Personalized Cancer Treatment
Importance of Biomarkers in Personalized Cancer Treatment
 Biomarkers help doctors know more about an individual person’s tumor, allowing them to make better, more informed decisions about treatment options. Thus, the identification of biomarkers is the first step in personalizing cancer treatment. Biomarkers are grouped according to their type — protein and genetic — and function — screening, diagnostic aid, determining prognosis, guiding treatment, monitoring response to treatment and detecting recurrence or progression. Each function, except screening, has a role in personalizing cancer therapy (Table 1).
Table 1. Classification of Cancer Biomarkers By Function
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Screening |
Most tumor markers are not useful for screening; only 1 tumor marker (prostate-specific antigen [PSA]) is used for screening, and its value in detecting prostate cancer has been heavily debated. |
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Diagnostic Aid |
Tumor markers can add to the information about the molecular features of a tumor, helping to define its molecular subtype. |
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Determine Prognosis |
Some tumor markers are factors considered when determining prognosis, or a prediction of the outcome. |
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Guide Treatment |
Some tumor markers can provide information about what types of treatment are more or less likely to be effective. |
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Monitor Response to Treatment |
Tumor markers can monitor the effectiveness of treatment, especially for advanced cancers. |
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Detect Recurrence or Progression |
Some tumor markers can indicate that cancer has recurred or progressed; if the level of a tumor marker is elevated before treatment, is low after treatment, and then begins to increase after treatment, it is likely that cancer is recurring or progressing. |
Types of Biomarkers
Protein Biomarkers
Protein biomarkers include substances that are either produced by cancer cells themselves or by other cells in response to cancer. Most protein biomarkers related to cancer are used to monitor response and/or detect recurrence or progression during follow-up after treatment (Table 2). Some biomarkers are used to predict the outcome, or prognosis.
Your doctor may use a protein biomarker in combination with clinical information gained from blood tests and imaging studies (such as x-ray, computerized tomography [CT] or magnetic resonance imaging [MRI]) to see if the tumor is responding to treatment. If the tumor has not shrunk, more treatment or a different drug may be needed. Biomarkers can often be detected in the blood before changes in the size of the tumor can be detected on imaging studies, which means that new treatment can be started earlier, increasing the chance it will be effective.
When used to detect recurrence or progression, protein biomarkers help personalize treatment by giving your doctor more information to consider when determining which treatment option is best for your individual level of risk.
Biomarkers that help determine prognosis are useful in personalizing treatment: If the prognosis is poor according to biomarker testing and clinical features (such as stage of disease), it may be best to begin treatment with a more aggressive approach than that used when the prognosis is good.
One example of a protein biomarker is carcinoembryonic antigen (CEA). This biomarker, which has been used since the 1970s, is valuable because it serves several functions. Measuring the CEA level in the bloodstream is recommended for monitoring colorectal cancer to detect recurrence or metastasis after treatment. Testing for CEA levels is also recommended for monitoring the response of metastatic colorectal cancer to chemotherapy. In addition, CEA can help determine prognosis in colorectal cancer; a high level at the time of diagnosis may mean that cancer is metastatic.
Some biomarkers in the protein category are used to help guide treatment decisions. Among the most well-known biomarkers to guide treatment are estrogen receptor (ER) and progesterone receptor (PR), which have made a substantial impact on the treatment of breast cancer. These biomarkers will be discussed later (see Biomarkers + Targeted Therapy, Breast Cancer section)
Table 2. Protein Biomarkers According to Type of Cancer
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Tumor Marker |
Type of Sample |
Function |
Use |
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Breast Cancer |
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CA (cancer antigen) 15-3 or CA 27.29 |
Blood |
Monitor response |
May be used to monitor response to treatment in conjunction with diagnostic imaging, history and physical examination. |
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CEA (carcinoem-bryonic antigen) |
Blood |
Monitor Response |
May be used to monitor response to treatment in conjunction with diagnostic imaging, history and physical examination. |
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ER/PR (estrogen receptor)/(progesterone receptor) |
Tissue |
Guide treatment |
Experts recommend that the ER/PR status be determined at the time of diagnosis for all primary invasive breast cancers. The presence of these hormone receptors identifies tumors that are most likely to respond to hormone therapy (such as tamoxifen). |
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uPA (urokinase-type plasminogen activator), PAI-1 |
Tissue |
Determine prognosis
Guide Treatment
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Experts recommend using this test to determine prognosis in newly diagnosed disease that has not spread to lymph nodes. Low levels indicate low risk of recurrence in ER/PR-positive breast cancer.
May be used to determine risk and need for adjuvant chemotherapy. Low level (low risk) indicates that woman will have minimal benefit from chemotherapy.
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Colorectal Cancer |
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CEA |
Blood |
Determine prognosis
Monitor response
Detect recurrence/
progression
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Experts recommend determining the level during initial work-up: high level before treatment may indicate cancer is metastatic.
Experts note that CEA is marker of choice for monitoring metastatic colorectal cancer during chemotherapy.
Experts recommend CEA testing during follow-up of nonmetastatic disease to detect recurrence or metastasis.
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Liver Cancer |
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AFP (alpha-fetoprotein) |
Blood |
Aid diagnosis
Detect recurrence/progression
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Level should be determined at initial work-up: very high levels can indicate liver cancer (but high levels can be increased in other noncancerous conditions).
Level should be measured throughout follow-up if it was initially elevated.
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Melanoma |
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LDH (lactate dehydrogenase) |
Blood |
Determine prognosis |
Level should be determined at initial work-up: level is a factor in determining the stage of disease. Level is measured throughout follow-up of stage IV disease (metastatic melanoma): high level is predictor of poor prognosis. |
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S-100 |
Blood |
Detect progression |
Evidence is currently insufficient to recommend its use, but level is elevated in most individuals with metastatic melanoma. |
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Multiple Myeloma |
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Beta-2-microglobulin |
Blood |
Determine prognosis
Detect progression
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Level should be determined at initial work-up: level is factor in determining stage of disease.
Level should be measured throughout follow-up: high level indicates high tumor burden (poor prognosis).
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Ovarian Cancer |
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CA-125 |
Blood |
Aid diagnosis
Detect recurrence/
progression
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Level should be determined at initial work-up (if symptoms suggest ovarian cancer).
Level should be measured throughout follow-up.
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Pancreatic Cancer |
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CA 19-9 |
Blood |
Determine prognosis
Monitor response
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Level should be determined at initial workup: high level is associated with poor prognosis.
Level may be measured to monitor response during active treatment for locally advanced metastatic disease; if level increases after treatment, imaging studies and/or biopsy are done to confirm recurrence. (Decreased level after surgery or chemotherapy indicates better survival.)
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Prostate Cancer |
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PSA |
Blood |
Screening
Aid diagnosis
Detect recurrence/
pregression
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Usefulness of PSA as screening tool is debated, as the level is elevated in benign conditions of the prostate.
Level should be determined at initial work-up: level is factor in determining stage of disease.
Level is measured throughout follow-up.
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Testicular Cancer |
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AFP |
Blood |
Aid diagnosis |
Level is determined at initial work-up; level is a factor in determining stage of disease. |
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hCG (human chorionic gonadotropin) |
Blood/urine |
Aid diagnosis |
Level is determined during initial work-up: level is a factor in determining stage of disease. |
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LDH |
Blood |
Guide Treatment |
More aggressive treatment is recommended if elevated levels persist. |
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Thyroid Cancer |
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Thyroglobulin |
Blood |
Detect recurrence/
progression |
Level is measured throughout follow-up. |
Genetic Biomarkers
Several genetic alterations have become biomarkers because they are linked to the development of cancer. Genetic biomarkers offer the most benefit in guiding treatment decisions (Table 3). A genetic biomarker is sometimes referred to as a pharmacogenetic marker because it affects the response or resistance to a drug. Again, one of the most well-known examples of a genetic biomarker is found in the setting of breast cancer: the HER2 gene. The development of drugs designed to attack tumors with a higher level of this gene changed the treatment of breast cancer. This biomarker also will be discussed later (see Biomarkers + Targeted Therapy).
Table 3. Some Genetic Biomarkers Used to Guide Treatment
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Gene |
Genetic Mutation |
Type of Cancer |
Use |
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ABL, BCR |
Translocation |
Chronic myeloid leukemia |
Aids in diagnosis and guides treatment decision; testing done routinely, as it is associated with response to specific targeted therapy; found in almost all cases |
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BRAF |
Mutation |
Malignant melanoma |
May help to determine response to targeted therapy; testing should be done for people who may be eligible for clinical trials of targeted therapy |
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EGFR |
Mutation, amplification |
Non-small cell lung cancer |
Helps guide treatment decisions, as it determines response to some targeted therapy; routine testing has started in many cancer centers; found in up to 50% of cases |
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EML4-ALK |
Translocation |
Non-small cell lung cancer |
Found in about 2%-13% of cases; testing should be done for people who may be eligible for clinical trials of targeted therapy |
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HER2 |
Amplification |
Breast cancer |
Guides treatment decisions, as appropriate treatment depends on results; routine testing highly recommended; found in about 20% of cases |
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KIT |
Mutation |
Gastrointestinal stromal tumor (GIST) |
Aids in diagnosis and guides treatment decisions; testing recommended; found in about 80% of cases |
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KRAS |
Mutation |
Colorectal cancer
Non-small cell lung cancer
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Helps guide treatment decisions, as it is associated with lack of response to some targeted therapies; testing recommended; found in about 40% of cases
Helps guide treatment decisions, as it is associated with lack of response to some targeted therapies; testing recommended; found in about 25% of cases
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MMR |
Mutation |
Colorectal cancer |
Helps guide treatment decisions, as it is associated with good prognosis; testing recommended for some patients; found in about 15%-20% of sporadic cases |
Limitations of Biomarkers
Biomarkers are becoming increasingly valuable in treating cancer, but they have limitations. For example, many protein biomarkers are not cancer-specific; that is, conditions other than cancer may cause a protein biomarker to be present or be at a higher level. As a result, other tests may be needed to confirm the results. If no cancer is detected on these tests, the biomarker result is said to be false-positive. In addition, the levels of some biomarkers are not high in all patients with a particular cancer; if other tests detect cancer in a person with no evidence of a biomarker, the biomarker test result is said to be false-negative. The rate of either false-positive or false- negative results for a biomarker test determines how reliable the test is.
Changes in genes and in how genes are regulated may serve as biomarkers and are usually more reliable than many protein biomarkers, but genetic changes have not yet been identified for every type of cancer. Also, testing for some genetic biomarkers is limited by the availability of laboratories that have the equipment needed to perform the testing.
It is also important to note that many genetic changes in cancer are just being identified, and their discovery alone does not mean that testing for the change should be done. Testing is useful only after large studies have shown that the genetic change is a factor in making treatment decisions. The impact of the identification of genetic changes on personalized cancer therapy is described in Biomarkers + Targeted Therapy.
How Is Biomarker Testing Done?
Protein biomarker levels are usually determined by analyzing a blood specimen, which is typically obtained through a vein in the arm. Testing is done on the serum, the watery liquid that separates from the blood. Test results are sometimes reported as positive or negative, based on the presence or lack of the biomarker, or as a specific number to indicate a level. Testing on urine samples are done in a similar manner.
When the specimen is tissue, testing can be done to identify the specific genetic mutation and to measure its expression — that is, the amount or level found. Because genes help build proteins, testing can also be done to measure the level of the protein product of the gene. For example, with breast cancer a tumor can be examined for the presence of the HER2 protein or the HER2 gene.
Testing for single genetic mutation biomarkers can be done using several methods. With some tests, pathologists can examine the whole chromosome to look for abnormalities. Sophisticated methods have been developed for studying more than one gene at a time in a specimen. Experts can now define tumors more precisely by analyzing its tissue for several different types of mutations in a number of genes. This type of testing, known as genetic profiling, provides a genetic “fingerprint” or “signature” that is unique to an individual tumor. Genetic profiling has just begun for some types of cancers, mostly at large cancer centers (see Mapping the Genetics of Cancer below).
Researchers have identified some specific genetic signatures that are related to a greater chance of recurrence or metastasis of certain types of cancer. A test known as gene expression profiling can be done on some types of cancers to see if a tumor has the identified signature. Knowing if there is a higher risk of recurrence or metastasis is important for choosing treatment plans in some cases. The use of gene expression profiling is currently limited to two cancers — breast and colorectal cancer — and the results are used in combination with the findings of other tests. The use of gene expression profiling will be discussed later (see Biomarkers + Targeted Therapy).
Because the treatment of your cancer often depends on the results of biomarker testing, it is important that the tests be carried out by approved methods at accredited facilities. You should talk to your doctor about the accuracy of your biomarker testing results and whether testing should be repeated to confirm the results.
Talking to Your Doctor About Biomarkers
You should openly discuss your questions and concerns about biomarkers with your doctor or another member of your health care team. If you understand the information about biomarkers and their value, you will have confidence in your diagnosis and you will be able to help make decisions about how your cancer is treated. It is always a good idea to write down your questions before speaking with your doctor so that you have them in hand and can readily recall the questions that are important to you.
Questions You Might Want to Ask Your Doctor About Biomarkers:
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Does having a biomarker mean I have a specific cancer or that cancer will develop?
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Is there only one biomarker associated with my type of cancer?
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Can biomarkers be inherited?
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Are there other health problems or medicines that could affect my biomarker levels?
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How is testing done to find biomarkers related to my type of cancer?
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Are there false-positive and false-negative results of biomarker testing?
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Does finding a biomarker affect my treatment?
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Will I need repeated testing for biomarkers?
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Does the absence of a biomarker mean my cancer is gone?
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What is a subtype of a cancer?
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Does the presence of a biomarker predict my prognosis?
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Can testing for a biomarker tell me if my treatment is working?
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How much does testing for biomarkers cost and will my insurance pay for it?
Words to Know
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Biobank |
Collection of biologic material (such as tumor tissue or blood specimens) and the associated data and information stored in an organized system, for a population or a large subset of a population (such as people with cancer); also known as a biorepository |
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Biomarker |
A specific substance in the body that can be measured and may indicate the presence of cancer |
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Biospecimen |
Sample from a living thing; for example, tissue or blood |
Mapping the Genetics of Cancer
The Human Genome Project, a 13-year undertaking to map the entire sequence of human DNA, was completed in 2003. The project led to the discovery of more than 1,800 genes associated with disease (all types) and has helped researchers to develop more than 2,000 genetic tests for human disorders. An outgrowth of the Human Genome project is the Cancer Genome Atlas, which is designed to identify all the genetic abnormalities in 20 major types of cancer. This Atlas includes thousands of tumor samples that have been collected from cancer centers across the United States and allows researchers to examine the tumors to look for genetic patterns that can help classify more types of cancer into molecular subtypes and to develop drugs targeted to specific genetic profiles. The other benefit of the Atlas is that as new drugs are developed, doctors can easily find people who have tumors with specific genetic features to join clinical trials that offer the most advanced treatment.
One of the first studies to be conducted with samples from the Cancer Genome Atlas found four distinct molecular subtypes of gliobastoma multiforme, the most common form of malignant brain cancer in adults. Before the discovery of these subtypes, glioblastoma multiforme was considered to be a single cancer type. The researchers of the study also found that response to aggressive chemotherapy and radiation therapy differed according to molecular subtype. The study is the first step toward creating personalized treatment plans for people with gliobastoma multiforme based on the specific molecular subtype of their tumor.
“Personalized cancer medicine isn’t going to be a reality for everyone tomorrow,” says Anna Barker, PhD, former Deputy Director of the NCI. “But we want to get to the point where we can perhaps treat cancers as chronic diseases, and hopefully cure some outright based on the knowledge we are building. In an era of personalized cancer medicine, cancer could become a disease you live with successfully as opposed to dying from it.”
The Cancer Genome Atlas is a collaboration between NCI and the National Human Genome Research Institute.
Tissue, Please
The success of research to find more effective cancer treatments depends on the willingness of people with cancer to donate tissue samples. Efforts such as the Cancer Genome Atlas rely on the donation of tumor specimens.
“People who donate tissue specimens help physicians make better treatment decisions and also help others a great deal in the future, as the specimens are used to help design more effective drugs,” says Jeff Allen, PhD, Executive Director of Friends of Cancer Research.
New biomarkers and genetic profiles are constantly being discovered. If a sample of your tumor is stored in a biobank such as the Cancer Genome Atlas, your information can be accessed if a clinical trial for your type of tumor becomes available. This would give you an opportunity to be treated with the latest targeted therapy.
If you are scheduled for biopsy or surgery, you may be asked if you would consider donating a tissue specimen (also known as a biospecimen) for research. If you express interest, you will be given a brochure that describes the process and you will be asked to sign a consent form. No specimens will be taken for research purposes unless you sign a consent form. Your care will be the same regardless of whether you donate tissue. If you donate tissue, it will be labeled with a random identification number to protect your privacy.
If your doctor does not ask you about donating tissue, ask him or her if this is possible. Cancer research depends on it.
Additional Sources of Information
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