BiomarkersPersonalized Medicine

What Are Biomarkers and Precision Medicine in Oncology? An Interview with W. Michael Korn, MD

Understanding the specific biomarkers associated with each patient’s cancer helps to select the best therapy that targets that unique biomarker to improve the chance of survival for that patient.
May 2020 – Biomarkers & Genetic Testing
W. Michael Korn, MD

Dr. Korn is Chief Medical Officer, Caris Life Sciences, and Professor of Medicine, Division of Hematology/Oncology at the University of California, San Francisco.

Precision medicine in cancer is an approach to medicine that uses tailored treatment for the individual patient based on the specific disease characteristics that are unique for each patient. This approach recognizes that each patient is medically different, and that the way the disease is manifested in the patient is also different.

The idea behind precision medicine is that by matching a treatment to a patient’s individual characteristics, we can optimize the use of best available therapies. By using this method, we can achieve better outcomes, reduce the side effects of treatment (or the treatment toxicity), and this can often result in overall lower costs.

Researchers have now identified molecular features or biologic markers (biomarkers) that are specific to some cancer types that make the disease particularly sensitive or resistant to certain treatments.

By knowing the unique biomarkers of a person’s cancer, oncologists can now match that patient to the treatment that has the greatest chance of improving the outcome, or even provide a cure.

How Does Precision Medicine Help a Cancer Diagnosis?

Typically, a cancer diagnosis is made by a pathologist who looks through a microscope at sections of tissue and interprets certain features of that tissue. But now, we can make a more precise diagnosis by using molecular features (or biomarkers) to understand subtypes of disease that we can’t distinguish with a microscope.

For example, we now know that there are many subclasses of colon cancer. If a patient with colon cancer has a mutation in a gene called BRAF, this will affect the course of treatment for that patient, as well as the prognosis (or likely outcome) of the disease.

There are also situations where the pathologist cannot make a diagnosis. For example, carcinoma of unknown primary site is a rare disease in which cancer cells are found in the body, but the place that the cancer began is not known.

By performing molecular analyses (or next-generation sequencing analysis), in many cases we can now identify where that patient’s cancer began.

What Are Cancer Biomarkers?

Biomarkers are biologic features (markers) that are part of the tumor that help to guide treatment, when treatment related to that specific marker is available.

In the past few decades, drug manufacturers have been focused on developing drugs that specifically target those tumor biomarkers to improve the success of therapy. Therefore, understanding cancer biomarkers plays a key role in finding the best treatment for each patient.

Some biomarkers are expressed as gene changes (mutations) in the person’s DNA, some are expressed in the RNA (RNA is transcribed, or copied, from the DNA), and others are changes in the cell’s protein levels. We use these 3 types of biomarkers to make the best treatment decisions for patients.

It is very important for patients to understand what clinically relevant biomarkers are currently known in the specific type of cancer they have, the best way to test for those biomarkers, and what it means if the cancer has a biomarker (positive) or does not (negative).

An example is the HER2 gene amplification in breast cancer. When a patient has the HER2 gene amplification, that patient has HER2-positive breast cancer and it is standard of care to use drugs that specifically target this molecular feature.

Biomarker Testing

One way to identify biomarkers is through genetic testing. Genetic testing involves tests that examine the patient’s DNA that they inherited from their parents, which is called “germline” DNA. If the germline DNA includes any abnormalities, some of these inherited abnormalities (or biomarkers) will affect the patient’s course of treatment.

For example, in pancreatic cancer (which is still very difficult to treat), if the patient’s germline DNA has a mutation in the BRCA gene, that knowledge can guide a tailored treatment for that specific gene mutation to increase the chance for an improved outcome.

Another way of finding biomarkers is by looking at the DNA of the tumor itself. The DNA is the molecule that holds all the information needed to make a cell and a human being. It is present in every cell, and in the case of cancer, changes to its content lead to abnormal cells, which don’t follow common rules and make up the malignant tumor. So, by looking at DNA changes or mutations, we can learn a lot about the individual patient’s cancer and how best to treat it.

How Should I Ask My Doctor About Genetic Testing?

First, ask your doctor whether your cancer has any potential of an inherited component. Simply ask, “Do I need germline testing of my DNA?” This information is important to you and to your family, because other family members may have the same DNA mutations that you have, which are inherited from parents or grandparents.

However, most cancers are not inherited, so it’s always advantageous to know what is going on in the DNA of the tumor itself. Cancer cells get “addicted” to specific mutations, so we can exploit that therapeutically by using the drugs that specifically target those mutations. Therefore, you should also ask your doctor if any information can be gathered from analyzing the DNA in your tumor. The goal is to identify any biomarkers that could affect how your treatment will be determined.

The classic example of this is EGFR mutation in lung cancer. Lung cancer cells are so-called addicted to EGFR mutations, so if we treat these patients with a drug that blocks EGFR (known as EGFR inhibitor), we can induce very dramatic responses that last a long time.

A recent example of an EGFR inhibitor is Tagrisso (osimertinib), which is used in patients with lung cancer that is associated with EGFR mutations.

It’s extremely important to have a strategy that can best treat the cancer of each individual patient, so this discussion with the doctor should occur at the time of diagnosis.

Many cancer types—such as breast, stomach, colorectal, brain, melanoma, and lung cancer— now have several very well-established biomarkers and drugs that target those biomarkers, and even more drugs are now in development for the biomarkers in different cancers.

Biomarkers Can Help to Find the Best Treatment for You

The essential principle of precision medicine was first applied in breast cancer. The amplification of the HER2 gene is an important therapeutic target in breast cancer. In the late 1990s, the drug Herceptin (trastuzumab) was shown to prolong the life of a woman with breast cancer if she had HER2 gene amplification (HER2-positive), but not if she didn’t have the HER2 gene (HER2-negative). This is a classic example of how precision medicine and biomarkers can help improve outcomes for patients with cancer.

An inherited mutation in the BRCA gene is probably even better known among patients and family members of those with some types of cancer, especially those with breast or ovarian cancer. Put simply, if a patient has an inherited BRCA1 or BRCA2 mutation, she has a massively increased risk of having breast or ovarian cancer, in addition to many other types of cancers.

Because a mutation in one of the BRCA genes is inherited from a parent, it is important for people to know their BRCA status, so that those with a family member who has a BRCA-positive status can be enrolled in prevention and surveillance programs. This makes it possible to diagnose cancer at an early stage, if it occurs, which increases the chance of recovery and cure.

However, if the molecular profiling testing reveals that the patient with a BRCA mutation already has cancer, especially if that cancer is at an advanced stage, there are now some exciting non-chemotherapy strategies, known as targeted therapies, that directly treat the cells that harbor this mutation. This type of treatment leads to the death of cancer cells but does not affect healthy cells.

Is Precision Medicine More Expensive?

The simple answer is “no.” The fear is that if we start performing all these analyses and molecular tests, we’ll drive up the cost of cancer care. However, we know from scientific studies that exactly the opposite is true.

For example, if we perform a systematic analysis of the molecular composition of a patient’s lung cancer, we can very quickly figure out the best therapeutic target for that disease. This allows people to live longer and, because they don’t have to constantly go to the emergency department for complications, they don’t have immediate disease progression, which results in lower healthcare costs. By being more precise in our treatments, we in fact reduce the overall healthcare costs to patients as well as to the healthcare system.

Important Differences in Genomic Testing

It is very important for patients with cancer to understand that there are technological differences in molecular testing, and that those differences can affect their survival.

One example of these technological differences is the detection of gene fusion events. Sometimes when the DNA gets mixed up in a tumor, there is a connection of 2 genes that we call a “fusion event.” In such a case, the cancer becomes addicted to the fusion gene protein, so if we inhibit the activity of the fusion protein with a targeted drug, we can achieve significant tumor responses.

The best examples of fusion events are NTRK gene fusions. In patients whose cancer is associated with NTRK fusions and who receive treatment with NTRK inhibitors, the response rate can be as much as 70% or 80%, meaning that 70% or 80% of the patients will have a positive response to treatment, which are largely unheard of rates in the treatment of most cancers.

However, NTRK fusions are rare and only occur in less than 1% (about 0.5%) of patients. So, because of their very high impact in terms of getting positive results for those patients, we cannot afford to miss any of these events to be able to select the best treatment for them with NTRK inhibitors.

When testing for NTRK gene fusion events with the currently available DNA analysis methods, they are being missed in at least 15% of cases, if not more. However, when NTRK fusion is tested at the RNA level, then we have a much higher chance of detecting these fusion events.

So, when patients are asking if molecular profiling has been done on their tumor, it is important they clarify whether the most cutting-edge technology was used, including RNA testing. Patients should therefore feel confident asking for RNA testing, in addition to DNA testing, because it has become very clear that these fusion events occur in all cancer types.

By investigating cancer from the molecular perspective, we are breaking down the barriers between cancer types. We’re looking at what treatment makes the most sense for the specific patient based on the patient’s molecular makeup of the cancer instead of classifying patients by the site of the cancer (such as breast, lung, or prostate cancer).

It is my belief that there is almost no cancer for which people shouldn’t get molecular profiling, because the molecular features that we identify can drive the use of very modern, highly effective treatments.

Overall, doctors are increasingly becoming aware of and are willing to use molecular profiling technologies, but there are still pockets of resistance. We need to make sure that oncologists understand where molecular medicine is right now. Patients can play an extremely important role in combating this resistance, by demanding to receive these modern types of testing to improve their chance of getting the best treatments available today.

Key Points

  • Precision medicine in cancer is an approach that uses tailored treatment for the individual patient based on the specific disease characteristics of each patient
  • Biomarkers are biologic features (or markers) that are part of the tumor that help to guide treatment, when treatment related to that specific marker is available
  • In pancreatic cancer, for example, if the patient’s germline DNA has a BRCA gene mutation, that knowledge can lead to treatment that can improve the disease outcome
  • Patients should also feel confident asking for RNA testing, because it has become clear that these fusion events occur in all cancer types
  • Cancer cells get “addicted” to specific mutations, so we can exploit that therapeutically by using the drugs that specifically target those mutations
  • Patients can play an important role in combating oncologists’ resistance, by demanding to receive these types of testing to improve their chance of getting the best treatments

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Last modified: June 18, 2020

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