Preventing Viral Pandemic Associated Risk of Cancer Death Using Less Invasive Diagnostic Tests- Liquid Biopsies

The purpose of this study is to investigate the feasibility of using ctDNA to support cancer diagnosis and risk stratification where invasive aerosol generating testing (and/or tissue biopsy) is challenging due to infection risk, technical impracticalities and resource limitations, such as during the COVID-19 pandemic and the subsequent recovery period.

This is a prospective, single-centre cohort pilot study using ctDNA informed treatment decisions. If the pilot study is successful within certain tumour types then this protocol may be extended to investigate further the benefit of ctDNA informed treatment decision in those tumour types.

Patients with suspected malignancy for whom invasive biopsy for definitive histological diagnosis is challenging either due to COVID-19-related resource limitations, infection control or technical feasibility will be considered for this study. In this setting liquid biopsy may be used in lieu of tissue biopsy to facilitate treatment or may be used to prioritise standard of care invasive diagnostic tests. The former includes patients who require repeat biopsies for genomic analysis following non-informative results where these would inform standard of care treatment (i.e. NICE (National Institute for Health and Care Excellence)/Cancer Drug Fund (CDF) approved drugs). Tumour types included in this study are therefore those where invasive aerosol generating diagnostic tests such as bronchoscopy, gastrointestinal endoscopy (including endoscopic ultrasound (EUS)) are part of the standard diagnostic pathway and where capacity for these tests has become severely constrained during (and likely after) the COVID-19 pandemic. Tumour types affected include some suspected biliary tract, bladder, colorectal, GIST, lung and pancreatic cancers.

The study is planned to continue until a total of 144 patients have been enrolled. This is anticipated to take up to 12-18 months. Follow-up will continue until patients have diagnosis made (based on ctDNA result) and treatment decision made (deferred or immediate).

Potential patients will be identified in and will usually at the multidisciplinary team (MDT) meeting. They will give consent to participate in the trial and offered a liquid biopsy (ctDNA) in lieu of a tissue biopsy if considered suitable for PREVAIL - ctDNA. This may include patients who require repeat biopsies for further genomic analyses when repeat biopsies are not feasible where liquid biopsy may support prioritisation for invasive diagnostics earlier. ctDNA analysis will involve copy number variant detection and low coverage whole genomic sequencing. ctDNA gene panels have already been validated against tissue based molecular diagnostics for paediatrics (ct_PAED) and colorectal cancer (ct_GI).

This analysis will be performed in an accredited clinical diagnostic laboratory (Translational Research Laboratory, Institute of Cancer Research). Patients will be stratified for treatment or further investigation based on their ctDNA result (either positive or negative), suspected tumour type, radiological (including PREVAIL-imaging risk stratification pathway) and clinical characteristics.

PREVAIL ctDNA- Part 2 Study:

PREVAIL part 2 is a multi-centre, prospective study assessing the impact of Guardant360© liquid biopsy in patients with radiologically suspicious pancreatic cancer (PC) and biliary tract cancer (BTC)without histological confirmation of malignancy.

Liquid biopsies will be implemented into the routine diagnostic pathway across 6 RMP sites for patients with radiologically suspicious stage III/IV PC/BTC as part of the ACCESS implementation programme. Over 12 months, approximately 650 patients will be identified at individual sites by the local team when seen for an invasive procedure and referred in parallel to the Guardant360© test. These patients will proceed through an invasive diagnostic pathway as is standard of care and have a liquid biopsy as a new standard of care. Most patients will undergo both invasive tissue biopsy and liquid biopsy.

Patients with informative liquid biopsy result, but without a histological diagnosis of cancer (either due to inconclusive biopsy result or if the invasive procedure hasn't been performed) will be considered suitable for the study. Only patients with detectable ctDNA without histological confirmation will be suitable for this study (approximately ¼ of patients entering the ACCESS programme). The study is planned to run parallel to the ACCESS implementation programme and it aims to enrole 150 patients.

As part of this study, treatment may be recommended based on the liquid biopsy result. Patients with an invasive biopsy result which is suitable to guide treatment will not be eligible.

ctDNA results will be discussed at the molecular tumour board (MTB) to provide clinical context and validity of the genomic result. In addition, all patients will be discussed at a central upper gastrointestinal cancer multidisciplinary team meeting (MDM) to discuss treatment based on ctDNA results. Treating clinicians will have access to the MTB outcome and patients may be treated based on the ctDNA result in the context of symptoms, tumour markers, and imaging results as a complete diagnostic package.

Eligibility Criteria:
Inclusion Criteria:

* Participants aged ≥18 years old
* Patients with suspected malignancies of early stage colorectal cancer (FIT intermediate and high risk), early and late stage pancreatic cancer, biliary tract cancer, gastro-intestinal stromal tumours, lung cancer or bladder cancer, without a definitive histological diagnosis (including those with inconclusive biopsy result) or
* Patients with histological diagnosis of lung cancer without adequate tissue for NHS genomic test directory predictive biomarker testing
* Ability to provide informed consent.
* Patients with performance status suitable for oncological treatments (ECOG performance status 0-2).

Exclusion criterion:

• Patients with an established histological diagnosis adequate to support standard of care treatment

PART 2:

Inclusion criteria

* Included in the ACCESS implementation programme
* Has detectable ctDNA on Guardant360© assay
* Discussion at molecular tumour board and central multi-disciplinary meeting confirming ctDNA variant is supportive of diagnosis of PC/BTC (diagnostic or consistent with)
* Performance status suitable for oncological treatment
* Ability to provide informed consent

Exclusion criteria

1. Previously diagnosed invasive or haematological malignancy within the past 3 years
2. Outcome at the molecular tumour board not supportive of cancer diagnosis (possibly consistent or not consistent)