The ZEST trial sheds light on the use of ctDNA to predict breast cancer recurrence

Although the ZEST trial was prematurely terminated due to insufficient enrolment of patients positive for circulating tumour DNA (ctDNA), it offered valuable insights, suggesting that ctDNA testing should be performed earlier in the treatment process rather than waiting until its completion.

“Approximately 20–30% of patients with early-stage breast cancer [BC]  relapse, yet no standard-of-care exists to detect molecular residual disease [MRD] and guide further therapy to prevent relapse,” said Prof. Nicholas Turner (Royal Marsden Hospital, UK) [1]. Testing of ctDNA in plasma may identify MRD after definitive therapy, with ctDNA detection being associated with a high risk of future relapse [2]. Approximately 60% of patients with triple-negative breast cancer (TNBC) have homologous recombination repair deficiency [3]. Prof. Turner commented that niraparib, a highly selective PARP inhibitor approved for the treatment of ovarian cancer, may be beneficial in this group of patients [1].

The ZEST trial (NCT04915755) was the first randomised, double-blind, phase 3 trial in BC to evaluate MRD-directed therapy. The trial aimed to evaluate whether niraparib could improve disease-free survival (DFS) in patients with stage II–III TNBC or HR-positive, BRCA-mutated BC who, after completing treatment, were ctDNA-positive without radiographic recurrence. Of the 2,746 participants who entered the study, only 147 tested positive for ctDNA. After further assessment, this number was reduced to 40 participants, who were then randomly assigned to receive either niraparib (n=18) or placebo (n=22).

A higher ctDNA detection rate was observed in participants with stage III BC compared with those with stage I–II, and in participants without pathologic complete response (pCR) versus those with pCR. In participants with TNBC, 60% of ctDNA detections occurred within the first 6 months following the completion of definitive treatment. A high rate of radiographic recurrence was observed at the time of ctDNA detection.

Prof. Turner highlighted that patients with TNBC with residual disease after neoadjuvant chemotherapy face a high risk of early relapse, making timely detection of recurrence by the ctDNA assay challenging. “This data supports the need to start ctDNA testing before treatment completion, particularly for patients with TNBC with residual disease after neoadjuvant chemotherapy who are at high risk of early relapse,” concluded Prof. Turner.

1. 
   
   1. Turner N, et al. Circulating Tumor DNA Surveillance in ZEST, a Randomized, Phase 3, Double-Blind Study of Niraparib or Placebo in Patients with Triple Negative Breast Cancer or HER2−, BRCA-Mutated Breast Cancer with Molecular Residual Disease After Definitive Therapy. GS3-01, SABCS 2024, 10–13 December, San Antonio, TX, USA.
   2. Nader-Marta G, et al. ESMO Open. 2024;9(3):102390.
   3. Staaf J, et al. Nat Med. 2019;25(10):1526-1533.

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Posted on 23 January 202523 January 2025