MRD Testing Requires Prospective Data to Assess Clinical Utility in Breast Cancer

Lajos Pusztai, MD, DPhil

Although assays measuring molecular residual disease (MRD) have demonstrated analytical validity, data from prospective trials are necessary to assess the clinical utility of using MRD and circulating tumor DNA (ctDNA) status to inform real-world treatment decisions for patients with breast cancer, according to Lajos Pusztai, MD, DPhil.

“The vital missing piece in the current literature is the clinical utility. [Will] acting on the [MRD] assay results improve outcomes?” Pusztai said in an interview with OncLive® during the 23rd Annual International Congress on the Future of Breast Cancer^® East, where he presented on the progress and challenges in monitoring MRD in early-stage breast cancer.

In the interview, Pusztai, a professor of medicine at Yale School of Medicine and co-leader of Genetics, Genomics, and Epigenetics at Yale Cancer Center in New Haven, Connecticut, underscored the transformative potential of liquid biopsy technologies in MRD monitoring in breast cancer, highlighted the challenges of integrating these techniques into clinical practice, and discussed ongoing studies looking at the role of ctDNA in patients with early-stage breast cancer.

OncLive: What is currently known about the role of MRD in early-stage breast cancer?

Pusztai: MRD monitoring in the blood is now available through multiple different commercial companies. The Signatera assay by Natera was approved for reimbursement by the Centers for Medicare & Medicaid Services [in 2023] for stage IIB and III early-stage breast cancer.

There are multiple other platforms that have analytical and clinical validity. Analytical validity means that they reliably measure the molecules that they are supposed to measure, which is tumor-derived DNA in the blood. The clinical validity implies [the ability] to predict outcomes, which in the MRD monitoring setting is the outcome that ctDNA positivity predicts disease recurrence. Most patients [who] become ctDNA positive will [do so] 6 to 9 months before [their disease] becomes clinically metastatic or they deal with symptoms from their metastatic disease.

What challenges still exist for the use of MRD status in breast cancer?

The fundamental challenge is the initial decision whether to request the actual assay. If you decide to monitor [for MRD], the next major decision point is [deciding] what to do if the assay result comes back positive. The initial steps are fairly straightforward [in the event of a positive MRD test]. Most of us would repeat staging studies, CT scans of the chest, head, and pelvis, and a PET CT to look for metastatic recurrence that's apparent on imaging. However, the expectation is that the ctDNA assay will turn positive before the disease [recurrence] can be diagnosed with more traditional imaging modalities.

What should we do with a patient who is ctDNA positive but imaging negative? We refer to this as molecular relapse. There are no clinical trial results to guide [next steps in this situation]. We have a registry study at Yale, and setting up registries is doable in almost any practice setting. You want to follow what happens to patients and discuss the theoretical benefit of treating early [after a patient becomes ctDNA positive] vs waiting until a clinical recurrence, which is unfortunately likely. [Conversely], if a patient does not want to receive treatment that can only decrease their quality of life in the absence of any disease, then you wait and repeat the imaging and testing later. Following patient outcomes, regardless of how they decide [to approach treatment after a positive ctDNA test] could be informative in the long run, [even though the data are] not as informative as a randomized trial.

We do have the [ongoing] randomized phase 2 DARE trial [NCT04567420] that directly addresses the question of whether early intervention for molecular relapse improves outcomes. DARE is open in 15 different locations across the United States, and we would encourage physicians to refer patients to the DARE clinical trial sites so that we can learn from these experiences.

However, in the absence of [clinical trials], ctDNA monitoring is best done in the context of a registry, [allowing] you to build evidence about clinical utility [of MRD testing].

Are there any clinical trials currently exploring the use of ctDNA monitoring within EBC?

Our academic community hasn't done a great job exploring the potentially paradigm-shifting impact of [MRD testing]. The main message should be clear: [we have the] opportunity to potentially capture and intercept an impending recurrence. The hope here is that capturing recurrence at a micro-metastatic state—at a molecular relapse state—and intervening with an effective, first-line–like regimen could offer a chance of cure. That's basically the idea of a second line of adjuvant therapy. However, there is only 1 randomized clinical trial in the United States addressing this question, and that's the DARE study.

There are single-arm phase 2 trials that are looking at various options and ctDNA clearance in [patients with] triple-negative disease. There is a randomized trial at a Dana-Farber Cancer Institute—the phase 2 LEADER study [NCT03285412]—that is comparing different sequencing of ribociclib, but it doesn't have a [placebo]-controled arm.

There is the phase 3 [TREAT] trial [NCT05512364], but it is unfortunately outside of the United States in Europe. [TREAT is] using elacestrant [Orserdu] in a randomized fashion. Patients [ with stage IIB or III estrogen receptor–positive, HER2-negative breast cancer who test positive for ctDNA will be randomly assigned to] switch to elacestrant or continue their endocrine therapy regimen. We need more studies in this space.

What advice would you give to providers seeking to monitor MRD in EBC?

The current, commercially available ctDNA assays are technically valid. They do identify tumor-derived DNA in the blood. [If a patient is found to be] ctDNA positive, unfortunately, their risk of recurrence is very high. Studies consistently show that with a lead time of 8 to 9 months, most patients start to experience clinical signs of recurrence and become overtly metastatic.

However, these assays are not perfect. There are patients who recur in the absence of detectable ctDNA, at least at the time point when these studies [were conducted]. On the flip side, there may be some patients who are ctDNA positive but continue to do well for a long time.

The biggest challenge for us is to learn whether acting on ctDNA positivity in the absence of any other measurable lesions will improve outcomes. There is a strong and rational hypothesis that this should happen; however, there are no clinical trial data to either prove or disprove this. On the other hand, the assays are commercially available and reimbursable, and this gives us an opportunity to learn, even from routine practice.

At [Yale Cancer Center], we have a registry and a randomized trial. The registry is open for patients with triple-negative breast cancer and for patients who, for various reasons, don't qualify or don't participate in the DARE trial. We can use these two learning opportunities— the registry and the randomized trial—to justify the use of ctDNA monitoring.

Reference

Pusztai L. Progress and challenges in monitoring for molecular residual disease in early-stage breast cancer. Presented at: 23rd Annual International Congress on the Future of Breast Cancer East; July 19-20, 2024; New York, NY.