Biomarkers are substances found in blood, other body fluids, or tissues that signal the presence of absence of a condition or disease, such as cancer

The current trend in cancer care is personalized medicine, in which treatment programs are individualized to provide the best care for you based on certain biological characteristics you have.

Two events that have made this trend possible are the discovery of biomarkers and their offspring targeted therapies. Biomarkers are substances found in blood, other body fluids, or tissues that signal the presence of absence of a condition or disease, such as cancer. They can also be used in monitoring patients to determine whether a disease is progressing, the effect of treatment, and the toxicity of treatment.

Targeted therapies are treatments that work on a molecular level to stop a cancer from growing or spreading. These therapies may block certain growth factors the allow a tumor to progress, or interfere with substances in the body that lead to the development of blood vessels that supply a tumor (tumors need a blood supply in order to survive and grow).

How Biomarkers Work

Biomarkers can be used to

• develop targeted therapies,
• predict risk for cancer,
• help screen for cancers,
• forecast how well a person is likely to respond to a cancer treatment, or
• monitor the patient.

For example, cholesterol, a fatty substance produced by the body, is a biomarker for heart disease. A doctor can take a blood sample and determine your cholesterol levels to predict your risk for having a heart attack. If your doctor puts you on an anticholesterol medication, your cholesterol can be measured in a follow-up appointment to determine whether the medication is working; that is, whether it has lowered your cholesterol and reduced your risk for having a heart attack.

Biomarkers are used in the same way to manage cancers.

Role of Biomarkers in Cancer

In cancer, “a biomarker is a substance above and beyond routine testing that gives some insight into how the cancer is behaving now or will behave in the future,” says Daniel F. Hayes, MD, Clinical Director of the Breast Oncology Program and Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor. Hayes has been researching biomarkers for much of his career.

Some biomarkers are in the cancer or made in normal tissue by the cancer to help it grow and spread. The human body makes other biomarkers to facilitate everyday body function. Each one is different and each does a different thing.

“There are hundreds of different cancers. There are hundreds of biomarkers, and there are many ways to use them. How they are used depends on the patient, it depends on the biomarker, and it depends on the cancer,” Hayes says. “You might use biomarkers to determine risk, to screen, to do differential diagnosis, to do prognosis, to do predictions and to do monitoring.”

Someday, biomarkers may be the key not only to cancer treatment and cure, but also to the management of other diseases. Right now, they are used to help manage specific cancers.

Targeted Therapies

With targeted therapy, the treatment targets a particular biological substance (the biomarker) to stop the cancer or prevent it from spreading. Two such therapies are trastuzumab and lapatinib. They target the HER2 biomarker in women who have HER2-positive breast cancer. These targeted therapies will not work in women who do not have the biomarker, even if they have breast cancer.

Another well-known targeted therapy is imatinib, which treats certain types of chronic myloid leukemia and gastrointestinal stromal tumors. Imatinib targets two biomarkers that are abnormal proteins: BCR-ABL kinase and Kit. By targeting these two abnormal proteins, imatinib slows the growth of cancer in some patients.

Predicting Hereditary Risk

Some biomarkers are inherited, and these are called germline biomarkers. Germline biomarkers can be used to predict a person’s risk of getting a particular cancer and can indicate what treatment might help put that cancer in remission.

For example, two germline biomarkers that are inherited are the genes BRCA1 and BRCA2. The proteins made by BRCA1 and BRCA2 stabilize the cell’s genetic material or DNA and help prevent uncontrolled cell growth. These normal actions inhibit, or suppress, the growth and appearance of new cancers. Therefore, when they function normally, they are called “tumor suppressor” genes.

However, some people inherit an abnormal or mutated BRCA1 or BRCA2 gene that does not function correctly. People with these abnormalities are more likely to develop cancers, since the tumor suppressor properties of the genes are not working properly.

It is important to realize that not all mutated genes are harmful. Some gene mutations or changes may be beneficial, while others don’t do anything. However, harmful mutations can increase a person’s risk of developing cancer.

A woman who inherits a harmful BRCA1 or BRCA2 mutated gene (which can be passed on from either her mother or her father) has a higher risk of developing breast or ovarian cancer than a woman who does not inherit a harmful mutation. Harmful BRCA1 mutations may also increase a woman’s risk of developing cervical, uterine, pancreatic, and colon cancer, whereas harmful BRCA2 mutations may also increase risk for pancreatic cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma (a type of skin cancer).

Men can also inherit abnormal BRCA1 or BRCA2 genes. Those who inherit a harmful BRCA1 or BRCA2 mutation are more likely to develop breast, pancreatic, testicular, or prostate cancer, although they are not nearly as likely to develop breast cancer as women who inherit abnormal BRCA1 or BRCA2 genes.

These genes are used as biomarkers in the clinic to determine if selected people are at very high risk for developing breast and ovarian cancer.

That does not mean that everyone who has one of these biomarkers will get one of these cancers. We all have other tumor suppressor genes, and more than just one abnormality is needed to develop a new cancer. Therefore, having an abnormal BRCA1 or BRCA2 gene increases susceptibility, but it does not guarantee that you are destined to get a new cancer. It simply means that those who carry that biomarker are at a higher risk for getting one of these cancers than someone without the genetic mutation.

If a woman has inherited an abnormal BRCA1 or BRCA2 gene, she may undergo more aggressive screening for breast or ovarian cancer than another woman her age who does not have these abnormal genes. She might elect to pursue preventive strategies, such as using a selective estrogen receptor modulator (SERM), or having her ovaries removed, or even having her breasts removed prophylactically.

Cancer Screening

One of the ultimate and desired goals of cancer management is early detection. In many cases, the earlier a cancer is detected and treated, the better the patient’s chances of recovery. Developing biomarker tests that could detect cancers early is a major area of research.

One test that the FDA has approved for cancer screening is the prostate-specific antigen (PSA) test, which is used along with a digital rectal examination to detect prostate cancer in men aged 50 years and older. However, although PSA screening has been widely applied in North America, the clinical value of doing so has been brought into question recently by the results of two large trials that failed to demonstrate a substantial reduction in prostate cancer mortality in men who were screened compared with those who were not.

Companies are trying to develop biomarker screening tests for many different cancers, including colon and bladder cancers, but these are not available yet.

Because cancers can spread (metastasize) from one organ to another, screening biomarkers might be used to tell the type of cancer a person has, which might alter its treatment.

For instance, if a woman has a lung tumor, especially if she is a non-smoker, she is more likely to have breast cancer than lung cancer. Therefore, an oncologist might test that tumor for the HER2 or estrogen-receptor (ER) biomarkers that can be present in breast cancer. Then her cancer would be treated with a breast cancer drug, rather than a lung cancer drug, even though the cancer appeared in her lung.

Forecasting

Another way to use biomarkers is to determine a patient’s prognosis after initial treatment for a cancer. Prognosis helps doctors decide if a patient needs more therapy at that time.

“Let’s say that you have a basal cell skin cancer on your hand, and that cancer is excised (removed). You have a 0% chance of that cancer coming back,” says Hayes, “You would not need more therapy.”

However, patients with newly diagnosed breast cancer who are found to have involvement of the lymph nodes in their armpit have a very high chance of developing what are called metastases (meaning the breast cancer comes back in other organs, like bone or liver or lung) in the next few years. Many more patients are cured if they receive additional (called “adjuvant”) therapy right away rather than waiting for metastases to occur. In this case, the doctor would suggest additional therapy.

Biomarkers can also be predictive factors. “A predictive marker is one that will predict whether a therapy will work,” Hayes adds. “Breast cancer is a great example. ER-negative patients do not benefit from anti-estrogen therapy like tamoxifen or aromatase inhibitors, but many ER-positive patients are likely to benefit from anti-estrogen therapy. Therefore, an oncologist will not recommend that type of therapy for ER-negative patients, but will recommend it for ER-positive patients.”

Monitoring

The final area that biomarkers are used is for monitoring patients. The PSA test is also used to monitor how well the patient is responding to treatment.

“With prostate cancer, when PSA goes up, people are doing worse; when PSA goes down, they are getting better,” Hayes says. “Likewise, doctors use other blood tests to monitor patients with other cancers, such as CA125 for ovarian cancer, CEA for colorectal cancer, CA19-9 for pancreas cancer, and CA15-3 or CA27.29 for breast cancer.”

Oncologists might use biomarkers to monitor patients in the beginning of treatment to see if the treatment is working. Biomarkers may also be used to monitor patients in remission to make sure they stay in remission, and to allow oncologists to respond quickly if the cancer recurs.

Today and Tomorrow

You should make sure your biomarker tests are processed in a laboratory that is accredited by the College of American Pathology (CAP) to ensure that the proper procedures were followed. Ask your oncologist where the tests will be performed and find out if that laboratory is CAP-approved or sends their biomarker samples to a CAP-approved facility for testing. It is important to note that all laboratories are CLIA-approved, but that just certifies them to perform any test; it does not mean they are proficient at biomarker testing.

“I think the single most important thing for a cancer patient to know about biomarkers is that the biomarker [tests] that should be done are done correctly,” Hayes says.

The results are important because oncologists use them to develop treatment strategies. For instance, if a woman has breast cancer and she is HER2-positive, she might receive trastuzumab. That drug would not be given to a HER2-negative patient.

“If you have a biomarker test that says she is HER2-positive, and it is wrong, you have exposed the woman to a year’s worth of intravenous chemotherapy every 3 weeks that she did not need. You have exposed her to the potential side effects of trastuzumab,” Hayes cautions. “And you’ve exposed her insurance company to about $100,000,” he adds.

“On the other hand,” Hayes continues, “if you don’t treat a patient who has HER2-positive breast cancer, you have denied her a chance to improve her odds of being cured by as much as 50%.”

Biomarkers have changed the way doctors handle many cancers, but there is still a long way to go before biomarkers reach their full potential in cancer management. Researchers like Hayes are working hard to bring these little miracle molecules into the clinic.