MRD Testing Presents Challenges and Opportunities in Breast Cancer Care

Although circulating tumor DNA (ctDNA) technologies are becoming increasingly advanced, the breast cancer field has a long road ahead toward increasing the applicability of ctDNA testing results and appropriately integrating minimal residual disease (MRD) status into treatment decision-making, according to Heather McArthur, MD, MPH.

“We are overtreating the majority of patients because we don’t have clinical insights to refine our treatment recommendations,” McArthur said during the 41st Annual Miami Breast Cancer Conference.¹ “There’s an opportunity to move from following holistic risk stratification to deterministic risk [stratification].”

In her presentation, McArthur discussed the prognostic benefits of ctDNA testing, the limitations that prevent ctDNA results from achieving their predictive potential, and ongoing research efforts that may enhance the use of ctDNA in the future.

McArthur is an associate professor in the Department of Internal Medicine, the clinical director of the Breast Cancer Program, and the Komen Distinguished Chair in Clinical Breast Cancer Research at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas.

The Evolution of ctDNA Testing

McArthur began by explaining that as cancer cells undergo necrosis, apoptosis, and are released into the bloodstream, healthy tissue cells are also released through this process. Therefore, the bloodstream is composed of varying kinds of DNA. Optimal ctDNA testing detects several different DNA components, including tumor mutational burden, mutational signatures, gene alterations, epigenetic changes, and viral sequences. Those genetic changes in the DNA need to be translated into biomarkers that can be used in clinical practice, McArthur emphasized. A comprehensive ctDNA biomarker assay requires a personalized clinical ctDNA sample that is informed by the tumor, the number of targets, actionable alterations, “omic” content, and sequencing depth, as well as an understanding of this technology’s future potential, she explained. McArthur also noted the factors associated with challenges in interpreting ctDNA testing results, including tumor heterogeneity, the primary site of tumor metastasis, field defects, brain metastases, and aspects of the blood-brain barrier.

“We’ve become more comfortable using liquid biopsies, especially for ESR1 mutations,” McArthur said, noting the advantages and disadvantages of liquid and tissue biopsy.

For instance, tissue biopsy can provide pathology information, assess the presence of both DNA and non-DNA biomarkers, and assess PD-L1 expression.² However, it has a longer turnaround time than liquid biopsy, patient tissue quantities are often limited, the biopsy procedure is invasive, rebiopsy is not always feasible for patients with progressive disease, and tumor heterogeneity can interfere with results. Meanwhile, liquid biopsy has a high concordance rate with tissue biopsy results and a rapid turnaround time, is minimally invasive, repeatable over time, and can capture tumor heterogeneity and clonal evolution better than tissue biopsy. However, this testing method cannot evaluate non-DNA biomarkers, incurs increased costs if used concurrently with tissue biopsy, and has the potential for false negative results.

“The recommendation for us is to do liquid biopsies, and then if you don’t identify a mutation, then to go back to the tumor and do the tumor biopsies,” McArthur said.¹

She stated how the 2023 FDA approval of elacestrant (Orserdu) for patients with estrogen receptor­ (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer ignited more widespread use of liquid biopsy to determine whether patients were eligible to receive this therapy.³

Translating Metastatic Success to Early-Stage Disease

Several studies in the metastatic breast cancer setting are stratifying patients based on mutations that are identified in ctDNA. For example, in the phase 2 plasmaMATCH trial (NCT03182634), patients underwent ctDNA testing, and based on the actionable mutations that were identified, were assigned to cohorts where they received extended-dose fulvestrant (Faslodex) for ESR1-mutated disease, neratinib (Nerlynx) for HER2-mutated disease, capivasertib (Truqap) plus fulvestrant for AKT1-mutated disease, or capivasertib for AKT1/PTEN-mutated disease.⁴ However, McArthur noted that challenges remain regarding the optimal use of ctDNA testing strategies in the early-stage setting.¹

In the early-stage setting, the hope is that ctDNA can be used to identify patients’ specific risk of recurrence to provide targeted treatment delivery, expand the range of potential treatments, and lengthen the time during which patients are eligible for these treatments, McArthur explained.

“We are struggling in clinic because we are overtreating the majority of patients to benefit about 10% or fewer patients with almost everything that we do,” McArthur emphasized. “We are overtreating the majority of patients to benefit the minority because we can’t see these micrometastatic problems, so we are erring on the side of overtreating, rather than refining our treatment recommendations.”

McArthur explained that the existing thresholds for breast cancer treatment are low, and that metastatic recurrences often occur regardless of patients’ therapeutic history. Some of the rationale for this overtreatment of patients with early-stage breast cancer stems from the clinical presentation of the disease. Most patients diagnosed with breast cancer present with nonmetastatic disease and are cured. However, most cases of metastatic breast cancer are considered recurrent cases, “not because it was recurrent but because it was there…in the first place, we just didn’t detect it upfront,” according to McArthur.

Intercepting Disease Recurrence With ctDNA Testing

Despite the large absolute number of patients who experience relapse with incurable breast cancer, the proportion of all patients who relapse is small, McArthur noted. Although prognostic models informed by primary tumor or disease characteristics can identify patients at higher risk for recurrence, only a small number of this patient subset will relapse, and a narrow focus on relapse potential in high-risk patients may lead to missed relapses in patients not determined to be high risk. Ideally, tools such as ctDNA would be used to more accurately identify patients who are most likely to recur, allowing for more specialized clinical trial enrollment of only patients who are most likely to benefit from a novel therapy, as well as to avoid overtreating patients who would not benefit from those therapies because they would never recur.

McArthur emphasized that this use of ctDNA could directly inform clinical trial design, noting that by these standards, trials could be smaller and more focused, patient populations could be more specific, and follow-up times could be shorter. These trials would be faster and cheaper than many current trials, and the indications of agents validated in these trials could be extended to any patients positive for their respective biomarkers, she said.

Applying ctDNA Results in Early-Stage Breast Cancer

McArthur summarized the potential applications of ctDNA in early-stage breast cancer, including early detection, patient selection for specific therapies, treatment response measurement, and identification of disease biology insights, which may allow for an increased understanding of treatment resistance mechanisms. ctDNA is prognostic, but its real value lies in its potential predictive capabilities, McArthur noted. However, for ctDNA testing to be truly predictive, it must be conducted at the proper time.

Moreover, MRD clearance could serve as a surrogate end point for ctDNA-guided adjuvant therapy, indicating patients who are more likely to be cured. However, questions remain regarding which patient subsets should be tested for MRD status, how this testing should be conducted, which assays should be used, and how often serial testing should be done.

“Specificity is super critical in this setting as well,” McArthur emphasized.

Research such as the phase 2 I-SPY 2 trial (NCT01042379) has shown that MRD detection and dynamics are associated with neoadjuvant therapy outcomes. However, although ctDNA is informative, uncertainties remain regarding clear definitions of MRD and lead times to incurable metastatic disease, McArthur noted.

Several ongoing studies are investigating MRD-guided treatments in patients with early breast cancer across several disease subtypes, including the phase 3 ZEST trial (NCT04915755) of niraparib (Zejula) in patients with ctDNA-positive, BRCA-mutated triple-negative breast cancer (TNBC), the phase 2 C-TRAK-TN trial (NCT03145961), which is evaluating pembrolizumab (Keytruda) in patients with ctDNA-positive TNBC, and the phase 2 LEADER trial (NCT03285412) of ribociclib (Kisqali) in patients with ER-positive disease.

Additionally, the phase 2 KAN-HER2 trial (NCT05388149) is investigating neratinib plus ado-trastuzumab emtansine (Kadcyla) in patients with HER2-positive MRD, with a primary objective of ctDNA clearance at 12 weeks. Notably, this trial is evaluating the efficacy of changing prescriptive patterns based on patients’ ctDNA loss. So far, many of these trial findings have provided prognostic information, but not predictive information, regarding the use of ctDNA, McArthur emphasized.

“ctDNA technologies are rapidly evolving,” McArthur concluded. “They’re available, but we don’t yet have that nice predictive impact, which is so desperately needed. But there are rigorous trials [being conducted], and large-scale academic collaboration can enhance opportunity for success.”

Disclosures: McArthur reported being a consultant for Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi Sankyo, Seattle Genetics, AstraZeneca, and TapImmune; and receiving grant/research support from Bristol Myers Squibb, MedImmune, LLC/AstraZeneca, BTG, and Merck.

References

1. McArthur H. Minimal residual disease in early-stage disease: ready for prime time? Presented at: 41st Annual Miami Breast Cancer Conference. March 7-10, 2024; Miami, Florida.
2. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-1662. doi:10.1016/j.jtho.2021.06.017
3. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed March 10, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/
4. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21(10):1296-1308. doi:10.1016/S1470-2045(20)30444-7