Learn how ctDNA testing can help inform breast cancer management
About ctDNA
Cancer is caused by genetic mutations, and these mutations can be detected by measuring circulating tumor DNA, or ctDNA, in the blood. Detection of ctDNA allows for personalized cancer surveillance based on an individual’s unique set of cancer mutations. Circulating tumor DNA is 150–200-base-pair fragments of DNA, which originate from cancer cells and are present in the bloodstream or other body fluids. ctDNA is different than cell-free DNA (cfDNA) which is ALL the DNA in the bloodstream including germline DNA and tumor DNA. ctDNA is the portion of cfDNA that is derived specifically from the cancer.
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The Personalized Medicine Foundation and CancerConnect are pleased to provide patients and caregivers the opportunity to ask questions about the role of Circulating Tumor DNA (ctDNA) in the Management of Cancer. We have put together a panel of leading cancer experts to answer questions and publish a forum for the exchange of information.
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How is ctDNA used for the management of early-stage cancers?
Across all stages of surgically removed cancer, detection of ctDNA following surgery is a strong predictor of cancer recurrence. For example, measurement of ctDNA is performed routinely in early-stage colon cancer and can help clinicians decide when to intensify therapy in certain situations, and conversely, the absence of ctDNA can provide an opportunity to minimize surveillance or avoid adjuvant treatment. In breast cancer the most immediate application of ctDNA monitoring for MRD will be for the early detection of cancer recurrence and immunotherapy monitoring.
As many as 30% of early-stage breast cancers recur and recurrence surveillance currently relies on imaging techniques like computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). These imaging tools are limited in their ability to detect MRD - ctDNA can be detected in the blood long before it appears on a CT or MRI scan and has the potential to change how breast cancer is managed.
The Centers for Medicare & Medicaid Services has determined that Signatera’s molecular residual disease (MRD) test designed to detect circulating tumor DNA, or ctDNA, has met coverage requirements for adjuvant and recurrence monitoring in patients with stage IIb or higher breast cancer. Medicare’s coverage applies across all breast cancer subtypes including HR-positive, HER2-positive, and triple-negative breast (TNBC) cancers.
Dr. John Strickler of Duke University recently conducted a webinar to explain ctDNA and entertain patient questions.
About Signatera
Signatera is a custom-built ctDNA test for treatment monitoring and molecular residual disease assessment in patients diagnosed with cancer. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. Signatera is intended to detect and quantify cancer left in the body, at levels down to a single tumor molecule in a tube of blood.
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What is circulating tumor DNA (ctDNA)?
Circulating tumor DNA (ctDNA) is 150–200-base-pair fragments of DNA, which originate from cancer cells and are present in the bloodstream or other body fluids.
How is ctDNA different than cfDNA?
Cell-free DNA (cfDNA) is all the DNA in the bloodstream including germline DNA and tumor DNA. ctDNA is the portion of cfDNA that is derived specifically from the tumor.
How can ctDNA help manage cancer?
There are currently four clinical applications of ctDNA to guide precision medicine in patients with cancer:
- Detection of minimal residual disease (MRD) following surgery.
- Monitoring the treatment response in the metastatic setting.
- Identifying genomic drivers of therapeutic sensitivity and resistance.
- Guiding treatment strategies to overcome resistance to treatment.
How is ctDNA used for the management of early-stage cancers?
Across all stages of surgically removed cancer, detection of ctDNA following surgery is a strong predictor of cancer recurrence. The detection of ctDNA could lead clinicians to intensify therapy in certain situations. Conversely, the absence of ctDNA could provide an opportunity to minimize surveillance or adjuvant treatment.
How is ctDNA used for the management of metastatic cancer?
ctDNA can be used to monitor treatment response, identify genomic drivers of treatment sensitivity or resistance, or identify new therapies that could overcome genomic drivers of treatment resistance.
When should ctDNA be collected?
Both tissue and blood samples are used to build a patients individualized ctDNA test. Once the test is built, only blood samples are required for the periodic follow-up tests performed to monitor for MRD or recurrence. Since DNA assays require ctDNA shedding into the bloodstream, the performance of ctDNA assays is improved when blood is collected after—rather than during—active chemotherapy. For building the initial test, tissue should be sent as soon as it is available. The optimal time for the initial blood collection is 2-3 weeks after surgery (earlier is better)
Do you need to wait a certain amount of time, post surgery, to have the ctDNA performed?
It is advised that blood samples used for the Signatera assay should be collected 2 weeks following any surgery.
Can a “stored” tissue sample be used to build the Signatera assay?
Yes and this is important. The Signatera assay can be useful in the management advanced cancers and patients may not have had the assay built at the time of their original diagnosis. Tumor tissue stored as a formalin-fixed paraffin-embedded (FFPE) block or on slides can be used from the original diagnosis can be used to build the assay even when stored for several years.
What is the procedure for ordering a ctDNA test?
Currently ctDNA testing must be requested by a provider so the test can be sent to the company performing the test. Patients cannot order this test. Only a physician can order the test.
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Is ctDNA different from NGS testing?
Yes “Next Generation Sequencing,” or “NGS” is a platform that allows simultaneous testing of multiple molecular targets. NGS testing can be performed on tumor tissue or blood (ctDNA).
If my doctor orders NGS testing on tumor tissue, will ctDNA testing also be performed?
Not always - ctDNA is typically a separate test and will usually not be ordered together with NGS testing unless specifically requested. Providers and hospitals use a variety of different companies to perform DNA testing. Some companies, like Natera perform both ctDNA and NGS testing, while others do not.
Does insurance pay for ctDNA testing?
Signatera is covered by Medicare for: Monitoring disease progression, recurrence, or relapse for stage IIB and higher breast cancer in both the adjuvant and surveillance settings and for monitoring of response to immunotherapy treatment.
Natera welcomes all commercial insurance plans and works with patients to ensure cost is not a barrier for testing. Please refer to our website for In-Network plans that we participate with or call your insurance company. An affordable cash pay rate is available for patients who do not wish to use insurance (exclusions apply). For questions or financial assistance, please contact Natera’s Patient Coordinators:
Phone: 650.489.9050 Fax: 650.412.1962
Email: oncologybilling@natera.com
Patient-Submitted Questions
Can you explain what "Positive Below Analytical Range" means on a Signatera test? This has happened twice and both time the values were under 1.
There is a complicated explanation for this from Natera, however this is technically a positive test meaning that cancer was detected in the sample but at a lower level of detection than can be accurately quantified. Sometimes the amount of material being measured by a test is less than the ability of the test to detect it. This can often be the case when looking for individual cells or parts of cancer cells. The Signatera test is best used serially (every 3 months) to look for residual cancer - in some situations the detection of ctDNA moves above and below the threshold of detection possible reflecting the bodies immune systems effort to eradicate the cancer.
Can you explain what "Higher than expected cell free DNA (cfDNA) events were found in the plasma sample. Excessive cfDNA may decrease clinical sensitivity of the test."
Higher levels of germline cfDNA are released when patients receive surgery (wound healing) or chemotherapy (cell death). Higher cell free DNA requires increased filtering and lowers the sensitivity for detecting tumor derived fragments which means the test may not be as accurate at detecting cancer when it is present. There are more false negative results.
I have TNBC and been treated with chemo, keytruda, trodelvy and now have signatera of 7.2 but PET scan cant find any cancer?
Signatera can be positive for many months before a PET scan detects a recurrence - you begin thinking about what next for treatment as your doctors increase surveillance for recurrent disease. You can keep current with new TNBC treatments here.
Are the outcomes better for breast cancer patients when their recurrences are caught early using ctDNA tests?
The answer is yes but the magnitude of the benefit is unclear. Because there is currently no post treatment surveillance programs for the very early detection of a breast cancer recurrence doctors detect recurrence’s very late – when they either causes symptoms or can be detected by a PET/CT scan. Recurrence detection by ctDNA may proceed detection by PET/CT by as much as 8-12 months. Early detection of a recurrence is local to the breast or isolated can often be treated with additional surgery or radiation with curative intent.
The benefit of early detection of a systemic recurrence i.e. cancer present in more that a single location is still unclear. Although it makes intuitive sense that early treatment should improve outcomes it is currently unknown if this is the case. Early detection however does have the benefit of providing more time to explore treatment options and evaluate the role that clinical trials may play in the next phase of treatment. Finding the right clinical trial can be time consuming.
I am 17 years post mastectomy for early stage breast cancer. I have had a positive Oncoblot test as well as circulating tumor cells detected on multiple MAINTRAC tests performed in Germany. I am not a candidate for the Signaterra test as my tumor tissue was discarded 10 years post-surgery. What is a good substitute test in the US to determine the progression of recurrence?
That sounds like a tough and anxiety-provoking situation. Unfortunately all the sensitive ctDNA tests (Signatera, RadaR) are tumor-informed, because otherwise the technology isn’t very sensitive…so without any tumor tissue (which is used to create a unique fingerprint that you can then look for in the ctDNA), there is no sensitive testing option available to the best of our knowledge. The only available way to perform ongoing monitoring would be to check typical tumor markers every few months (CEA, CA15-3) and repeating PET if they are clearly increasing at some point in the future.
I have stage 1A breast cancer, estrogen and progesterone positive, oncotype 31, negative lymph nodes, clear margins, had segmental mastectomy on 1/23/23, brachial radiation on 3/8/23. Just had my ctDNA 3/30/23 and came back detected. Going to get 4 rounds of chemo. With a positive ctDNA does it means my cancer is more advanced?
A positive ctDNA means the cancer can be detected in your blood which means it is more advanced than we would typically think of with a clinical stage of IA. This is consistent with your oncotype score of 31 suggesting that you would benefit from chemotherapy treatment and the reason your oncologist recommended treatment.
How does your ctDNA interact with active chemo drugs - beyond the chemo's inhibition of the cancer cells, how do they interact with the ctDNA probe measurement itself?
Chemotherapy does not directly interact with the probes. Chemotherapy suppresses the ctDNA in the bloodstream, making it harder to detect the cancer.
What is difference between ctDNA tests for early cancer detection vs MRD?
Early detection tests are similar but not identical to MRD tests. Early detection tests are typically optimized to detect the early presence of an unknown malignancy. MRD tests are designed to detect the presence of a cancer that was previously known to be present but removed. As a general rule, an early detection test is broad (can detect multiple cancers) but is not as sensitive for 1 specific cancer. MRD tests are more sensitive for 1 specific cancer, but are not designed to detect other cancers.
What is difference between tumor-naive vs. tumor-informed CRC MRD assays. How much do we know about ct DNA as a forecasting tool?
Tumor naïve tests do not require genomic sequencing of tumor tissue. These tests rely on a standard mutation and methylation panel that is common to the cancer under study. Tumor informed tests require sequencing the patient’s tumor, and then building a custom panel to detect those tumor mutations in blood. We have no head to head studies comparing the two different approaches.
I have had nine negative Signatera tests and now a positive. What are the chances I really do have a recurrence versus a false positive?
False positives are extremely rare, but there have been reports of transient positive results that spontaneously clear. If there is any doubt, I recommend rechecking the test 4-8 weeks after the positive result to confirm. If the ctDNA result remains positive it confirms the result. Liver MRI is a great test to consider if the CT scan is clear.
How reliable is ctDNA testing during chemotherapy treatment? Should the test be performed while on chemotherapy?
ctDNA testing is less likely to be positive during chemotherapy treatment. Despite that, it can still be useful during treatment. Reduction in ctDNA is associated with favorable response to treatment and better prognosis.
Why do these tests sometimes miss cancer in the lungs/liver?
These tests rarely miss disease in the liver. MRD tests tend to miss disease in the lungs, because those metastases secrete less circulating tumor DNA into the bloodstream and tend to be slower growing overall (less cell turnover to release DNA)
Can CTDNA go up as part of pseudoprogression on immunotherapy?
No… pseudoprogression is associated with lower circulating tumor DNA levels, but worsening disease on imaging.
I have stage 4 breast cancer and my primary oncologist is using the Signatera test for me and says the Guardant test is not for my situation. I went for a second opinion by another oncologist who recommended using Guardant and that Signatera is the wrong one. Can you help me understand their opposing views? Also they both came back negative how common is that for stage 4 breast cancer?
Signatera is approved by Medicare for Breast Cancer surveillance and the test appears to be more sensitive than Guardant in general (less likely to be falsely negtive). Both tests are fairly specific (meaning if they are positive cancer is highly likely to be present) The signatera test is more sensitive because its “tumor informed” meaning it tracks your actual cancer mutation identified on the actual cancer. Guardant uses “markers” associated with breast cancer in general but these are not specific to your cancer.
My 63-yr old husband was diagnosed at Stage 2A, T2NDMX0 with male breast cancer in Feb 22. He had positive lymph nodes after chemo and surgery. He completed radiation and began Kadcyla until neuropathy. We were very discouraged & the oncologist said we could do the circulating DNA test but she didn’t know if it would change her treatment plan. His ctDNA is NEGATIVE and the oncologist switched him to perjeta. He has 5 more to go and we wondered if there was enough reason to continue with the “poison” when he had a negative dna test.
I am sorry your husband has had such a rough go of it. Although the ctDNA is negative he has not completed the prescribed course of perjeta. The standard of care would be to complete the perjeta if possible. Being ctDNA negative is a good prognostic sign but does not mean the risk of cancer recurrence is zero but should provide some level of reassurance should you need to discontinue the Perjeta.
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