Reshape the EValuation Efficiency and Accuracy of non-small cell Lung cancer (REVEAL) – 5th Call for proposals RHU 2021

Gustave Roussy was the first cancer center to formalize a consultation based on liquid biopsy for molecular research on circulating DNA (circDNA) in patients with lung cancer (ORACLE consultation). Patients followed by the Institute, or not, were offered a EFGR gene mutation testing in 5 days. It is thus possible to identify treatment’s resistance and adapt the therapeutic choice. Since 2017, the research has been extended to other genes of interest in lung and breast cancers and since 2020 to all cancer type in a refractory situation. But circDNA can act way behind a surrogate tool to tissue biopsy. The goal of this new project, named REVEAL, is to substitute CT-scans by the analysis of circDNA, or liquid biopsy, in non-small lung cancer‘s monitoring.

Lung cancer is the leading cause of cancer mortality worldwide. Incidence in France is 46,300 cases diagnosed and 33,100 deaths each year. Non-small cell lung cancer (NSCLC) is the most prevalent subtype (85%). When diagnosis is made at an early stage (I,II, IIIa), while the disease is not obviously disseminated, treatment relies on surgical tumor resection and/or radiotherapy when feasible, which can be combined with systemic treatments. In Stage IV cases, first-line treatment was, 10 years ago, typically chemotherapy, with median overall survival approximately 8–10 months.

Despite poor historical outcomes, the management of NSCLC has been revolutionized by targeted therapy and immunotherapy. For both classes of drugs, analyses of tumor biomarkers are mandatory for drug selection. Development of circulating cell-free DNA (cirDNA) based assays, often referred to as liquid biopsies, have offered an alternative method to avoid repeated tissue biopsies. REVEAL is an ambitious program that aims to take advantage of longitudinal cirDNA disease monitoring to move from treatment selection to strategic decisions.

Imaging based approaches, in particular CT scans, remain the standard of care to detect lung cancer relapse after radical treatment or to measure response to systemic treatments. This method has become partially outdated in this immunotherapy setting due to its inability to characterize response in 15% of cases. CT scans have several additional limitations, including a poor definition (3 mm tissue threshold, corresponding to 7 million cancer cells), and safety issues (radiation-induced cancers and renal failure). No biological markers, such as PSA for prostate cancer, are currently available for biological follow-up of NSCLC. As longitudinal cirDNA is directly associated with tumor burden, it offers a powerful potential alternative to imaging.

In patients in whom the NSCLC was radically treated, the detection of minimal residual disease (MRD) by cirDNA analysis will be assessed by our project with two main objectives. First, the absence of MRD one month after the surgery could help avoid the need for adjuvant therapy, and thereby have an obvious impact on treatment de-escalation strategies. Commercially available assays have a low sensitivity. We will develop a unique combination device and plasmapheresis to tackle this issue. During follow-up, the current assays are designed to detect a molecular recurrence but not a second cancer, a frequent issue in patients who were or are smokers. To overcome this limitation, we propose a second objective of the development of a cirDNA multiplex molecular biomarker based on mutation-agnostic cirDNA molecular features such as cirDNA quantification or size profile identification. Mutation status will be simultaneously determined with concurrent techniques.

Since we anticipate that molecular recurrences will be detected by cirDNA before the event of metastasis on CT scans, there is a predicted need for circulating biomarkers able to predict response to immunotherapy without a need for tissue biopsies. We will investigate and validate candidate circulating biomarkers, primarily based on the patient’s phenotype, including: immunosenescence markers, acceleration of telomere shortening, inflammation markers and neutrophil phenotyping.

For monitoring at the metastatic stage, our project will study a new cirDNA assay, specifically designed for NSCLC patients, with the aim to propose cirRECIST criteria. The assay will be developed with digital PCR (cdPCR) and will also combine mutation-agnostic cirDNA molecular markers. This easy-to-access and cost-effective test will allow us to evaluate treatment efficacy faster and more safely than CT scans. It should contribute to decreasing the inequality of cancer care in regions where access to CT scans is limited.

The consortium gathers recognized experts in thoracic oncology, immunology, cirDNA analysis and machine learning (Gustave Roussy Cancer Center, Université de Montpellier, Inserm, CentralSupélec, Université Paris-Saclay) and three biotech companies (Stilla® Technologies, IntegraGen, Cell Environment). The project will be carried out over 60 months.