Advice

The technology

The technology

Signatera (Natera) is a personalised molecular residual disease (MRD) assay that measures circulating tumour DNA (ctDNA) in the body. It is intended to help identify ctDNA in people with solid tumours, including colorectal, breast, bladder, renal and lung cancer. ctDNA is a type of cell-free DNA (cfDNA) that can suggest the presence of cancer cells.

Initial testing requires samples of a person's blood and solid tumour tissue from surgical resection. Signatera sequences the tumour tissue to identify the person's unique signature of tumour mutations. This is used to design a multiplex polymerase chain reaction (PCR) assay targeting 16 patient-specific clonal tumour mutations. Once a personalised assay is designed, subsequent blood samples can be used to monitor the presence or absence of MRD over time and assess disease burden in response to treatment. In NHS settings, patient samples would be collected and shipped to Natera laboratories in the US for Signatera testing. Initial testing takes 2 to 3 weeks, while subsequent tests take around 5 to 7 days from receipt of blood sample to return of results.

Innovations

Experts advised that several ctDNA technologies are being tested across a range of tumour types. Signatera is designed to detect and track tumour‑specific clonal mutations with a low limit of detection below 0.01% variant allele frequency. The company said that other ctDNA tests tend to report average variant allele frequency which can be affected by increases in cfDNA unrelated to disease burden. Signatera calculates mean tumour molecules per millilitre, which the company said is more accurate for tracking cfDNA over time. Signatera also filters out clonal haematopoiesis of indeterminate potential and germline mutations to reduce false-positive results.

Current care pathway

Treatment for solid tumour cancers varies depending on the type and stage of cancer. Surgery is often the first treatment because solid tumours can usually be removed. People may also be offered systemic anti-cancer therapy or radiotherapy. Molecular biomarkers may be used to guide treatment decisions. Some people will have residual disease that may cause recurrence of cancer. Adjuvant therapies such as chemotherapy or biological therapy may be offered depending on the cancer stage and grade, and a person's general health. Prognosis and risk classification may be assessed by:

  • cancer staging systems such as the TNM staging system

  • risk prediction tools such as the PREDICT tool for breast cancer

  • tumour profiling tests

  • discussing risk and disease progression at multidisciplinary team meetings.

Follow up after treatment is offered to monitor treatment response and to detect recurrence. It may include health checks and clinical assessment, imaging such as CT scans and carcinoembryonic antigen (CEA) tests. Surveillance varies depending on cancer type and risk classification.

The European Society for Medical Oncology (ESMO 2020) guideline for localised colon cancer states that postoperative ctDNA shows some benefit in determining risk of recurrence. ctDNA could be considered in addition to standard care to help make decisions about adjuvant care in difficult cases. ESMO does not recommend the routine use of ctDNA to detect MRD because more evidence is needed on its clinical utility (Pascual et al. 2022).

The following publications have been identified as relevant to this care pathway:

Population, setting and intended user

Signatera is indicated for use in people with solid tumour cancers. There are about 375,000 new cases of cancer each year in the UK. Breast, prostate, lung and bowel cancer make up more than half of new cases.

Signatera would be used in addition to standard care. There are 2 Signatera testing settings depending on which treatment the person has had:

  • Adjuvant setting: Signatera can be used in secondary care within 6 months after surgery to evaluate the need for adjuvant therapy. The company proposes that Signatera would be used 2 to 8 weeks after surgery to determine MRD status and to inform if adjuvant treatment is needed. Follow-up testing may be done to increase sensitivity of detecting MRD. People who test MRD-positive and have adjuvant therapy may continue to have follow-up tests every 4 to 8 weeks to monitor treatment response.

  • Surveillance setting: Signatera can also be used after the initial 6‑month postoperative period to detect recurrence and to monitor treatment response. It would be used alongside follow-up visits and tests for up to 5 years in line with monitoring guidelines.

Costs

Technology costs

Signatera costs between £2,900 and £3,500 per test (excluding VAT). Costs include exome sequencing and design of patient-specific primers. There will be some cost to NHS laboratories to collect and prepare samples for testing.

Costs of standard care

Signatera is an addition to standard care. ctDNA assays such as Signatera are not currently part of standard care for solid tumour cancers in the NHS. Costs of standard care will vary depending on type and stage of cancer.

Resource consequences

Signatera is not routinely used in the NHS. It is an external test and is unlikely to need changes in facilities. Signatera may help identify people whose cancer is at risk of recurrence and for whom adjuvant therapy or escalation of treatment is suitable. This may reduce the use of adjuvant therapy in people whose cancer is lower risk. Signatera may also detect recurrence earlier and while the tumour is potentially resectable and may reduce false-positive results from less sensitive markers. It may therefore increase efficiency by offering the right treatment to people when needed. There is evidence from an Australian payer perspective that ctDNA-informed adjuvant chemotherapy may be cost effective compared with standard care (To et al. 2021). There is no evidence on the resource consequences of using Signatera in the NHS.