Title: Integration of Liquid Biopsy into Lung Cancer Diagnostic Pathway.
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Aims: • Expedite the clinical implementation of routine NHS diagnostic liquid biopsy testing at cancer suspicion in the diagnostic lung cancer pathway. • To evaluate the impact of patient outcomes with lung cancer following earlier diagnostic testing leading to personalised treatment and remove the requirement of repeat tissue biopsies. Background Lung Cancer is the third most common cancer in Wales and the leading cause of cancer death(1). The majority of patients are diagnosed at an advanced stage in Wales. The 1-year survival with stage IIIB and IV lung cancer is poor(15.5%) for these patients (2). The discovery of targeted genomic changes has significantly advanced treatment options. Clinical trials have demonstrated improved outcomes for patients with a driver mutation who receive targeted therapy compared with chemotherapy(3). National guidelines recommended genetic testing to detect driver mutations in the diagnostic pathway(4). Genomic analyses are currently requested from tissue biopsy at the lung cancer multidisciplinary(MDT) meeting, around 21-28 days after primary referral, where the histological diagnosis is reviewed, and future treatment is decided. Genomic analysis can take another 14-28 days or longer if repeat biopsies are required. Second biopsies are required in 11.5% of patients(3).The diagnostic pathway can take a total of 8 weeks from primary referral to treatment. The National Optimal Pathway currently recommends that the genetic results should be available within 10 days of the biopsy in time for the MDT. The current pathway is not meeting nationally recommended standards in Wales. Patients with advanced lung cancer can deteriorate rapidly and die if treatment is not received in time. There is a critical need to improve the current diagnostic pathway. Circulating tumour DNA(ctDNA) is obtained from a blood sample and allows genomic biomarker testing. CtDNA is shed from cancer to the bloodstream and thus, a blood test can establish a cancer genome without needing an invasive tissue biopsy. The All Wales Genomics Laboratory(AWGL) currently offers ctDNA testing for patients in Wales for a small number of mutations in lung and colorectal cancer using droplet digital PCR, where second biopsy has failed or is not possible. More recently, due to improvements in technology, the AWGL has successfully validated a 500-gene panel for ctDNA. We propose to collect blood samples from patients at the rapid access lung clinic where patients with high clinical cancer suspicion are evaluated and provide a genomic report from ctDNA testing for MDT when critical treatment decisions are made. We plan to recruit 100 participants. This study will be discussed with patients by their treating clinician and consent obtained prior to the study. Treatment and assessment will be carried out as per standard clinical practice. In addition, we ask study participants to consent to long term follow up using routinely collected data to assess patients’ outcomes. Our project aligns with the vision of The Welsh Government ‘A Healthier Wales: plan for health and social care’(5) and with the ‘Quality Statement for Cancer’(6) through the use of precision medicine being accessible by everyone to improve both the quality and value of cancer care within Wales. The importance of developing genomic approaches with the Welsh population to improve Healthcare has also been highlighted in Genomics for Precision Medicine Strategy(7).

Lay abstract: Research Aims • The introduction of a non-invasive blood test(called ctDNA) for patients with a high suspicion of lung cancer will shorten the time from referral to the start of treatment. Personalised treatment will be guided by the blood test result. • Early treatment should mean better outcomes for patients. Objectives • Blood samples will be collected from patients with a high suspicion of lung cancer. • The Genomic results from the ctDNA test will be made available to the lung cancer multidisciplinary team meeting(MDT), where cancer diagnosis and treatment decisions are made. • Patients will receive personalised treatment after the MDT without the further delay of waiting for the genomic report from the tissue biopsy. Background Cancer genomic profiling is the mainstay of personalised cancer treatment and allows clinicians to select the most appropriate treatment for the individual patient. Clinical trials have proved that targeted therapies improves patient outcomes, including survival, and has fewer side effects than chemotherapy or immunotherapy. They are also convenient for patients as they can be taken orally compared to intravenous hospital based chemotherapy/immunotherapy. It is vital for doctors and patients to receive a genomic profile with their diagnosis as early as possible, as this will direct patients towards the most effective therapy. In the current diagnostic pathway, genomic analysis is requested from tissue biopsy at the lung cancer multidisciplinary(MDT) meeting, around 21-28 days after the first referral. Following the MDT, genomic analysis can take 14-24 days or longer if repeat biopsies are required. The current pathway is not acceptable or efficient for clinicians or patients. Patients with advanced disease often deteriorate rapidly and become too unwell or die if no treatment is received and a potential treatment opportunity is lost. Liquid biopsy (a blood sample) collected early in the diagnostic pathway, before biopsy, could transform and improve timelines by providing genomic results for MDT, and allowing access to the most appropriate therapy sooner. Additionally, patients may avoid repeat 'risky' biopsy procedures. What you hope to discover In this study, we will compare the new ctDNA diagnostic pathway to the current tissue biopsy diagnostic pathway. Timing: • Can ctDNA be used to deliver genomic results to inform treatment decisions sooner than tissue biopsy-based approaches? • Can we start appropriate, personalised treatment sooner in patients diagnosed with lung cancer in the ctDNA pathway than the standard pathway? Patient outcomes: • Can we improve survival in patients with lung cancer by improving access to personalised therapy at an earlier time? Public involvement Patients have been involved in the study's design from the outset and wil l participate in the management of the project. In addition, ctDNA testing was presented to the Genomic Partnership Wales Patient Sounding Board 2021 and was widely supported. Dissemination The results of this project will be sent to participants with a 'thank you' letter. The wider public will be informed via public and social media, Wales Cancer Research Centre, Welsh Cancer BioBank and Genomic Partnership Wales websites. We plan to present results at conferences and through publications in scientific journals. The results will inform the planning of future national cancer pathway and funding for future liquid biopsy services in NHS Wales.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS