Ultrasensitive circulating tumor DNA (ctDNA) assays are enabling earlier detection of minimal residual disease (MRD) in patients with breast cancer, although their role in directing therapeutic decision-making is still being defined through ongoing research, according to Marla D. Lipsyc-Sharf, MD.
“My dream world is a world in which we know how to use these tests to their best capabilities,” Lipsyc-Sharf said in an interview with OncLive®.
In the interview, Lipsyc-Sharf discussed the evolving role of MRD ctDNA testing in breast cancer management, explaining that it is now identifiable through liquid biopsies, aiding in early detection of disease recurrence. She noted that commercially available MRD tests like the Signatera Genome Test for Breast Cancer use whole-genome sequencing to personalize assays for patients and could inform treatment escalation and de-escalation strategies accordingly.
Notably, data from a retrospective analysis presented at the 2025 San Antonio Breast Cancer Symposium (SABCS) showed the recurrence detection capabilities of Signatera Genome across breast cancer subtypes following surgery or definitive treatment. The assay’s specificity and sensitivity rates for distant recurrence–free survival and recurrence-free survival were both 100%.1
Lipsyc-Sharf also emphasized the importance of MRD-focused clinical trials, patient-provider discussions, and considerations of real-world data to optimize MRD testing frequency and utility in clinical decision-making. Based on the Signatera Genome findings presented at SABCS 2025, the SIGNAL-ER 101 trial (NCT07214532) will further evaluate the clinical utility of Signatera Genome in patients with intermediate-risk hormone receptor (HR)–positive, HER2-negative early-stage breast cancer.1,2 In this trial, baseline ctDNA test results will determine whether patients initiate CDK4/6 inhibition in addition to hormone therapy, or receive hormone therapy alone with ongoing ctDNA surveillance.2 Outcomes from the trial will be compared with historical control data from the phase 3 NATALEE trial (NCT03701334) of ribociclib (Kisqali) plus endocrine therapy in patients with HR-positive, HER2-negative disease to identify whether ctDNA-guided therapeutic timing aids treatment efficacy and reduces over-treatment in certain patients.
Lipsyc-Sharf is a breast medical oncologist with UCLA Health in California.
OncLive: What is the current role of MRD in breast cancer management and the potential utility of ctDNA testing for these patients?
Lipsyc-Sharf: This answer is evolving. Historically, MRD has been evidence of cancer that has not been identified clinically, and we have not had blood tests or scans that have been able to find MRD. We think that MRD is the reason we see breast cancer recurrence. When patients are treated for early-stage breast cancer with curative intent, unfortunately, they can relapse or recur many years later. We think this is because of the persistence of MRD.
Only relatively recently have we been able to detect MRD on blood tests, whether that’s with liquid biopsies [looking for] ctDNA, or other circulating biomarkers. The most common one we see today is with ctDNA blood tests. When we talk about MRD, we’re typically talking about MRD in the early-stage breast cancer setting, before evidence of cancer recurrence on radiographic imaging. There has been recent research investigating MRD in metastatic disease, which is when patients have had radiographic evidence of metastatic disease, but may not currently have evidence of radiographic metastatic disease. MRD [assays can] detect microscopic molecular amounts of cancer.
When we think about the evolving role of MRD in breast cancer, I tend to think about metastatic disease [separate from] early-stage disease. Focusing on early-stage disease, which is a huge area of investigation in this field, typically, we are not recommending blood tests or scans to monitor patients for breast cancer recurrence or MRD.
Signatera Genome Capabilities Across Breast Cancer Subtypes1
- In a retrospective analysis, the Signatera Genome assay demonstrated 100% clinical sensitivity and specificity for detecting both local and distant relapses in a cohort of over 200 patients with breast cancer.
- Patients who tested ctDNA positive at the 3-month post-surgery landmark or during the post-definitive treatment window had significantly inferior distant recurrence–free survival outcomes compared with those who were ctDNA negative at these time points.
- These findings show that monitoring for MRD with this assay allows for early detection of disease recurrence, providing a window for intervention or enrollment in clinical trials before a relapse is clinically visible.
Several MRD tests [are now] commercially available. These are blood tests, liquid biopsies. We are learning, as these tests become commercially available, what we can understand from real-world evidence from MRD testing done in clinical practice.
The other piece is: What can we learn from historical research on MRD testing in clinical practice, whether prospective or retrospective? And then, arguably most importantly: What can we learn from ongoing and planned investigational trials and therapeutic interception trials designed to assess how to intervene when a patient has ctDNA-positive or ctDNA-negative disease? Can we escalate treatment? Can we de-escalate treatment? What subtypes should we be using [these tests in]? How often should we be using the tests? Which tests should we be using? All these questions are currently at play, and it’s an exciting time to be in this specialty.
How have ctDNA and MRD assays evolved in recent years? What is the importance of having standardized testing approaches to collect consistent data from institution to institution, so findings can be applied across populations?
Assays have evolved over time. We think about MRD testing as having 2 major categories. One is tumor informed, meaning we do whole-exome or whole-genome sequencing on the patient’s tumor that has already been via biopsy or surgery, and then create an assay that’s personalized for that patient to look for different genomic alterations in their own blood. That’s an assay created specifically for that patient. We also have tumor-agnostic ctDNA tests, which are general tests that are not personalized. The same tests are used for all patients who have had a history of cancer, [and these tests look] for cancer recurrence.
We’ve seen evolution in both these areas in breast cancer. Regarding commercially available tests, we are seeing more tumor-informed tests in breast cancer. These tests have evolved from historically being targeted to only assess 1 or 2 genomic alterations to, as time went on, whole exome sequencing of tumors. Now we’re conducting whole genome sequencing of tumors, and adding to that, some assays look at other features of the genome, whether those are structural variants, methylation changes, epigenomic changes, or other features. Assay capabilities are evolving a lot.
How does the Signatera Genome Test for Breast Cancer work? How is this assay currently being used in breast oncology, and what might the future look like here?
A former version of a Signatera [assay] was based on whole-exome sequencing. The whole-genome sequencing [assay] was developed as a more sensitive assay for detecting MRD in breast cancer and all cancer types. This test is a personalized ctDNA breast cancer MRD test.
Natera performs whole-genome sequencing on the patient’s tumor. They develop a targeted, tailored assay that looks at several different genomic alterations from that patient’s whole-genome sequencing from their tumor. It looks for these different genomic alterations in the plasma as time goes on, so when you draw blood over time, this assay is used to look for these genomic alterations.
This test is special in a lot of ways, and it marked an effort to get below 1 part per million in terms of how we can identify breast cancer in MRD to such great sensitivity. In breast cancer, when we have long latent periods between when a patient is diagnosed and when they have a breast cancer recurrence, it becomes all the more important to have an ultrasensitive ctDNA test. [Signatera Genome] is a further advancement toward this effort.
This is being used commercially in routine practice in practices across the US and the world, and it’s also being incorporated into multiple ongoing clinical trials. We hope the real-world data will advance simultaneously with the prospective investigational trial [data], so we can learn the best ways to use this test. How often should we be getting this test, and how we can escalate and de-escalate [treatment] based on the results?
As data accumulate and demonstrate the optimal applications for biomarker tests, how might MRD and ctDNA status inform the future development of breast cancer treatment strategies?
I am hopeful that with the ongoing trials, we will learn how to tailor treatment appropriately. The goal of MRD testing, in my mind, is to escalate therapy in patients who require escalation for cure, and to de-escalate therapy in patients who we’re currently over-treating. Both of these are common themes in breast cancer, so ideally, we will use MRD for both of those indications.
Historically, MRD testing and trials had focused on triple-negative breast cancer, and I am pleased to see the field moving toward studying this in estrogen receptor–positive breast cancers because I feel that there is a larger window between when patients develop detectable MRD and when they develop radiographic evidence of metastasis. That is our potential intervention window. I’ve been pleased to see the field move toward studying this in a more systematic way, and I’m hopeful that may be our first area in which we have investigational data.
Overall, what should colleagues know about the evolving role of MRD and how it may ultimately affect breast cancer clinical practice?
If your practice has access to clinical trials [that are investigating MRD], please discuss these with your patients. Discuss with your research colleagues how you may be willing to get involved. We need more data.
If you are currently using these tests in clinical practice, I encourage you to discuss risks and benefits with your patients beforehand and consider with the patient what might be done with a positive vs negative result and in which setting. When we think about how often oncologists are ordering [MRD tests] in clinical practice, I encourage you to look at some of the real-world data we have and the negative predictive values [of these tests], which are excellent, over 3 to 6 and sometimes even 12 months. In certain [populations], we may not need to be testing as frequently as we are, and in certain [populations], perhaps we need to be testing more frequently.
Finally, my main take-home message would be that in the absence of discrete data on whether this testing improves breast cancer outcomes, this seems to be a patient- and oncologist-specific decision. Make sure, to the best of your abilities and within your time constraints, that you know your patients and understand their values to help them make a good decision.
References
- McHayleh W, Scalise C, Kalashnikova E, et al. Abstract PS2-07-26: Clinical performance of Signatera Genome assay for predicting recurrence in patients with breast cancer. Clin Cancer Res. 2026;32(suppl 4):PS2-07-26. doi:10.1158/1557-3265.SABCS25-PS2-07-26
- Signatera-guided CDK4/6 inhibitor therapy in breast cancer (SIGNAL-ER 101). ClinicalTrials.gov. Updated December 23, 2025. Accessed March 20, 2025. https://clinicaltrials.gov/study/NCT07214532
