Introduction

Immunotherapy drugs like ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), and others are powerful tools to combat melanoma. Indeed, recent data from clinical studies show approximately half of patients treated with immunotherapy drugs alive after ten years, an enormous improvement in survival compared to just 15 years ago. Unfortunately, however, we know that approximately half of patients do not respond to these drugs and will need to change treatment course, so it’s important to determine as soon as possible if a patient is responding to therapy or not.¹

Fortunately, there are methods to determine which category a patient belongs to – those responding to treatment and those not showing a response.

How will your doctor know if you are responding to treatment?

Doctors use either imaging or blood tests to determine how patients are responding to treatment. The choice of methods depends on your disease, your clinician’s judgment, and clinical circumstances.

It is important to note that although recommendations exist, current guidelines debate appropriate surveillance methods and the frequency of exams for following up with patients diagnosed with melanoma. ^NCN2025

Imaging tests are the traditional way doctors use to check whether your treatment is working. Sometimes more than one type of imaging is used, depending on the location or stage of melanoma. The following are various imaging methods that may be used to determine how a patient is responding to treatment.

A chest x-ray is a method that uses radiation to image the bones and lungs through the skin. Dense materials like bone appear white, whereas open-air spaces, like the lungs, appear black. Shades of gray are other structures, like the heart.

A chest X-ray can be used to surveil and monitor patients with high-risk Stage II melanoma.² However, this method has limited value because it gives a relatively high false-positive rate and is often unreliable for detection.³ In one study, chest X-rays suggested that about half of the melanomas had metastasized to the lungs when later imaging and surgery showed the true number was much lower.⁴

A CT scan uses X-rays to create images of cross-sections, or slices, of the body. It gives a view of internal organs, muscles, bones, and tumors. This imaging method can be used as a way to determine whether the tumor is shrinking and assess treatment efficacy.

CT scans use ionizing radiation to generate images, which may further damage DNA. In addition, the ionizing radiation from CT scans is a known carcinogen, which is particularly dangerous if the exposure occurs during childhood. Radiation from scans is projected to account for 5% of all new cancer diagnoses.⁵ Therefore, physicians should be careful to not use CT scans unnecessarily. Another version of a scan is described below – FDG PET/CT.

An MRI scan or test uses a magnet and radio waves to generate detailed pictures anywhere inside the body. It requires a patient to remain still in a closed space and takes much longer to generate results than other tests. An MRI does not use X-rays or radioactive elements. It is also more sensitive than a CT scan when imaging soft tissues, except for small metastases in the lungs, for which CT scans are better.

Like a CT scan, an MRI can determine whether a tumor is shrinking and the treatment is working. In particular, an MRI is the ideal method to image the brain for metastasis in patients diagnosed with melanoma.³ For patients with prior brain metastases, frequent surveillance with brain MRI is recommended.²

A fludeoxyglucose-18 (FDG) positron emission tomography (PET) scan (referred to as FDG PET scan or FDG PET/CT or simply PET) is a method for imaging and detecting cancer in the whole body. This method uses radioactive sugar (FDG) and radiation exposure to detect active cancer metabolizing nutrients. It can determine whether a tumor is shrinking and the treatment is working. Like CT scans, FDG PET scans employ ionizing radiation, and doctors should not use them unnecessarily.

A FDG PET scan is a sensitive and specific tool used to detect metastatic disease in patients with melanoma in transit, or in the bone, liver, lymph nodes, lungs, muscle, and other organs, in one examination.6 In a study from Denmark, FDG PET scans given at regular intervals to patients diagnosed with Stage IIB-IIID melanoma detected distant recurrences within the first two years of surveillance in many of the patients.⁷

Ultrasonography or Ultrasound is an imaging method that uses high-intensity sound waves to non-invasively produce black and white images of organs and soft tissues in real time. In patients diagnosed with melanoma, an ultrasound is used to examine the surgical scar of the primary tumor, lymph nodes in the region, and lymph node basins.³

Ultrasound has a variety of uses for melanoma patients. It can be used for surveillance in patients who are eligible for, but did not undergo, sentinel lymph node biopsy.³ Ultrasound can also be used to find local spread in a melanoma patient of any stage because it is associated with a high sensitivity for detecting lymph node metastases from the primary melanoma.²

Blood Tests

In place of imaging or in addition to it, doctors may use a newer way to check if your treatment is working—a blood test. The type of blood test that is used is called a liquid biopsy or, more specifically, a ctDNA test. This newer method allows clinicians to identify non-responders earlier and use a less-invasive technique than most imaging tests.

Liquid biopsy for biomarker detection

A liquid biopsy removes a blood sample to search for evidence of a tumor in your body by looking for specific biomarkers in circulation. If biomarker evidence is detected, it could indicate whether treatment is or is not working and/or the presence of residual disease in melanoma. In this way, a liquid biopsy monitors the response to therapy and cancer progression.⁸

After you provide a blood sample, a laboratory will examine your blood for DNA biomarkers. The DNA is shed from the tumor as fragments not ordinarily found in the bloodstream. These DNA biomarkers are called circulating tumor DNA, or ctDNA. Because liquid biopsies are minimally invasive, they can be performed, if desired, more frequently than some of the imaging tests noted above. Additionally, liquid biopsies provide an easier means of continually monitoring disease status over time, because blood tests are simpler to perform, are less expensive, do not have radiation risks, and do not need a separate appointment. Additionally, liquid biopsies can be more accurate in some timeframes: For example, there can be delays before a tumor shrinks after treatment with immune checkpoint inhibitors, so imaging can give the false impression that treatment isn’t working; ctDNA tests may show reduced tumor biomarkers more quickly than imaging shows a reduction in tumor size.

What is circulating tumor DNA (ctDNA), the biomarker sought in a liquid biopsy?

At the crux of a liquid biopsy is a type of DNA not found circulating in otherwise healthy individuals. Blood plasma may contain DNA referred to as circulating tumor DNA (ctDNA). As the name suggests, this DNA comes from shedding by the cancer cells of a tumor. If ctDNA is detected in peripheral blood, it indicates a tumor is in the body and shedding DNA fragments.

Circulating tumor DNA is different from the DNA of a normal cell, which is how it is positively identified as cancer. For example, cancer cells contain very specific DNA mutations, which are considered ctDNA when they are found circulating in the bloodstream. An example would be a BRAF mutation (i.e., V600E), which is only found among transformed cells, not normal cells inherited from your mom or dad. If a tumor were shedding fragments of BRAF V600E into blood when it was found, it would be called ctDNA.

Similarly, cancer cells contain abundant DNA that is not be found at all in normal cells. An example is the BCR-Abl gene which causes the development of chronic myelogenous leukemia but is otherwise absent from all normal cells. Melanoma cells have specific factors, like BRAF, that contribute to their growth and replication.

Lastly, ctDNA may also contain lots of malicious DNA. This DNA is the kind that should be expressed at very low levels in adult cells, not at high levels, because it has the potential to create, or contribute to the creation of, a tumor protein. An example of a positive indication of ctDNA could be finding an abnormal number of chromosomes, which is a common feature of a cancer cell.

One limitation of ctDNA testing is that if cancer spreads to the brain, ctDNA is unlikely to be found in the bloodstream. This is due to the blood-brain barrier, which prevents most substances from crossing in and out of the brain. In other words, the normal physiology of the brain prevents ctDNA from indicating brain tumors.

What does a positive or negative ctDNA test indicate?

Circulating tumor DNA is a biomarker that may be predictive of melanoma and have the ability to monitor disease recurrence. According to one study, ctDNA can be used alongside current guidelines to help screen patients for the recurrence of their cancers after surgery, throughout drug therapy, and after treatment.⁹

• A positive test would indicate the presence of cancer.
• A negative test would indicate there was no residual disease detected.

In a study with Stage III and IV patients diagnosed with melanoma, ctDNA predicted their outcomes. Although the study only included 10 patients in the follow-up group, the patients without ctDNA, or “ctDNA-negative patients,” had no melanoma progression. This group of patients had previously completed treatment with immunotherapy and remained progression-free for a median follow-up of 14.67 months. In contrast, those patients who had malicious ctDNA detected in circulation, or “ctDNA-positive patients,” experienced melanoma progression. This shows the ability of ctDNA to predict outcomes and allow clinicians to alter treatment preemptively after the completion of immunotherapy.¹⁰

In a feasibility study with Stage II and III patients diagnosed with melanoma and a high-risk for relapse, ctDNA was used to monitor clinical recurrence. A majority, but not all, of the patients had elevated ctDNA after surgery during their surveillance period, and their cancers relapsed.¹¹ Another study found that all of the ctDNA-negative patients remained free of cancer, but several patients that showed ctDNA did have their cancer progress. ¹⁰

What else is important for patients to know?

Your ctDNA measurements are likely to change depending on where you are in your treatment plan. For example, in a feasibility study using ctDNA, the levels of ctDNA detected fluctuated substantially depending on whether patients had completed surgery. Before surgery, about half of the patients had detectable ctDNA. Four weeks after surgery, all but one patient tested negative for ctDNA.¹²

However, with drug treatment, some levels of ctDNA may spike due to the body clearing out the cancer. If the cancer cells start dying, they may shed their contents into the bloodstream and lymphatics. In some cases, this results in the detection of an increased amount of ctDNA in circulation. This requires careful interpretation of a positive ctDNA test during treatment.

Conclusion

If you are worried whether your treatment is working, the first step is to consult with your healthcare providers about your concern. There are multiple methods available for your doctor to use to assess your response to treatment and to detect cancer. Routine imaging throughout treatment will be used to measure the success of your treatment plan. However, new blood tests may also enhance the ability of your health care team to monitor your status. Discussing these options with your healthcare team may be appropriate for you.

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References:

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