SABCS24 | ZEST trial challenges provide insights into the use of ctDNA in predicting breast cancer recurrence
Data presented at SABCS 2024 emphasizes the importance of early ctDNA testing for the prediction of breast cancer recurrence.
The results of the ZEST Trial, presented at the San Antonio Breast Cancer Symposium (SABCS) held 10–14 December 2024 (TX, USA), have provided new perspectives for future trial design and the use of circulating tumor DNA (ctDNA) to predict breast cancer recurrence, despite the trial’s early termination.
The ZEST trial, a randomized, Phase III, double-blind study of Zejula® (niraparib) or placebo, was terminated early due to low enrolment of stage I-III breast cancer patients positive for ctDNA. The trial aimed to evaluate whether niraparib, a PARP inhibitor, could prevent breast cancer recurrence in patients with minimal residual disease, defined in the study as the presence of ctDNA, after the completion of curative intent therapy.
“The aim was to develop a new treatment strategy for patients with stage I to III breast cancer who have detectable ctDNA and therefore are at higher risk of recurrence,” commented study presenter Nicholas Turner (The Royal Marsden Hospital and Institute of Cancer Research, both London, UK).
Patients eligible for the trial included those with either stage I-III TNBC or BRCA-mutated HER2 negative breast cancer who had completed their recommended treatment and had detectable ctDNA. To detect ctDNA, a personalized, tumor-informed ctDNA assay was used, with testing for ctDNA-based molecular residual disease beginning any time after completion of curative intent therapy. A positive ctDNA result was followed by radiographic staging, after which, those without evidence of metastatic disease were randomized to receive either niraparib or placebo.
Of the 1,901 patients who underwent ctDNA testing, 147 were deemed eligible for the trial. Overall, 55% of the eligible patients had detectable ctDNA within 6 months of treatment completion. Out of 147 patients, 98 had detectable ctDNA on their first test, 51 of which already had disease recurrence that was detectable by imaging, invalidating their participation in the study.
Patients with positive ctDNA tended to have positive lymph nodes, stage III disease, residual disease following neoadjuvant therapy, and had received both neoadjuvant and adjuvant therapy, compared to patients with undetected ctDNA.
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A total of 40 patients were enrolled in the trial and were randomly assigned between the receipt of either niraparib or placebo prior to termination. Unfortunately, this was an insufficient number of patients to allow for meaningful evaluation of niraparib for the prevention of breast cancer recurrence. Although the trial was terminated, median recurrence-free interval was 11.4 months for patients in the niraparib arm and 5.4 for those in the placebo arm at the time of data cutoff.
Important insights can be taken away from the results of the ZEST trial, “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,” recommended Turner. This would allow for the early identification of ctDNA-positive patients after neoadjuvant treatment, benefiting those with rapidly relapsing subtypes after neoadjuvant treatment failure, such as TNBC.
“We may also want to focus on different subtypes where ctDNA is potentially more impactful with longer lead times over relapse,” Turner commented.