Monitoring How Tumors Respond to Treatment with ctDNA

Helio Costa, PhD

Helio Costa, PhD, is the medical director of oncology at Natera.

Q: How can ctDNA testing be used to improve cancer management?

A: Circulating tumor DNA (ctDNA) is tumor-derived DNA that is found in the bloodstream. As tumors grow, a portion of the tumor cells die and release fragments of tumor DNA into the circulatory system. These DNA fragments can be profiled by ctDNA tests, such as Signatera, to identify genetic biomarkers which can be used to monitor tumor response to cancer treatment or detect cancer recurrence post-remission.  

Q: Can you tell me more about Natera's

Signatera assay?

A: The Signatera assay is a tumor-informed test to detect ctDNA for molecular residual disease (MRD) assessment and disease recurrence for patients previously diagnosed with cancer. We custom build our Signatera assay for each patient by developing a 16-biomarker personalized tumor DNA signature for that patient's tumor, which allows us to non-invasively monitor cancer recurrence and inform treatment decisions. 

Q: The assay was used in a 2020 study on ctDNA-based surveillance in patients treated with immunotherapy published in Nature Cancer. What were the study's findings? 

A: The prospective Phase 2 INSPIRE study followed patients with advanced cancer across 25 different types of solid tumors being treated with pembrolizumab. Whole exome sequencing was performed using tumor and matched normal DNA, and bespoke ctDNA assays were designed using Signatera. ctDNA assessments were made at baseline in 94 patients, and every three cycles during treatment in 73 patients where serial plasma samples were available. Key findings from the study include:

• Signatera detected ctDNA before treatment in 98 percent of cases (92/94), emphasizing its validity as a universal biomarker across tumor types.
• ctDNA increase after just six weeks of treatment, together with increasing tumor volume on imaging, was identified in 42 percent of patients (30/73) and predicted treatment non-response with 100 percent accuracy. These patients received on average six extra weeks of treatment that potentially could have been avoided.
• ctDNA clearance at any time point during treatment was achieved by 16 percent of patients (12/73) and was associated with 100 percent overall survival with a median of 25.4 months of follow-up beyond first clearance.
• All findings were independent of tumor mutational burden (TMB) and PD-L1 status.

Q: In what ways does Signatera differ from traditional monitoring tests? 

A: The personalized design of Signatera for every patient is what sets it apart from traditional monitoring tests such as imaging or protein biomarkers from the blood. By profiling a patient's tumor, we are able to create a unique mutational “fingerprint” or “signature” that allows us to uniquely track the tumor's response to treatment over time from a non-invasive blood draw.

Q: How does Natera's Altera assay help to support patient treatment decisions?

A: Altera is a comprehensive genomic profiling test that can be used to identify somatic mutations, which can inform eligibility for FDA-approved treatments or ongoing clinical trials. Additionally, Altera can be used to identify somatic mutations for prospective therapeutic options for when standard of care is exhausted. 

By performing whole exome sequencing and whole transcriptome sequencing, Altera is able to identify somatic single nucleotide variants, insertions and deletions, copy number alterations, and structural variants that can inform therapy selection. Additionally, this information allows us to assess TMB, microsatellite instability, and profile genes related to homologous recombination deficiency.

The benefit of ordering Altera together with Signatera is that only one tumor tissue sample is needed to receive results from Altera for therapy selection and to design Signatera for treatment response and disease recurrence monitoring.