Predicting Breast Cancer Recurrence with ctDNA

Why Is Detecting Minimal Residual Disease Important?

Reducing the risk of recurrence after cancer treatment is one of modern oncology's greatest goals. Minimal residual disease (MRD) refers to cancer remnants that remain in the body after treatment but cannot yet be detected by standard imaging methods. Testing for circulating tumor DNA (ctDNA) enables early detection of MRD and proactive measures against recurrence risk. However, the 2024 San Antonio Breast Cancer Symposium presentation of the phase III ZEST study revealed various obstacles to the progress expected in this field.

• Related topic: What Is Minimal Residual Disease in Cancer? Its Importance and How Liquid Biopsy Detects It

The Aim and Design of the ZEST Study

The ZEST study aimed to evaluate the effectiveness of the PARP inhibitor niraparib in preventing cancer recurrence in patients positive for circulating tumor DNA (ctDNA).

The study included patients with stage 1 to 3 triple-negative breast cancer or hormone receptor-positive breast cancer carrying a BRCA mutation.

To participate, patients had to have completed the standard treatment protocol and be ctDNA-positive.

ctDNA positivity means that circulating tumor DNA is detected in the blood and generally indicates residual cancer in the body after treatment. This suggests that the risk of recurrence may be high and that early intervention may be needed.

Patients with hormone receptor-positive disease were allowed to continue stable endocrine therapy. To detect ctDNA and identify 16 disease-specific mutations, the personalized blood test Signatera was used.

Key Findings

• Of the 1901 patients who underwent ctDNA testing, only 7.7% were ctDNA-positive.

• Of the 147 patients who tested ctDNA-positive, 55% received this result within the first 6 months after completing treatment.

• Of the 147 patients, 98 were ctDNA-positive at the first test, and imaging detected disease recurrence in 51% of these patients.

• Among the 48 patients whose subsequent tests became ctDNA-positive, imaging also detected recurrence at the first ctDNA-positive test in 44%.

Insufficient Enrollment and Early Termination

The study randomized 40 patients to niraparib or placebo. However, this number was not large enough for a meaningful analysis. The mean recurrence-free interval was 11.4 months in patients receiving niraparib, compared with 5.4 months in the placebo group. Although early termination prevented statistically meaningful assessments, the data offered some clues.

Clinical Implications and Recommendations for Future Research

Dr. Nicholas Turner stated that the challenges encountered in conducting the study could guide future clinical trial designs:

1. Early ctDNA Testing: Starting ctDNA testing during neoadjuvant treatment rather than after treatment may help detect disease early.

2. Focusing on High-Risk Groups: ctDNA testing may be more useful in higher-risk patients, such as those with stage 2B or 3 disease who do not achieve a pathological complete response.

3. Subtype-Based Strategies: In subtypes such as triple-negative breast cancer, ctDNA may provide a longer lead time before disease recurrence.

Conclusion: Key Lessons for Future Research

The ZEST study highlighted many important considerations for integrating ctDNA testing into clinical practice. Low enrollment demonstrated the importance of testing timing and the need to focus on high-risk groups. Early detection, regular monitoring, and patient-specific strategies will be important in advancing this field.