Clinical trial NCT04957433: 'Lung Health Check' Biomarker Study
Official title: Lung Health Check Biomarker Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Lung Cancer
Cancer
Lead sponsor: Royal Marsden NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Royal Brompton & Harefield NHS Foundation Trust
name: Imperial College London
name: Royal Marsden Partners Cancer Alliance
First posted: 2021-07-12
Enrollment: 1000
Sex: ALL
Minimum age (years): 55
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients who had been identified using two lung cancer risk calculators, the modified Liverpool Lung Project (LLPv2) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) to be at high risk for lung cancer and recruited to The Lung Health Check (TLHC) pilot taking place in West London.

Brief summary: CT screening of lung cancer offers an opportunity to diagnose early stage lung cancers which is associated with better prognosis - indeterminate results delay diagnosis whilst interval imaging is awaited to assess risk of cancer. This study will allow us to examine the potential of blood-based biomarkers to augment CT screening for lung cancer.

Hypotheses

1. Blood and sputum samples can be collected in patients attending lung health checks as part of the Lung Health Check pilot in West London at fixed and mobile scanners and safely transported for processing and storage in preparation for biomarker development.
2. The biomarkers will help to identify cohorts of

   1. High-risk patients in whom CT surveillance should be conducted more readily/frequently and diagnostic procedures performed earlier.
   2. Low-risk patients who might need reduced surveillance intensity.
   3. Patients with interstitial lung abnormalities that share similar biomarker characteristics to patients with clinically significant interstitial lung disease

Detailed description: 1. Background 1.1 Lung cancer \& CT screening Over 46,000 cases of lung cancer are diagnosed every year in the UK, making it the 3rd most common cancer type. Lung cancer is the biggest cause of cancer mortality in the UK and worldwide due to late presentation in the majority of cases. One year survival for lung cancer ranges from 83% at stage I to 17% in stage IV disease (CRUK data).

   Reduced lung cancer mortality (20-26%) can be achieved by Lung Health Checks - which use 'low dose' CT (LDCT) scans of high-risk populations (e.g. heavy smokers), by increasing the proportion of cases diagnosed at an earlier stage when the treatment options are better (National Lung Cancer Screening Trial and NELSON studies). A number of pilot trials within the UK have led to a commitment by NHS England to roll-out a £70m national pilot. RM Partners commenced recruitment to one of the earlier pilots across two clinical commissioning groups (CCGs) in West London in 2018, inviting approximately 1000 patients for an LDCT scan at a fixed and mobile scanner (based in a supermarket car park). This pilot will be extended in 2019-2020 with a further 1000-2000 patients - this will include both new patients and others who will have a 24 month 'incident scan' to re-examine for any new cancer after a previously normal baseline scan). This study will test the uptake and feasibility of biomarker testing and potential scientific opportunities from specimens received.

   1.2 Current Limitations of Lung Health Checks A) Patient Selection: Two lung cancer risk calculators, the modified Liverpool Lung Project (LLPv2) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) are both multivariate risk prediction models which have been used to select patients for screening. Both models have been used to support the identification of high risk individuals during the Lung Health Check pilot to determine the risk of lung cancer and stratifying for LDCT screens. Improved patient selection has been identified as a priority to improve the sensitivity and specificity of lung health checks.

   B) Indeterminate Findings: In addition management of indeterminate 'nodules' which can be either small, possibly early cancers, or benign scarring requires delayed e.g. 3 or 12 month surveillance scans to stratify more invasive procedures such as lung biopsy to confirm the diagnosis. Blood biomarkers capable of identifying patients at increased risk of developing or harbouring lung cancer would be valuable adjuncts to protocols for surveillance and invasive monitoring. Nodules are seen in approximately 10% of scans.

   Existing clinical scores (e.g. Brock score) could be improved upon (see British Thoracic Society guidelines) and there remains significant clinical uncertainty about best management in patients with indeterminate nodules.

   1.3 Circulating and sputum biomarkers in lung cancer early diagnosis Identification of blood-based biomarkers is an important priority of lung health check research. Integrating biomarker data along with nodule size and/or volume with other radiological indices may enable improved risk stratification of surveillance, identifying those at high risk of lung cancer and requiring more frequent following up, versus those at low risk and requiring less follow up.

   Current technology recognises the potential to detect tumour specific proteins, metabolites or cell free DNA are examples of biological material in the circulating blood of patients with lung cancer. Existing approaches under investigation include genomics, epigenomics, microbiomics, gene methylation and metabolomics. Some groups have also looked at circulating tumour cells and immune responses to identify patients with higher risk of cancer. There is also a growing interest in using other bodily fluids, such as sputum, for this purpose. These have not reached readiness for clinical studies thus far but in other tumour types, such as in bowel cancer equivalent tests such as the nationally commissioned stool biomarker ('FIT test) improve diagnostic yield of bowel cancer screening to stratify resources more cost-effectively.

   Existing approaches in lung cancer screening research suggests that further work will be needed to identify circulating DNA from the smallest lesions where sensitivity remains highly variable between studies (10-100%) depending upon the technique selected and the stage of disease. There is a continued need to explore the role of these approaches in lung cancer early diagnosis populations, which will likely require a multi-modality approach of several technologies, for example combining genomics imaging biomarkers with radiomics. Sputum sensitivity has been shown previously to be in excess of 50% in a number of settings
2. Rationale CT screening of lung cancer offers the opportunity to diagnose early stage lung cancers which is associated with better prognosis - indeterminate results delay diagnosis whilst interval imaging is awaited to assess risk of cancer. This study will allow the investigators to examine the potential of blood-based biomarkers to augment CT screening for lung cancer.

Poor patient uptake and logistical issues are perceived to be key challenges to CT screening that may preclude clinical utility of a blood/sputum biomarker. Assessing whether such biomarkers can contribute to clinical decision making could then be explored.

Technologies for choosing laboratory biomarkers for risk stratification is evolving rapidly. Currently there is interest in genomics and circulating tumour cells, but as the potential for epigenomics, metabolomics, proteomics and exosome analysis evolve, the investigators hope to have prepared a suitable biobank with which can be used to challenge the latest of these approaches to the aim of stratification. This may be derived from germline or tumour-based markers of risk or be derived from the interaction between the tumour cells, host and immune response.

3. Hypothesis

1. Blood and sputum samples can be collected in patients attending lung health checks as part of the Lung Health Check pilot in West London at fixed and mobile scanners and safely transported for processing and storage in preparation for biomarker development.
2. The biomarkers will help to identify cohorts of

   1. High-risk patients in whom CT surveillance should be conducted more readily/frequently and diagnostic procedures performed earlier.
   2. Low-risk patients who might need reduced surveillance intensity.

7. Methodology This study is designed to collect sputum and blood specimens for laboratory development of a biomarker that will guide stratification and personalisation of CT screening study interval. The investigators seek access to basic, link-anonymized clinical and imaging data which can be integrated with data obtained from the sputum/blood biomarkers - this will be linked by the study ID number.

These data are not expected to influence clinical decision-making. There are no routine clinical arrangements in place to account for research findings. If a result is identified for which there is concern, which could be significant for the patient's care, the principle investigator will seek advice from the patient's clinical team. This is discussed in the patient information sheet and consent form.

This is a collaborative research project across RM Partners, Royal Brompton \& Harefield Hospitals NHS Foundation Trust, Royal Marsden Hospital NHS Foundation Trust, and Imperial College London.

Eligibility criteria: Inclusion Criteria:

* Patients invited to participate in the Royal Marsden (RM) Partners Lung Health Check pilot study who undergo one or more CT scans:
* Between the age of 55-75 years of age; and
* Current smokers or ex-smokers who have quit after the age of 40.

Exclusion Criteria:

* Patients excluded from the Lung Health Check:
* On the palliative care register;
* Any active malignancy undergoing treatment
* Daily activity levels equivalent to performance score 3 or 4; and
* Unable to consent to Lung Health Check Biomarker Study

Primary outcomes:
measure: Feasibility of the primary objective to collate a lung health check biobank
timeFrame: 2 Years
Secondary outcomes:
measure: Confirming if a lung cancer genomics panel differs between participants who receive a diagnosis of lung cancer at the time of the baseline scan and those who do not
timeFrame: 2 Years
measure: Confirming if a lung cancer genomics panel (taken at baseline LDCT screening scans) differs between those who receive a diagnosis of lung cancer and those who do not after completion of follow-up imaging
timeFrame: 2 years
measure: Confirming if peripheral blood telomere length can determine those who have interstitial lung abnormalities at those who do not, and who is at higher risk of developing overt pulmonary fibrosis
timeFrame: 2 years
Other outcomes:
measure: Are sputum and blood specimens of suitable volume and quality for given proposed laboratory biomarker tests
timeFrame: 2 Years
measure: Do given biomarker panels differ between patients who receive a diagnosis of lung cancer and those who do not.
timeFrame: 2 years
Locations:
city: London
country: United Kingdom
facility: The Royal Brompton NHS Foundation Trust
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: Richard Lee
role: PRINCIPAL_INVESTIGATOR
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