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

Circulating tumor DNA (ctDNA) positivity occurred most frequently on the first test and 6 months or less after treatment in patients with triple-negative breast cancer (TNBC), which is consistent with early recurrence typically observed 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 the first phase 3 trial for minimal-residual disease (MRD)–guided therapy in breast cancer. However, the trial was terminated early because of low randomization rates.

“The trial was terminated because of a low randomization rate, 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, from Ralph Lauren Center for Breast Cancer Research in London, explained during the presentation.

An exploratory analysis 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 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) and who had low ctDNA levels at baseline had a median recurrence of 7.4 months (95% CI, 2.6-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).

Recurrence-free interval—as defined per STEEP 1.0—events in the placebo arm (n = 22) occurred in 77.3% of patients (n = 17) and 77.8% of patients (n = 14) in the niraparib arm. Median recurrence 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).

ZEST Design and Patient Characteristics

ZEST was the first phase 3, randomized, double-blind clinical trial that included patients with stages I-III breast cancer, TNBC regardless of BRCA status or tBRCAm HR-positivity or HER2-negativity, 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 neoadjuvant chemotherapy and tumors showed no response were excluded from the study.

Primary end point was initially disease-free survival, but it was changed to safety and tolerability of niraparib when enrollment stopped.

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

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

Baseline characteristics of randomized patients demonstrated a median age of 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%) and HR-positive disease (5.6%, 13.6%), centralized tBRCA status including 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 disease (61.1%, 63.6%). 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 post-end of definitive treatment (EODT), 5.2% between 3-6 months, 2.5% between 6-9 months, 3.1% between 9-12 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 6-12 months (n = 40), and 10.4% were identified after 12 months (n = 14). For HR+ patients, 50% of ctDNA–positive cases were detected within 6 months (n = 6), 16.7% between 6-12 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.

Regarding ctDNA detection associations, ctDNA positivity was found in patients with TNBC (8.0%) compared with HR–positive disease (5.5%), those with local BRCA status including mutant (5.0%), wild type (8.0%), and unknown (9.0%). Node statuses included positive (11.7%), negative (5.3%), and not available (6.6%). Stages included stage I (2.3%), stage II (6.9%), and stage III (13.7%). Pathologic outcome from neoadjuvant treatment included pathological complete response (pCR; 2.1%) and non-pCR (13.7%). Systemic anticancer therapies included neoadjuvant (6.8%), adjuvant (4.2%), neoadjuvant plus adjuvant (12.8%), and no systemic therapy (4.4%). Prior therapies included capecitabine (13.5%), endocrine therapy (4.0%), pembrolizumab (9.1%), and platinum-based chemotherapy (9.1%).

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, TX. Abstract GS3-01.