Glossary:
End of definitive treatment (EODT): completion of primary cancer therapy.
Minimal residual disease (MRD): small amounts of cancer remaining after treatment.
Recurrence-free interval: time that the cancer stays undetected after treatment.
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Low ctDNA Levels May Show Longer Recurrence-Free Interval in Breast Cancer
Key Takeaways
- The ZEST trial, a phase 3 study on MRD-guided therapy in breast cancer, was terminated early due to low randomization rates.
- ctDNA was most frequently detected within six months post-treatment, aligning with TNBC's early recurrence pattern.
In patients with triple-negative breast cancer, ctDNA was most commonly identified within six months after treatment, reflecting the disease’s typical pattern of early recurrence.
Low levels of circulating tumor DNA (ctDNA) may indicate a longer recurrence-free interval in patients with triple-negative breast cancer.
Among patients with triple-negative breast cancer (TNBC), circulating tumor DNA (ctDNA) was detected most frequently on the initial test and at six months or less after treatment, which was consistent with the disease’s typical pattern of early recurrence rates in TNBC, according to data from the terminated phase 3 ZEST trial 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.
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,” Dr. Nick Turner, head of Ralph Lauren Centre for Breast Cancer Research Breast Unit and Clinical Research director at The Royal Marsden and Institute of Cancer Research NIHR Biomedical Research Centre, London, 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 (13 patients) who had high ctDNA levels at baseline had a median disease recurrence of 3.2 months compared with 5.7 months in those treated with Zejula (niraparib; seven patients). Furthermore, patients treated with placebo (nine patients) who had low ctDNA levels at baseline had a median disease recurrence of 7.4 versus 15.9 months in patients treated with Zejula (11 patients).
Median recurrence-free interval in the placebo group was 5.4 months and 11.4 in the Zejula group.
Additional Efficacy Data
Overall, ctDNA was detected in 6.7% of patients within three months following the end of definitive treatment (EODT), 5.2% between three to six months, 2.5% between six to nine months, 3.1% between nine to 12 months and 1.8% beyond 12 months. The study included 147 patients, with the majority having TNBC (135 patients) and a smaller subset having HR–positive breast cancer (12 patients).
Among patients with TNBC, 60% of ctDNA-positive cases were identified within six months post-EODT (81 patients), 29.7% were identified between six to 12 months (40 patients) and 10.4% were identified after 12 months (14 patients). For HR-positive patients, 50% of ctDNA-positive cases were detected within six months (6 patients), 16.7% between six to 12 months (2 patients) and 33.3% beyond 12 months (4 patients). 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 3, 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 Xeloda, (capecitabine) 13.5%).
Trial Design and Patient Characteristics
Patients were eligible for the phase 3 clinical trial if they had stages 1 to 3 breast cancer, TNBC regardless of BRCA status or tumor BRCA1 or 2 pathogenic variant status HR-positive, HER2-negative disease, completed prior standard curative intent therapy including endocrine therapy for HR-positive cancer and adjuvant Keytruda (pembrolizumab) 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.
Patients entered ctDNA surveillance (1,901 patients), 147 patients were ctDNA positive and 96 entered screening. Patients were then randomly assigned (40 patients) to receive placebo (22 patients) or Zejula (18 patients). The trial was unable to evaluate the effect of Zejula veruss placebo because of its termination.
Regarding baseline characteristics, the median age was 59 years in the Zejula group and 53.5 years in the placebo group. Disease types included TNBC (94.4%; 86.4%, respectively) and HR-positive disease (5.6%; 13.6%); centralized BRCA 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 1 (5.6%; 22.7%), stage 2 (33.3%; 13.6%) or stage 3 (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 Xeloda (61.1%; 31.8%), endocrine therapy (0%; 13.6%), Keytruda (0%; 9.1%) and platinum-based chemotherapy (33.3%; 40.9%).
The primary end point was initially disease-free survival, but it was changed to safety and tolerability of Zejula when enrollment stopped. Turner noted that the trial was not powered to evaluate the effect of Zejula versus placebo given early termination; however, recurrence-free interval was numerically longer with Zejula. Turner did not present on the safety or tolerability at the symposium.
Reference:
“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.” By Dr. Nick Turner, et al., 2024 San Antonio Breast Cancer Symposium.
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