The overall goal of DISCERN is to understand the causes of three poorly understood cancers in Europe; renal, pancreatic and colorectal cancer, and help to explain their geographical distribution, including their high incidence in central and eastern Europe. This will be achieved by combining large-scale European biorepositories comprising population-based cohorts and tumour case-series with state-of-the-art molecular profiling techniques and machine learning approaches. In particular, DISCERN will identify potential new causal risk factors for the three cancers using novel exposomics and proteomics scans, as well detailed geospatial and environmental exposure information from 16 large-scale epidemiological cohorts including almost 900,000 individuals. It will also explore biological mechanisms on how these risk factors are potentially causing these cancer types with a focus on promoting factors in normal tissues using deep sequencing, single cell multi-omics and spatial proteomics. The causal effects of identified cancer risk factors and the cellular signalling responses they trigger will be further evaluated using a panel of stem cells and colon, renal and pancreatic 3D organoids. The results from DISCERN will be disseminated to citizens, patients and policy makers through collaborating patient and participant organizations. DISCERN will provide the critical evidence base required to develop new prevention strategies to tackle the growing burden of renal, pancreatic and colorectal cancer in Europe. This action is part of the Cancer Mission cluster of projects on "Understanding".

In 2020, there were an estimated 431 288 new cases of kidney cancer (Renal Cell Carcinoma, RCC) globally with 138 611 cases in Europe, leading to 179 368 deaths worldwide, including 54 054 deaths in Europe (source: IARC/Globocan). To define high priority topics in academic research and launch dedicated trials, European RCC academic physicians have gathered into a European initiative – the CARE group. Systemic therapy for RCC relies on two classes of agents: anti-angiogenic targeted therapy (Vascular endothelial growth factor Tyrosine Kinase Inhibitor- VEGFR TKI) and immune checkpoint inhibitor (ICI), targeting either PD-1/PD-L1 axis or CTLA-4. Combination therapy is standard of care (SOC) for clear cell RCC in all guidelines with either ICI-ICI or ICI-VEGFR TKI. However, no head-to-head comparison have been performed between the two approaches and patients are treated based on physician decision without clinical or biomarker factors to guide treatment selection. PD-L1 staining is, to date, the biomarker that has demonstrated its ability to enrich for overall survival benefit favoring ICI-ICI strategy in PDL1(+) and ICI-VEGFR TKI in PDL1(-) patients. CARE1 PCT is a prospective randomize phase III study, in first line setting for patients with metastatic clear cell RCC comparing ICI-ICI vs ICI-VEGFR TKI approaches stratified on PD-L1 by local determination. Primary endpoint is overall survival (OS). The trial will enroll 1250 patients over 3 years across eight European countries that are part of the CARE consortium. Study Sponsor is Gustave Roussy institute within the GETUG network for France, co-sponsor is developed through main academic networks (eg. SOGUG in Spain) and main institutions across Europe (eg. Cancer Core Europe – CCE). Study design has been develop to demonstrate that ICI-ICI is superior to ICI-VEGFR TKI in prolonging OS for PDL1(+) patients and that ICI-VEGFR TKI is superior to ICI-ICI in prolonging OS for PDL1(-) patients. CARE1 PCT has been designed and will be conducted with patient advocacy group representatives (ARTuR and IKCC) input. CARE1 is an academic phase III study designed to define the optimal combination using a pragmatic routinely implementable biomarker. Therefore, CARE1 will inform practice and has the potential to change treatment guidelines. Taken all together, CARE1 is a unique opportunity to build a large-scale platform to define new biomarker based therapy guidelines as well as to investigate quality of life, patient reported outcome and Health-Economic in front line setting, as well as pathological and blood biobank collection for further translational work. This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment’.