What is CT (Computed Tomography) DNA by Signatera?

Understanding Circulating Tumor DNA (ctDNA) by Signatera

Signatera is a personalized, tumor-informed ctDNA assay that analyzes circulating tumor DNA in blood samples to detect minimal residual disease, monitor treatment response, and predict cancer recurrence before clinical or radiological evidence appears. 1

What is ctDNA?

Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. It represents genetic material released from dying cancer cells and can comprise up to 10% of a patient's total cfDNA, depending on tumor type and burden. 2

Key characteristics of ctDNA:

• Short half-life (captures tumor burden in real-time)
• Allows non-invasive, repeated evaluation of tumor genomic profiles
• Can be detected at lower tumor volumes than conventional imaging
• Provides a "liquid biopsy" alternative when tissue sampling is not feasible

How Signatera Works

Signatera is specifically designed as a tumor-informed assay that follows these steps:

1. Personalization: Whole-exome sequencing of the patient's tumor tissue is performed to identify tumor-specific mutations
2. Custom Panel Creation: A personalized panel targeting 16 tumor-specific mutations is created for each patient
3. Ultradeep Sequencing: Blood samples are collected and analyzed using multiplex-PCR next-generation sequencing to detect these specific mutations
4. Quantification: Results are reported as mean tumor molecules per milliliter of blood 3, 4, 5

Clinical Applications of Signatera

1. Minimal Residual Disease (MRD) Detection

• Identifies microscopic disease after curative-intent treatment
• Can detect cancer recurrence months before conventional imaging
• In breast cancer, detected recurrence with a median lead time of 10.5 months (range: 0-38 months) 3
• 88.2% sensitivity for detecting relapse in breast cancer patients 3

2. Treatment Response Monitoring

• Evaluates efficacy of ongoing treatments in real-time
• Provides earlier indication of treatment failure than imaging
• Shows high concordance with radiographic response (83% in genitourinary cancers) 4
• Serial ctDNA negativity or clearance correlates with improved progression-free survival 6

3. Surveillance After Treatment

• Regular monitoring can detect early molecular relapse
• Patients with persistently negative ctDNA have superior outcomes
• In renal cell carcinoma surveillance, ctDNA positivity was associated with significantly inferior progression-free survival (HR 18, P=.00026) 6

4. Molecular Profiling

• Can identify resistance mutations when tumor biopsy is not available
• Helps guide treatment selection based on evolving tumor genomics 1

Advantages Over Conventional Monitoring

• Earlier Detection: Identifies recurrence months before clinical or radiological evidence
• Non-invasive: Requires only a blood sample, avoiding repeated biopsies
• Real-time Assessment: Short half-life ensures results reflect current tumor status
• Personalized: Custom-designed for each patient's unique tumor mutations
• Sensitive: Can detect very low levels of residual disease

Limitations and Considerations

• Tissue Requirement: Initial tumor tissue is needed to create the personalized assay
  • Testing fails in approximately 14% of cases due to insufficient tissue 5
• False Negatives: May occur in certain cancers, particularly hormone receptor-positive breast cancers 3
• CNS Limitations: May not detect brain metastases effectively 4
• Clonal Hematopoiesis: Can be a confounding factor that requires paired whole-blood control 2
• Clinical Integration: While promising, standardized protocols for clinical decision-making based on ctDNA results are still evolving 1

Current Status in Clinical Practice

While ctDNA testing shows tremendous promise, it is still being integrated into standard clinical practice. The European Liquid Biopsy Society and other organizations are working to establish guidelines for the reporting and interpretation of ctDNA results 1. Currently, ctDNA testing is most commonly used in research settings and specialized cancer centers, with growing adoption in routine clinical care.