Recurrence-Free Interval Is Longer With Low ctDNA Levels at Baseline in TNBC

Circulating tumor DNA (ctDNA) was detected most frequently on the first test and at 6 months or less after treatment in patients with triple-negative breast cancer (TNBC), which was consistent with the observed early recurrence rates in TNBC, according to data from the terminated phase 3 ZEST trial (NCT04915755) presented at the 2024 San Antonio Breast Cancer Symposium (SABCS).

The ZEST trial was considered the first phase 3 trial of minimal-residual disease (MRD)–guided therapy in breast cancer. However, the trial was terminated early because of low randomization rates.

“… and this largely reflected broad entry criteria that allowed a relatively large number of low-risk patients to enroll that resulted in a low rate of ctDNA detection,” Nick Turner, MD, head, Ralph Lauren Centre for Breast Cancer Research Breast Unit, Clinical Research director, The Royal Marsden and Institute of Cancer Research NIHR Biomedical Research Centre, London United Kingdom, explained during the presentation.

In an exploratory analysis, data demonstrated that the recurrence-free interval may be longer in patients with low ctDNA levels at baseline. Findings showed that patients with TNBC treated with placebo (n = 13) who had high ctDNA levels at baseline had a median disease recurrence of 3.2 months (95% CI, 0.3-9.3) compared with 5.7 months (95% CI, 0.6-14.1) in those treated with niraparib (Zejula; n = 7; HR, 0.91; 95% CI, 0.34-2.44). Furthermore, patients treated with placebo (n = 9) who had low ctDNA levels at baseline had a median disease recurrence of 7.4 months (95% CI, 2.6-not evaluable [NE]) vs 15.9 months (95% CI, 8.2-NE) in patients treated with niraparib (n = 11; HR, 0.60; 95% CI, 0.20-1.81).

Median recurrence free interval in the placebo arm was 5.4 months (95% CI, 2.8-9.3) and 11.4 months (95% CI, 5.7-18.2) in the niraparib arm (HR, 0.66; 95% CI, 0.32-1.36).

Trial Design and Patient Characteristics

Patients were eligible for the phase 3, randomized, double-blind clinical trial if they had stages I to III breast cancer, TNBC regardless of BRCA status or tumor BRCA1/2 pathogenic variant status HR-positive, HER2-negative disease, completed prior standard curative intent therapy including endocrine therapy for HR-positive cancer and adjuvant pembrolizumab (Keytruda) for TNBC, and had no clinical signs of recurrence. Patients who had received neoadjuvant chemotherapy and whose tumors showed no response were excluded from the study.

The primary end point was initially disease-free survival, but it was changed to safety and tolerability of niraparib when enrollment stopped. Turner noted that the trial was not powered to evaluate the effect of niraparib versus placebo given early termination; however, recurrence-free interval was numerically longer with niraparib. Turner did not present on the safety or tolerability at the symposium.

Patients entered ctDNA surveillance (n = 1901), 147 patients were ctDNA positive, and 96 entered screening. Patients were then randomly assigned (n = 40) to receive placebo (n = 22) or niraparib (n = 18). The trial was unable to evaluate the effect of niraparib vs placebo because of its termination.

The tumor-informed ctDNA Signatera assay was developed using whole-exome sequencing of tumor tissue and matched blood, and tracked 16 mutations per patient. ctDNA surveillance was conducted every 2 to 3 months, per investigator discretion.

Regarding baseline characteristics, the median age was 59.0 years (range, 37-76) in the niraparib arm and 53.5 years (range, 29-77) in the placebo arm. Disease types included TNBC (94.4%; 86.4%, respectively) and HR-positive disease (5.6%; 13.6%); centralized tBRCA status included mutant (5.6%; 22.7%) and wild type (94.4%; 77.3%). Node status was positive (66.7%; 63.6%), negative (33.3%; 31.8%), or not available (0%; 4.5%). Patients had stage I (5.6%; 22.7%), stage II (33.3%; 13.6%), or stage III (61.1%; 63.6%) disease. Systemic anticancer therapies received by patients included neoadjuvant (27.8%; 22.7%), adjuvant (11.1%; 31.8%), or neoadjuvant plus adjuvant (61.1%; 45.5%). Prior therapies included capecitabine (Xeloda; 61.1%; 31.8%), endocrine therapy (0%; 13.6%), pembrolizumab (0%; 9.1%), and platinum-based chemotherapy (33.3%; 40.9%).

Additional Efficacy Data

Overall, ctDNA was detected in 6.7% of patients within 3 months following the end of definitive treatment (EODT), 5.2% between 3 to 6 months, 2.5% between 6 to 9 months, 3.1% between 9 to 12 months, and 1.8% beyond 12 months. The study included 147 patients, with the majority having TNBC (n = 135) and a smaller subset having HR–positive breast cancer (n = 12).

Among patients with TNBC, 60% of ctDNA-positive cases were identified within 6 months post-EODT (n = 81), 29.7% were identified between 6 to 12 months (n = 40), and 10.4% were identified after 12 months (n = 14). For HR-positive patients, 50% of ctDNA-positive cases were detected within 6 months (n = 6), 16.7% between 6 to 12 months (n = 2), and 33.3% beyond 12 months (n = 4). However, the researchers noted that the data for HR-positive patients were limited due to the small sample size.

ctDNA detection was associated with disease stage (stage III, 13.7%) pathological outcome from neoadjuvant treatment (non-pathologic complete response, 13.7%), systemic anti-cancer therapy (neoadjuvant plus adjuvant, 12.8%), and prior therapy (capecitabine, 13.5%).

Reference

Turner N, Pimentel I, Cescon D, 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. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-14, 2024; San Antonio, Texas. Abstract GS3-01.