Terminated study’s ‘challenges’ may guide future trials of MRD-guided breast cancer therapy
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Key takeaways:
- A randomized phase 3 trial of minimal residual disease-guided therapy closed early.
- Future studies should evaluate ctDNA testing prior to the end of neoadjuvant therapy or in other breast cancer subtypes.
SAN ANTONIO — A randomized phase 3 clinical trial designed to assess whether circulating tumor DNA surveillance could be used to help prevent breast cancer recurrence closed early due to a lack of patients eligible for randomization.
Still, the “challenges” encountered in the ZEST study could help inform how future clinical trials of minimal residual disease (MRD)-guided therapy in breast cancer are conducted, according to researcher Nicholas Turner, MD, PhD, director of clinical research and development at The Royal Marsden Hospital and Institute of Cancer Research in London.
“MRD-guided therapy in breast cancer will become a reality,” Turner told Healio. “This is used routinely in hematologic malignancies, but it’s a new tool in breast cancer. We’re still learning the best way to use it in clinical practice, but it will happen.”
An estimated 20% to 30% of patients with early-stage breast cancer relapse after treatment, according to study background.
There is no standard approach to detect MRD and use that information to guide subsequent therapy to prevent or delay relapse. Circulating tumor DNA (ctDNA) in plasma may identify MRD that persists after definitive therapy, Turner said, with detection linked to higher relapse risk.
Turner and colleagues conducted the ZEST trial to evaluate whether niraparib (Zejula, GSK) — a poly(ADP-ribose) polymerase (PARP) inhibitor — could prevent recurrence among patients with stage I to stage III breast cancer who had completed definitive therapy and had ctDNA in plasma but had no evidence of radiographic recurrence.
The study population included patients with triple-negative breast cancer regardless of BRCA status, or patients with BRCA-mutated hormone receptor-positive, HER2-negative disease.
Investigators used a personalized ctDNA assay that assessed blood samples for 16 mutations specific to each patient’s tumor. They performed ctDNA surveillance every 2 to 3 months, with the intention of establishing two cohorts for randomization — one with 600 patients with triple-negative breast cancer and one with 200 patients who had hormone receptor-positive, HER2-negative disease.
Investigators prescreened 2,748 patients and performed ctDNA testing on 1,901 of them. The majority (88.5%) had triple-negative breast cancer.
Only 147 (7.7%) of those who underwent testing had detectable ctDNA and were deemed eligible for the trial. Broad eligibility criteria that allowed patients with low-risk disease to enroll likely contributed to the low rate of ctDNA positivity, Turner said.
More than half (55%) of those with detectable ctDNA had it within 6 months of treatment completion. The majority (66.6%; n = 98) had detectable ctDNA on their first test and, by that time, 51 (55%) of those 98 patients already had imaging-detectable disease recurrence.
Forty-eight patients had detectable ctDNA on later tests, and 21 (44%) of them had imaging-detectable recurrence at the time of their first positive test.
Patients found to be ctDNA positive more frequently had larger tumors, positive lymph nodes, stage III disease and residual disease after neoadjuvant therapy. They also were more likely to have received neoadjuvant and adjuvant therapy.
The study was terminated early because of the low randomization rate.
Before termination, researchers had enrolled 40 patients and randomly assigned them to receive niraparib (n = 18) or placebo (n = 22).
Median recurrence-free interval reached 11.4 months in the niraparib group and 5.4 months in the placebo group (HR = 0.66; 95% CI, 0.32-1.36). Six patients assigned niraparib and four assigned placebo remained free of recurrence at data cutoff.
However, Turner emphasized the number of patients was insufficient to perform a “meaningful assessment” of niraparib’s efficacy for preventing recurrence.
“The challenges the study faced have implications for future clinical trial design,” Turner said in a press release. “First, given our observation that half of patients with detectable ctDNA already had relapsed disease, future studies should begin ctDNA testing prior to the end of neoadjuvant therapy instead of waiting for completion of treatment.”
Occasional ctDNA testing during neoadjuvant therapy could identify those who remain positive for ctDNA, he said. This approach could be especially important for people with triple-negative breast cancers, who may relapse quickly if neoadjuvant therapy does not eradicate the disease.
Future studies should include patients with higher risk for relapse who are more likely to have ctDNA-positive disease, Turner said. These include patients with stage IIB or stage III cancers who do not achieve pathologic complete response to neoadjuvant therapy.
It’s also possible that ctDNA surveillance may be more impactful in breast cancer subtypes other than triple-negative disease, where it may take longer to relapse and allow more time for therapeutic intervention.
“That is absolutely one of the conclusions you can reach from the ZEST study,” Turner told Healio. “Some triple-negative breast cancers — in this monitoring phase — come back so quickly that they can be very hard to intercept. We don’t see that rapidity with other subtypes.”
Perspective
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Carlos Arteaga, MD, FAACR
The fact so many patients who tested positive for ctDNA already had evidence of radiographic recurrence suggests the possibility that the kinetics of [triple-negative breast cancer] are so fast that ctDNA may not be that helpful. ctDNA is definitely a way to detect minimal residual disease. The problem is that, in some cases, there may not be enough lead time between that detection and clinical recurrence, as we usually diagnose it. Maybe that will happen in other tumor types that are not triple negative — perhaps ER-positive tumors — and with better assays. So this continues to evolve and is a work in progress.Perspective
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This study aimed to answer a question that is very important for a number of reasons. This phase 3 trial examined whether adding the PARP inhibitor niraparib — compared with placebo — would prevent or delay recurrence among patients with triple-negative breast cancer or BRCA-mutated hormone receptor-positive breast cancer who had completed active therapy and had a positive ctDNA result without radiologic evidence of disease.
This is an important issue because we know a vast majority of patients who test positive for ctDNA will ultimately develop recurrence, and we don’t yet know how to intervene in those cases. Trials are ongoing testing interventions in different patient populations.
Unfortunately, this particular study was terminated early. Although 1,901 patients underwent ctDNA testing, only 7.7% had detectable ctDNA. After excluding patients who already had radiologic evidence of disease at time of the positive ctDNA test and others who were ineligible, only 40 patients were able to be randomly assigned to niraparib or placebo because nearly half of patients who had positive ctDNA already had evidence of radiographic recurrence at that time.. Patients who tested positive for ctDNA were more likely to have later-stage disease, residual disease after neoadjuvant therapy, and have received both neoadjuvant and adjuvant therapy. The numbers were too small for a statistical analysis to be performed but numerically, patients assigned niraparib had a median recurrence-free interval of 11.4 months vs. 5.4 months for patients assigned placebo. Because of the small sample size, we cannot make any definitive conclusions.
The fact that approximately half of the patients with positive ctDNA already had radiographic evidence of progression and that over half of the patients had a positive ctDNA within 6 months of completing treatment really highlights the importance of risk stratification and monitoring in a high-risk population. We need more studies testing the clinical utility of ctDNA for monitoring and intervention with additional therapies. Future research will help guide the role of ctDNA, and hopefully we can use this technology to improve outcomes for our patients.
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Turner N, et al. Abstract GS3-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio.
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