Signatera for detecting molecular residual disease from solid tumour cancers

Level of innovation

All experts said that ctDNA technologies are novel, with 3 considering Signatera to be the first in a new class of procedure. Two experts said that Signatera is 1 of several ctDNA technologies being tested across a range of tumour types and clinical scenarios to determine their clinical utility.

Potential patient impact

The experts commented that Signatera has the potential to help with informing the need for adjuvant therapy and measuring treatment response. It may also help with earlier detection of recurrence. This could then prompt investigations to find the site of cancer and to offer treatment if found. But experts cautioned that they would not begin treatment based on a positive ctDNA test result without any radiological evidence of recurrence because this has not yet been prospectively validated. They advised that this could have a negative psychological impact if a person was told they tested ctDNA-positive but were not treated because of a lack of radiological findings.

One expert noted that if the ctDNA test is negative, a person may be reassured that their tumour has a lower chance of recurrence. But 1 expert cautioned that results from ongoing trials are needed before Signatera can be adopted in the NHS. They advised that without adequate testing and evidence, there is a risk that people could have not enough treatment or too much treatment. Another expert said there are uncertainties in the management of treatment based on test results which could increase patients' anxieties and clinical pressures.

Signatera needs an adequate sample of resected tumour to develop the assay. One expert advised that it is not suitable for small biopsies. Also, if the tumour relapses with different clonal mutations to the primary tumour, recurrence may not be identified. The frequency of this is uncertain and likely low. Non-genotype-informed ctDNA assays have a higher risk of false positives and are less reliable at detecting very low sequence variants. But they can detect evolving variants and allow for tumour heterogeneity.

Potential system impact

The experts advised that Signatera would be used in addition to standard care. Three experts said it could replace elements of standard care if evidence from prospective randomised trials was available. The experts said that using Signatera after surgery could reduce the use of adjuvant therapy in people who test negative. There is evidence that a ctDNA-guided approach to treating stage 2 colon cancer could reduce adjuvant chemotherapy without affecting survival (Tie et al. 2022) but this trial was not on Signatera. Selecting the right population for adjuvant therapy could have cost savings. But another expert noted that it could result in increased healthcare system burden if the frequency of imaging was increased to confirm ctDNA-positive results. Experts advised that detailed cost-effectiveness analysis is needed across different tumour types and clinical settings.

General comments

All experts advised that ctDNA testing is not routinely used in the NHS because of a lack of funding and a lack of prospective data on its clinical implementation. Signatera is currently used in research or pilots in limited NHS trusts. The experts advised that the evidence on ctDNA testing is strongest in colon cancer but more evidence is needed for other tumour types.

One expert advised that the European Society for Medical Oncology does not recommend molecular residual disease testing in adjuvant or surveillance settings because of a lack of data from prospective trials. There is uncertainty on whether ctDNA testing results in improved clinical decision making and clinical outcomes. All experts said more prospective evidence is needed. Data should be generated for each tumour type to inform the use of Signatera in both testing settings proposed by the company. Experts acknowledged that gaps in the evidence may be answered by ongoing trials