detected, with details about how these abnormalities might influence the prognosis or treatment plan.

What types of cancers are tested for biomarkers?

Biomarker testing is essential in diagnosing and treating many types of cancer. While not all cancers require biomarker testing, certain cancers are more likely to be associated with specific biomarkers that can provide valuable information about the disease’s behavior and how it might respond to treatment. The following are examples of cancer types where biomarker testing is commonly used to help guide clinical decisions.

Breast cancer

Breast cancer is one of the most common cancers in women. Biomarkers commonly tested in breast cancer include ER (estrogen receptor), PR (progesterone receptor), and mutations in the BRCA1 and BRCA2 genes. For instance, patients with ER-positive breast cancer may benefit from hormone therapy that targets the estrogen receptor.

Lung cancer

Lung cancer is a leading cause of cancer-related deaths. Biomarker biomarkers like EGFR mutations, ALK rearrangements, and PD-L1 expression are commonly tested in lung cancer. These biomarkers help guide treatment with targeted therapies, such as erlotinib for EGFR mutations and pembrolizumab for high PD-L1 expression.

Colorectal cancer

Colorectal cancer is the third most common cancer worldwide. Biomarkers tested in colorectal cancer include KRAS, NRAS, BRAF mutations, and microsatellite instability (MSI). KRAS mutations, for example, can predict whether the cancer will respond to specific targeted therapies.

Ovarian cancer

Ovarian cancer is often diagnosed at an advanced stage. Biomarkers like CA-125 and BRCA1 and BRCA2 mutations are commonly tested. These biomarkers help guide treatment decisions and monitor for recurrence.

Prostate cancer

Prostate cancer is one of the most common cancers in men. PSA levels are routinely tested to screen for prostate cancer. Additionally, mutations in the BRCA1 and BRCA2 genes can provide information about the risk and prognosis.

Melanoma

Melanoma is an aggressive type of skin cancer. Biomarkers like BRAF and NRAS mutations are commonly tested. BRAF mutations, particularly the V600E mutation, can be targeted with drugs like vemurafenib.

Lymphoma

Lymphoma is an immune system cancer. Common biomarkers tested in lymphoma include the expression of proteins like CD20, CD30, and BCL2 and rearrangements in the MYC gene. These biomarkers can help determine the type of lymphoma and guide treatment.

Thyroid cancer

Thyroid cancer is generally a slow-growing cancer, but some types can be more aggressive. Biomarkers tested in thyroid cancer include BRAF mutations, RET/PTC rearrangements, and thyroglobulin levels. BRAF mutations, for example, are commonly found in papillary thyroid cancer.

Stomach (gastric) cancer

Stomach cancer is a significant cause of cancer mortality. Biomarkers tested in gastric cancer include HER2 expression, microsatellite instability (MSI), and PIK3CA mutations. HER2-positive gastric cancer may respond to targeted therapy with trastuzumab.

Pancreatic cancer

Pancreatic cancer is often diagnosed at a late stage and has a poor prognosis. Biomarkers like KRAS mutations, CDKN2A deletions, and SMAD4 loss are commonly tested. KRAS mutations, for example, are present in many pancreatic cancers and help guide treatment decisions.

Leukemia

Leukemia is a group of blood cancers that affect the bone marrow and blood. Biomarkers with prognostic or predictive value in leukemia include mutations in the FLT3, NPM1, and TP53 genes and chromosomal translocations like the Philadelphia chromosome in chronic myeloid leukemia (CML). These biomarkers help determine the type of leukemia, predict how aggressive the disease might be, and guide treatment.

Endometrial cancer

Endometrial cancer is the most common type of cancer of the uterus. Biomarkers commonly tested in endometrial cancer include microsatellite instability (MSI), mutations in the PTEN and PIK3CA genes, and expression of the estrogen and progesterone receptors. These biomarkers can provide important information about the type of endometrial cancer and guide treatment decisions.

Cervical cancer

Cervical is often linked to infection with human papillomavirus (HPV). Biomarkers tested in cervical cancer include HPV status, p16 protein expression, and mutations in the PIK3CA gene. HPV testing helps identify the presence of high-risk virus types that are associated with a higher likelihood of developing cervical cancer.

CNS (central nervous system) cancers

CNS cancers include a variety of tumours that occur in the brain and spinal cord. Biomarkers commonly tested in CNS cancers include IDH1/2 mutations, 1p/19q co-deletion status, MGMT promoter methylation, and histone H3 mutations. These biomarkers help classify CNS tumours and guide treatment strategies.

Bladder cancer

Bladder cancer is a common cancer that affects the urinary system. Biomarkers tested in bladder cancer include FGFR3 mutations, HER2 amplification, and PD-L1 expression. These biomarkers can help guide treatment, especially in advanced or metastatic disease.

Kidney cancer

Kidney cancer typically arises in the renal cortex. Biomarkers commonly tested in kidney cancer include mutations in the VHL, PBRM1, and BAP1 genes and PD-L1 expression. These biomarkers can help predict response to therapies, including immunotherapy.

Gastrointestinal stromal tumour (GIST)

Gastrointestinal stromal tumour (GIST) is a type of cancer that occurs in the digestive tract, most commonly in the stomach or small intestine. Biomarker testing in GIST often includes checking for mutations in the KIT gene, which are present in most cases. Identifying KIT mutations is essential because it helps guide treatment with targeted therapies such as imatinib, specifically designed to inhibit the abnormal protein produced by the mutated KIT gene.

Understanding your results

The results described in your pathology report will depend on the specific test or tests performed. These results can provide important information about the type of cancer, how aggressive it might be, and how it could respond to treatment. Understanding these results can help you and your healthcare team make informed decisions about your care. The following list explains some of the most common types of results and what they mean.

Mutation

Mutation refers to a change in the DNA sequence of a gene. Some mutations can cause cancer by making cells grow uncontrollably. For example, the BRAF V600E mutation is commonly found in melanoma.

Variant

Variant refers to a change in the DNA sequence of a gene that may or may not affect how the gene functions. Variants can be classified as benign (harmless), pathogenic (disease-causing), or of uncertain significance (meaning it’s not yet clear whether they are harmful). For example, a variant of uncertain significance might be found in a gene like BRCA1, meaning that more research is needed to determine if the variant increases the risk of cancer.

Deletion

Deletion means that a section of DNA is missing. Deletions can sometimes lead to cancer if they remove essential parts of a gene. For instance, deletion of the CDKN2A gene is often seen in pancreatic cancer.

Amplification

Amplification occurs when there are extra copies of a gene. Gene amplification can lead to the production of too much protein, which can drive cancer growth. An example is EGFR gene amplification in lung cancer, which can lead to overproduction of the EGFR protein.

Fusion

Fusion describes a situation where two different genes become joined together. This fusion can create a new, abnormal protein contributing to cancer development. An example is the BCR-ABL fusion gene in chronic myeloid leukemia (CML).

Rearrangement

Rearrangement refers to a change in the order of genes or pieces of genes. This can disrupt normal cell function and lead to cancer. For example, ALK gene rearrangement is often seen in certain types of lung cancer.

Loss

Loss indicates that a gene or part of a gene is missing. This loss can remove essential functions that generally prevent cancer. An example is the loss of the PTEN gene in various cancers, which can lead to uncontrolled cell growth.

Overexpression

Overexpression means that a gene is making too much of its protein. Overexpression of certain proteins can cause cancer cells to grow and spread. For example, overexpression of the MYC protein is commonly seen in some types of lymphoma.

Wild type

Wild type indicates that the gene is normal and has no mutations. Wild type means the gene is in its original, unaltered state. For instance, a KRAS wild type results in colorectal cancer, which means the KRAS gene has no mutations.

Common cancer biomarkers

There are thousands of cancer biomarkers, and new ones are being discovered daily. The biomarkers in your report will depend on many factors, including your medical history, known genetic conditions, and the specific type of cancer identified. Below is a list of the more commonly tested biomarkers and what they can reveal about cancer.

KRAS

KRAS is a gene that plays a critical role in regulating cell division. Normally, KRAS helps cells grow and divide in a controlled manner. However, mutations in KRAS can cause the gene to be constantly active, leading to uncontrolled cell growth and cancer. KRAS mutations are common in colorectal, lung, and pancreatic cancers. Numerous targeted therapies, such as sotorasib and adagrasib, have been approved to target KRAS mutations specifically.

NRAS

NRAS is similar to KRAS and is involved in cell growth and division. Normally, NRAS functions to help regulate cell growth and division. However, mutations in NRAS can lead to uncontrolled cell growth, particularly in melanoma and some blood cancers. There are limited targeted therapies for NRAS mutations, but research is ongoing to develop effective treatments.

EGFR

EGFR is a receptor protein that helps cells grow and divide. In its normal state, EGFR regulates cell growth. However, mutations in EGFR can cause cells to grow uncontrollably, leading to cancer. EGFR mutations are commonly seen in lung cancer, and targeted therapies such as erlotinib and gefitinib are used to treat cancers with these mutations.

ALK

ALK is a gene involved in the development of the nervous system. Normally, ALK helps regulate the growth and development of nerve cells. However, rearrangements in the ALK gene can lead to cancer, particularly lung cancer. Targeted therapies such as crizotinib and alectinib have been developed to treat cancers with ALK rearrangements.

ROS1

ROS1 is a receptor tyrosine kinase involved in cell growth. Normally, ROS1 helps regulate cell growth and survival. However, rearrangements in the ROS1 gene can lead to cancer development, especially in lung cancer. Targeted therapies such as crizotinib are effective in treating cancers with ROS1 rearrangements.

RET

RET is a gene that plays a role in cell signaling and growth. Normally, RET helps regulate various cellular processes, including growth and differentiation. However, mutations or rearrangements in the RET gene can lead to cancer, particularly in thyroid and lung cancers. Targeted therapies such as selpercatinib and pralsetinib treat cancers with RET alterations.

MET

MET is a receptor tyrosine kinase that plays a role in cell growth and survival. In its normal state, MET helps cells respond to growth signals. However, gene amplification or mutations in MET can lead to cancer, particularly in lung and kidney cancers. Targeted therapies such as crizotinib and capmatinib treat cancers with MET alterations.

BRAF

BRAF is a gene involved in sending signals inside cells that promote growth. Normally, BRAF helps regulate cell growth by transmitting signals from the cell surface to the nucleus. However, mutations in BRAF, especially the V600E mutation, can lead to uncontrolled cell growth and cancer. BRAF mutations are commonly seen in melanoma, colorectal, and other cancers. Targeted therapies such as vemurafenib and dabrafenib treat cancers with BRAF mutations.

Estrogen receptor (ER)

The estrogen receptor (ER) is a protein that binds estrogen, helping cells grow. Normally, ER is involved in regulating cell growth in response to estrogen. However, in ER-positive breast cancers, the presence of ER can drive cancer growth in response to estrogen. Targeted therapies such as tamoxifen block the estrogen receptor, preventing it from promoting cancer growth.

Progesterone receptor (PR)

The progesterone receptor (PR) is a protein that binds progesterone and is involved in cell growth. Normally, PR helps regulate cell growth in response to progesterone. However, in PR-positive breast cancers, the presence of PR can drive cancer growth in response to progesterone. Hormonal therapies such as tamoxifen also affect PR-positive cancers by blocking the hormone receptors.

HER2

HER2 is a gene that encodes a protein involved in cell growth and repair. Normally, HER2 helps cells grow and repair themselves. However, when the HER2 gene is amplified, it leads to overexpression of the HER2 protein, driving cancer growth. HER2 amplification is commonly seen in breast cancer. Targeted therapies such as trastuzumab (Herceptin) treat HER2-positive cancers by blocking the HER2 protein.

BRCA1 and BRCA2

BRCA1 and BRCA2 are genes that help repair DNA damage. Normally, these genes are involved in repairing DNA and maintaining genetic stability. However, mutations in BRCA1 or BRCA2 can increase the risk of breast, ovarian, and other cancers. PARP inhibitors such as olaparib are targeted therapies for treating cancers with BRCA mutations by exploiting the cancer cells’ inability to repair DNA damage.

PIK3CA

PIK3CA is a gene involved in cell growth and survival. Normally, PIK3CA plays a role in the signaling pathways that regulate cell growth. However, mutations in PIK3CA can lead to uncontrolled cell growth and cancer, particularly in breast cancer. Targeted therapies such as alpelisib are used to treat cancers with PIK3CA mutations.

NTRK

NTRK genes are involved in the growth of nerve cells and help regulate their growth and development. However, fusions involving NTRK genes can lead to the development of cancer in various tissues. Targeted therapies such as larotrectinib and entrectinib effectively treat cancers with NTRK gene fusions.

IDH

IDH genes encode enzymes that are involved in cellular metabolism. Normally, IDH enzymes help convert nutrients into energy for the cell. However, mutations in IDH1 and IDH2 can lead to the production of abnormal metabolites that contribute to cancer development, particularly in gliomas and some blood cancers. Targeted therapies such as ivosidenib and enasidenib are used to treat cancers with IDH mutations by blocking the activity of the mutated enzyme.

FGFR

FGFR genes encode proteins involved in cell growth and division. Normally, FGFR proteins help regulate various cellular processes, including cell growth and differentiation. However, mutations and fusions in FGFR genes can lead to uncontrolled cell growth and cancer, particularly in bladder cancer. Targeted therapies such as erdafitinib are used to treat cancers with FGFR alterations by inhibiting the activity of the FGFR protein.

PTEN

PTEN is a tumour suppressor gene that helps regulate cell growth by preventing cells from growing and dividing too rapidly. Normally, PTEN acts as a brake on cell growth, ensuring that cells divide only when necessary. However, loss of PTEN function can remove this regulatory control, leading to uncontrolled cell growth and cancer development. PTEN loss is seen in various cancers, and while there are currently no targeted therapies specifically for PTEN loss, its presence can influence treatment decisions and the overall approach to cancer management.

KIT

KIT is a gene that encodes a receptor tyrosine kinase, which plays a critical role in cell growth and differentiation. Normally, KIT helps regulate the development of specific cell types, including those in the gastrointestinal tract. However, mutations in the KIT gene can cause it to be constantly active, leading to uncontrolled cell growth and the development of gastrointestinal stromal tumours (GISTs). Targeted therapies, such as imatinib, effectively treat GISTs with KIT mutations by inhibiting the activity of the abnormal KIT protein.

PD-L1

PD-L1 (Programmed Death-Ligand 1) is a protein that plays a role in immune system regulation. Normally, PD-L1 helps protect healthy cells from being attacked by the immune system. However, in cancer, high levels of PD-L1 on tumour cells can help them evade the immune system by turning off immune cells that try to attack them. High PD-L1 expression is often associated with a better response to immunotherapy, as blocking the PD-L1 pathway can restore the immune system’s ability to target and destroy cancer cells. Drugs like pembrolizumab and nivolumab target PD-L1 in various cancers, including lung cancer.

Mismatch repair (MMR)

Mismatch repair (MMR) genes fix mistakes that occur during DNA replication. Normally, MMR genes help maintain the integrity of the genetic material by correcting errors in DNA. However, deficiencies in MMR can lead to microsatellite instability (MSI), which is associated with an increased risk of certain cancers, including colorectal cancer. Immunotherapy drugs such as pembrolizumab are used to treat cancers with MSI by enhancing the immune system’s ability to target cancer cells.

Tumour mutational burden (TMB)

Tumour mutational burden (TMB) refers to the number of mutations in a tumour’s DNA. A higher TMB often indicates that the tumour has many genetic changes, which can make it more recognizable to the immune system. Tumours with high TMB are usually more responsive to immunotherapy, as the increased number of mutations makes it easier for the immune system to identify and attack the cancer cells. Immunotherapies such as pembrolizumab are used to treat cancers with high TMB.

Summary

Understanding the role of biomarkers in cancer can provide valuable insights into your pathology report and treatment plan. Biomarkers are powerful tools that help doctors tailor treatments to your specific condition, offering a more personalized approach to cancer care. While not all reports will include biomarker information, knowing what they are and how they are used can help you make more informed decisions about your health. If you have any questions about the biomarkers in your report, don’t hesitate to ask your healthcare team for further clarification.

Have a question about this article? Contact us.