MRD and ctDNA Could Shift into Larger Role to Guide Treatment Decisions in Breast Cancer

Praveen Vikas, MBBS

Although the use of minimal residual disease (MRD) and circulating tumor DNA (ctDNA) could serve as valuable tools to guide treatment decisions for patients with breast cancer, additional research and data are still needed to determine how to best integrate this testing into clinical practice, according to Praveen Vikas, MBBS.

“We see where the field is going, and we think [MRD testing] is going to be valuable. Of course, ctDNA in breast cancer and other cancers is being used at multiple time points. It could help us figure out how patients are doing with pre-operative neoadjuvant chemotherapy, as well as how to escalate or de-escalate adjuvant treatment based on MRD [status],” Vikas said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on breast cancer, which he chaired.

In the interview, Vikas discussed what is currently known regarding MRD testing in breast cancer, expanded on what still needs to be done to bring MRD and ctDNA testing to clinical practice, and highlighted the evolving treatment paradigm for patients with advanced hormone receptor (HR)–positive, HER2-negative breast cancer.

Vikas is a clinical associate professor of Internal Medicine-Hematology, Oncology, and Blood and Marrow Transplantation for the Department of Medicine at Carver College of Medicine, University of Iowa Health Care, in Iowa City.

OncLive: What is the current role for MRD/ctDNA testing for patients with breast cancer?

Vikas: MRD is still a new concept that [has been used] in a lot of hematological cancers and colorectal cancer. Although [MRD] is something that's not yet being used for breast cancer, we have more data from different trials, and we're hoping that as we get more data, we may be able to use these tests in our patient care. Right now, it's still considered early and we're using [MRD] mostly in the setting of clinical trials.

[MRD testing with the Signatera assay] is approved for [patients with] stage IIB or higher breast cancer by Medicare, and we are having fewer difficulties from payers. On a case-by-case basis, when we order these tests, we are sometimes able to get covered by insurance companies. However, we still have to be selective in using MRD testing, because we just don't have enough data on how to handle these positive results.

Could you elaborate on the specific cases where you would employ MRD testing?

One [situation] would be if a patient is eligible for clinical trials. Right now, there are a couple clinical trials ongoing where MRD positivity, based on ctDNA, would allow patients to get on the trials. [These studies include phase 2] trials called LEADER [NCT03285412] and DARE [NCT04567420]. These trials are looking for ctDNA, and based on positive ctDNA, those patients can be randomly assigned to an additional drug like a CDK4/6 inhibitor. That would be one scenario where we could do these kinds of tests.

I will occasionally do MRD tests for patients who are at a high risk of relapse. Oftentimes, the imaging studies may not give us positive results for a long time. Again, we don't know exactly how to act on [positive MRD tests] outside of enrolling [patients] into clinical trials. Therefore, we must be careful.

There are patients who are on long-term maintenance treatment, such as maintenance with an immune checkpoint inhibitor for patients with triple-negative breast cancer [TNBC]. Sometimes we're not sure how long we should continue that maintenance drug. Occasionally, patients may be getting tired, or they may have a long distance to travel to get the treatment. In those cases, even though their most recent imaging may have been negative, we could use MRD tests. If these tests are negative, that could give us some confidence in holding or discontinuing treatment.

Again, [MRD testing in breast cancer] is not ready for primetime yet; we are waiting for more data, but these tests are getting better. There are many studies that have shown that ctDNA can show microscopic cancer almost 9 to 10 months before cancer will show up on CT scans or other imaging.

Could you elaborate on how you define high risk for patients who may be candidates to undergo MRD testing?

A high-risk patient would be based on both the anatomy and biology of their cancer. For aggressive biology, like TNBC, tumors of more than 2 cm or positive lymph nodes, or based on their response to neoadjuvant chemotherapy or immunotherapy, could [make] certain patients at higher risk for relapse. In estrogen receptor [ER]–positive breast cancer, we are looking for patients with multiple positive lymph nodes or large primary tumors.

There's no clear definition for high risk, and that's something we have to consider. Some of the approvals for these [MRD testing] have been based on stage, and stage often takes into consideration biology. We are allowed to use these tests in select patients with stage IIB or higher breast cancer.

MRD testing appears to be a delicate balancing act of sensitivity and specificity. Could you elaborate on these factors and what has been seen thus far?

There are many companies that are [developing MRD] tests. Some of these tests are based on [a patient’s specific] tumor, which we call tumor informed, because based on the initial pathology, we track those abnormalities. However, some [MRD tests] are tumor agnostic. These are looking for any abnormal cell-free DNA, which [is thought to be] coming from the tumor.

The tests are getting better in the sense that they can detect a very [low] level of [MRD] positivity. The sensitivity that is being reported from many of these tests are anywhere from 80% to 90%. For specificity, if you are looking into a tumor-informed assay, you know that whatever you're going to be tracking, these gene signatures are coming from patients’ tumors, since that signature is based on the initial biopsy. Those tests are more specific. Other kinds of ctDNA [tests]—where they are tumor agnostic—are looking for abnormal, circulating cell-free DNA that could be from the tumor.

The tests are fairly sensitive, and they're getting more and more specific. From the many trials and studies that have been published, if there is a ctDNA positivity, that almost always leads to relapse of the cancer.

What additional research needs to be done to bring these MRD assays into clinical practice?

We must ensure that we know how to act on [MRD] results. The biggest challenge we have is that we don't know if these tests would translate into long-term outcomes for our patients. Those are things we still have to show. MRD is basically showing that patients still have miniscule, microscopic, and immeasurable disease. This is a concept that is informing us that these are patients where we're going to see a relapse or something abnormal on imaging in the next 6 to 12 months. We still have to figure out how to act on those [results] and improve the outcome for those patients.

A lot of [MRD testing] is still not ready for primetime. However, MRD is a concept that we have had in a lot of other cancers such as chronic myeloid leukemia and other acute leukemias. Now, it's coming in colorectal cancer and possibly breast cancer. It's just 1 of the tools to detect those patients who still have this minimal, microscopic cancer.

For patients with metastatic HR-positive breast cancer, how do you approach treatment for those who progress following treatment with a CDK4/6 inhibitor?

That has been an area where we have a great need. When we give [these patients] a CDK4/6 inhibitor in combination with endocrine therapy, most will have great outcomes, and we are able to control the cancer for multiple years. However, once they progress on this standard, first-line CDK4/6 inhibitor plus endocrine therapy [combination], that's where there's a great need because the standard of care thus far has been a monotherapy [with an agent such as] fulvestrant [Faslodex].

What we're learning from many clinical trials is that fulvestrant alone would control cancer and [lead to a] progression-free survival [PFS] for approximately 2 to 3 months. That's clearly dismal, so there has been a great need [to improve these outcomes]. That's why there are multiple different agents that are being looked at. Some of them are already approved, but most of these [strategies involve] agents targeting endocrine-resistant pathways or [combinations of] drugs with other targeted agents to get better disease control and potentially improve overall survival.

As we know, there are 2 [newer] drugs already approved [in the post–endocrine therapy setting]: alpelisib [Piqray], which is approved for patients with PIK3CA mutations, and elacestrant [Orserdu], which is approved for patients with ESR1 mutations. We use these drugs, [along] with fulvestrant. There are exciting things ongoing. We have early data from AKT inhibitors, and there are many other estrogen-targeted approaches that are still under investigation.

Some of these patients with ER-positive metastatic breast cancer would be considered HER2-low, and they may be eligible for antibody-drug conjugates in later lines of treatment. Those are also going to be the options for a lot of these patients with ER-positive metastatic breast cancer.

Although elacestrant was approved by the FDA as a single agent for patients HR-positive/HER2-negative breast cancer harboring ESR1 mutations, could this agent have a role in combination strategies in the future?

One thing we know from the phase 3 EMERALD trial [NCT03778931] is that even though the initial PFS benefit seems to be small, as time goes by, and patients who do benefit from the elacestrant benefit long term. The [PFS] curves separate, and we are learning that for patients who respond, they do get durable benefit.

[This approach] is definitely not helping to the same extent in all comers, and we're also learning that patients who have had responses in the first-line setting with CDK4/6 inhibitors are getting more from [elacestrant]. Yes, [elacestrant] doesn't help in a big, meaningful way for all patients; however, for the patients who receive benefit, this benefit can be durable and meaningful. There are trials ongoing looking into combining elacestrant or other oral selective estrogen receptor degraders with a CDK4/6 inhibitor. Those trials are ongoing.

The control arm [for these types of studies], which has been fulvestrant monotherapy, has not been in much use over last many years, and the PFS is approximately 2 months. The bar is low, and that's where elacestrant was able to get an approval. However, the key thing is there will be a subset of patients who would get much more benefit, and that's why we still need to try these drugs.

Looking at AKT inhibitors, where do things stand on these agents’ efficacy?

The challenge with all these drugs is that we not only want to make sure that those drugs are efficacious, but [we need to ensure] that they're not toxic. One of the challenges with alpelisib is the toxicity. What we're seeing is that the newer AKT inhibitors seem to have equal or better efficacy with fewer adverse effects.

There is excitement with these newer, next-generation AKT inhibitors, or inhibitors that would target that pathway. Even though the road has been long and there have been a lot of [negative] studies, now we're seeing a few [newer] AKT inhibitors [emerge]. Of course, none of them are approved yet, but we're excited about what's going to come.

What are your thoughts on retreatment with another CDK4/6 inhibitor after progression on a CDK4/6 inhibitor?

Traditionally we did not have much data about how to proceed in patients whose disease progressed on a CDK4/6 inhibitor; however, the first data came from the phase 2 MAINTAIN trial [NCT02632045], which was presented by Kevin Kalinsky, MD, [of Winship Cancer Institute, in Atlanta, Georgia]. That was the first trial where they showed that patients still had PFS benefit when switching from 1 CDK4/6 inhibitor to another. On this study, patients were predominately on palbociclib [Ibrance], and they were switched to ribociclib [Kisqali], along with a change in endocrine agent, and that was a positive trial that got us excited.

However, the phase 2 PACE study [NCT03147287] evaluated palbociclib beyond progression, and these patients basically stayed on the same CDK4/6 inhibitor, but their endocrine agent was switched. That was a negative trial. At the 2023 ASCO Annual Meeting, [data] presented [showed] the phase 2 PALMIRA trial [NCT03809988] was negative.

If we have to consider CD4/6 inhibition beyond progression, the [scenario] where we have some data [involves] switching from palbociclib to ribociclib. However, I would not continue the same agent beyond progression.

If I have a patient where I would strongly consider continuing a CDK4/6 inhibitor, I will at least consider switching the CDK4/6 inhibitor from palbociclib to ribociclib. Again, this strategy has to be done on a case-by-case basis. I would consider this mostly for patients who have mild progression. I wouldn't consider this a strategy for somebody who has significant progression.

Reference

FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed October 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer