By:Ashling Wahner
From: onclive.com
Key Takeaways
- ctDNA testing is emerging as a key tool in breast cancer management, aiding in early detection and treatment monitoring.
- Ultra-sensitive assays like Signatera demonstrate high sensitivity and specificity in detecting distant relapses in breast cancer.
- ctDNA testing could enable treatment de-escalation or escalation based on MRD status, potentially transforming clinical practice.
- Despite current challenges, ctDNA testing is expected to become integral in personalized oncology care, with future advancements enhancing predictive accuracy.
Circulating tumor DNA (ctDNA) testing is rapidly emerging as a powerful tool to detect minimal residual disease (MRD), guide treatment decisions, and potentially transform breast cancer care across the disease continuum, according to Jason Mouabbi, MD.
“I’m hoping ctDNA testing is going to [become clinically useful] sooner rather than later,” Mouabbi said in an interview with OncLive®. “It is emerging. It is here to stay.”
In the interview, Mouabbi highlighted the emerging role of ctDNA tests in breast cancer management, emphasizing their potential for use in early detection and treatment monitoring. He also explained the prognostic value of these tests, which continues to evolve despite current challenges regarding their predictive value and usage uptake within the oncology community.
Notably, he alluded to the promise of ultra-sensitive MRD assays like Signatera Genome. Findings from a study presented at the 2025 ASCO Annual Meeting showed that in a subcohort of patients with breast cancer (n = 446), the assay had clinical sensitivity and specificity rates of 100% in the longitudinal setting for the detection of distant, extracranial relapses.1
He also contextualized the application of ctDNA test results within the breast cancer treatment paradigm. For example, he cited ASCO 2025 data from the phase 2 DARE trial (NCT04567420), which demonstrated that in patients with estrogen receptor–positive breast cancer at high risk of recurrence who were receiving adjuvant endocrine therapy, at a median follow-up of 27.4 months, persistent ctDNA negativity per the Signatera assay (n = 442) was associated with a 36-month recurrence-free survival rate of 99.4% and a cumulative clinical relapse rate of 0.5% beyond 12 months.2
Mouabbi is an assistant professor in the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.
OncLive: What is the current role of MRD and ctDNA testing within breast oncology? Where might this field go next with future research?
Mouabbi: ctDNA is the future of breast oncology. We are going to see it at every step of the spectrum. We’re going to see it at screening. In the future, I would not be surprised if instead of mammograms, we do a blood test to screen for breast cancer and for every cancer.
Those tests are already available, but they’re not optimized at this point. That’s why a lot of guidelines or societies that make guidelines have not adopted them. But they’re available, and in the next 5 to 10 years, they’re going to be commercially available, and people are going to use them at primary care offices, where in patients’ annual exams, they will undergo a blood test that 30, 40, or 50 cancers. Depending on which markers are positive, [patients would] then undergo specific diagnostic imaging or test to confirm [the ctDNA assay findings] or disprove them.
[ctDNA testing may also have a role] before surgery. If patients receive neoadjuvant therapy, you can monitor whether they are responding by doing these blood tests and looking for tumor DNA in the circulation. You can [also perform these tests] after surgery. This is where the [role for] MRD [testing comes in, for] catching MRD and cancer recurrence before [the development of] overt metastatic disease. When the cancer comes back and you see it on imaging, it’s not curable anymore. The idea is: Can we catch it before we can see it on an image, and hopefully convert it back to [an MRD-negative state] and eliminate those tiny amounts of cells to cure patients? Finally, in the metastatic setting, we have a lot of data right now showing that [MRD testing] is an excellent tool to monitor treatment response. Multiple papers and studies have been published over the past years showing that this is a valid tool to monitor whether treatment is working before waiting for a scan to show us that.
[ctDNA testing is] emerging in breast cancer. In other cancers, it is already established, like in colorectal cancer. Our malignant hematology colleagues are already using MRD testing, and now they’re even using [MRD negativity] as a primary end point on clinical trials. For example, in a New England Journal of Medicine paper in multiple myeloma, [MRD negativity] was the primary outcome.
This is fascinating. This is the future we’re hoping for in breast oncology. A lot of breast oncologists are not comfortable with it yet, because we don’t like new technology sometimes, and we struggle to adopt it. But get comfortable with it. It’s here to stay. It is the future. The sooner we’re comfortable with it, the better physicians we are to our patients, and the more we can be set for the future.
How does Signatera and other similar assays work? How should these assays be used in clinical practice?
One of the biggest struggles for oncologists is that we consider ctDNA assays as similar or [interchangeable], like you can choose the company you want and run [the test] you want. [However, these assays are] not [interchangeable]. It’s important to know: What are we trying to look for?
If we’re trying to look for ctDNA to check for mutations, meaning to find out whether there is a targetable finding at the DNA level, then [we should perform] a liquid biopsy. There are multiple tests for those. A few that are commonly used in the US are the Guardant360 test, the Foundation test, the Tempest test, the BostonGene test, etc.
All those tools are commercially available. They are good for detecting a mutation. But if you’re looking for a test to check for MRD, then those tests are not good, because you want a test to have a limit of detection that’s good enough to detect a minute amount of cancer DNA in a sea of healthy DNA.
Every single healthy cell in our body can shed DNA into the bloodstream; that’s cell-free DNA. ctDNA is cell-free DNA from cancer cells. In the body, the immune cells in circulation don’t live long, and they shed tons of healthy DNA into the bloodstream.
You are looking for a needle in a haystack when you’re [performing] an MRD test, because you want to detect DNA amounts at the level of a few hundred cells, not at the level of a million cancer cells. Because of that, the minimum acceptable level of detection for an MRD test is 100 ppm, meaning the test needs to be able to detect 100 ctDNA [fragments] in a sea of a million DNA [fragments]. The [ctDNA] tests that look for mutations have limits of detection between 10,000 and 100,000 ppm. These are not good for MRD [detection]. That’s why the Signatera assay that we use right now in clinical practice and that a lot of oncologists order [has a limit of detection that] is approximately 100 ppm.
However, ultra-sensitive tests are coming. The company that [produces] Signatera—Natera—produced an ultra-sensitive test and showed the result at ASCO 2025. Those can detect [down] to 1 ppm, meaning they can detect 1 single cancer DNA [fragment] in a sea that contains a million healthy DNA [fragments]. That’s where we want to be.
Those ultra-sensitive tests are coming, but it’s important to know what each test delivers. It’s important to ask this question. I ask it all the time because companies come to me saying: “We have this technology, and it can be an MRD test.” I ask them: “What is [the test’s] limit of detection in ppm?” It needs to be below 100 ppm. The lower, the better.
How might MRD testing shift treatment standards or lead to treatment escalation/de-escalation for certain patients?
ctDNA testing is used across the spectrum in breast cancer. Before surgery, it’s been found to be an excellent tool to predict outcomes after surgery. At least 90% of patients will have detectable ctDNA before any treatment before surgery. [Approximately] 10% of patients will not have detectable ctDNA, but the good news is, [those patients have positive outcomes] regardless of how you treat them.
Because treatment now is often intensive, we do multiple parts of treatment, and it takes approximately 5 to 6 months directly. Treatments take a long time, and there are a lot of treatments being given. Data that are consistent across multiple studies [show] that if patients [with positive ctDNA assay results before treatment] can clear their ctDNA levels as they’re getting treated, they don’t need to go on to achieve a complete pathological response, meaning eliminating all cancer cells. By just eliminating the shedding of DNA, their outcomes can be the same as the patients who eliminate all that cancer. This is an excellent opportunity to de-escalate treatment.
I’m going to give an example from one of the most established platforms that adopted [this form of treatment de-escalation]: the I-SPY platform. On the I-SPY platform, across every study, [investigators] found that in hormone receptor–positive breast cancer, after just giving the first part of chemotherapy with just paclitaxel, you can eliminate the shedding of DNA in approximately 80% of patients. Why are we giving those 80% of patients additional chemotherapy before surgery? They already achieved what we need them to achieve for them to have excellent long-term outcomes. Only approximately 20% of patients still shed [ctDNA], and they would benefit from additional chemotherapy before surgery to hopefully eliminate [the shed of ctDNA].
We found [similar results] in triple-negative breast cancer [TNBC]. [In approximately] 50% of [patients with] TNBC, you can eliminate that shedding by just giving them half the treatment course. The other 50% of patients would benefit from additional chemotherapy, and we should give it to them. This is an excellent strategy to [determine which patients] you should de-escalate or escalate [treatment for] before surgery.
After surgery, [ctDNA tests are] extremely prognostic. If after surgery, you find shedding of DNA—MRD-positive disease—the positive predictive value is uncanny. We used to say that nothing in oncology or medicine is 100% However, the positive predictive value of [ctDNA tests] across multiple studies is always 100%. Finding a positive test will predict a recurrence, whether it’s going to happen in 1 year, 2 years, 3 years, 4 years, or 5 years. We have patients who turn [MRD] positive [after surgery, and] 8 years later, we discover the cancer.
However, having a negative test at this point is not 100%. We still have some false negatives, meaning you perform the test, [the results are] negative, but the cancer comes back anyway. However, the false negativity rate is low. At this point, [the false negative rate with a] single test is approximately 6%, but if you do serial tests, such as 3 or 4 tests back to back, and all of them come back negative, then the negative value keeps going higher.
What are the next steps for testing in breast cancer?
In the future, I’m expecting we’re going to find a test that can be 100% [predictive] both ways. [In that case, if the test is] positive, it would predict that the cancer will come back 100% of the time. If it is negative, you could also [guarantee that the] cancer is not there.
The problem is, at this point, if [the result is] positive, what am I going to do [to treat the disease] as a medical oncologist? That’s why there is a lot of resistance in our community to adopt these tests. What I say to this is: Doing nothing is the mistake, because [these tests are] prognostic. If it’s positive, something is going to happen. Try [a treatment].
Oncology is an art. Oncology is guidelines. Follow the practices that we do for our patients. It shouldn’t be the other way around. We shouldn’t wait for guidelines to tell us how we’re going to treat our patients.
We can switch the endocrine therapy. If they’re receiving tamoxifen, we can change it to a therapy like an AI and see if that converts them to [MRD negativity]. If they qualify for a CDK4/6 inhibitor and they never received it, you can start a CDK4/6 inhibitor; we have some data about that. We have 2 studies that showed that the addition of a CDK4/6 inhibitor can help convert patients from [MRD] positive to negative. A pilot study from the phase 3 monarchE study [NCT03155997] showed that using a CDK4/6 inhibitor [plus endocrine therapy] converted 3 out of 10 patients from [MRD] positive to negative.3 The DARE trial also showed some preliminary results at ASCO 2025. It showed that 56.3% of the patients [who switched from adjuvant endocrine therapy to receive fulvestrant (Faslodex) plus palbociclib (Ibrance)] converted from [MRD] positive to negative.2
We have data showing that converting a patient from [MRD] positive to negative changes [disease outcomes]. It seems like converting a patient from [MRD] positive to negative prevents recurrence from happening. [The prognostic abilities of] these tests are useful at this point.
[Tests to predict] responses to treatment are coming, but that should not negate us from using these tests in our patients. If I’m a patient, I want these tests because they’ll help me know the status of my cancer before it can be caught on imaging or become a symptomatic lesion that’s not going to be cured.
References
- George MA, Schwartz G, Mchayleh W, et al. Clinical performance of Signatera Genome assay in a cohort of patients (pts) with solid tumors. J Clin Oncol. 2025;43(suppl 16):3142. doi:10.1200/JCO.2025.43.16_suppl.3142
- Pusztai L, Scalise CB, Kalashnikova E, et al. Circulating tumor (ct)DNA monitoring of ER+/HER2- high-risk breast cancer during adjuvant endocrine therapy. J Clin Oncol. 2025;43(suppl 16):1010. doi:10.1200/JCO.2025.43.16_suppl.1010
- Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer. Loi S, Johnston S, Arteaga C, et al. Cancer Res. 2024;84(suppl 9):PS06-01. doi:10.1158/1538-7445.SAVCS23-PS06-01
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.