SAGITTARIUS aim to optimize the clinical management of locoregional stage II high-risk/stage III colon cancer (LRCC). Approximately half of all LRCC patients relapse within two years from time of curative surgery because of imaging-undetectable micro-metastatic residual disease (MMRD). Given the lack of reliable predictors of individual risk, LRCC patients are treated with a one-fits-all adjuvant chemotherapy. This gunshot approach results in either over- or under-treatment. Measuring circulating tumor DNA (ctDNA) in the patients’ bloodstream can diagnose MMRD. Retrospective studies show that ctDNA detection after surgery predicts cancer recurrence with high sensitivity and specificity. SAGITTARIUS will deploy a ctDNA assay to detect the absence, presence, or persistence of MMRD in individual patients. The diagnosis of MMRD will guide and personalize therapeutic interventions. SAGITTARIUS is a pragmatic trial whereby real-world patients are treated in two parallel trials based on their MMRD status and the genomic landscape of their tumors. ctDNA positive patients are randomized to conventional or personalized targeted therapy. ctDNA negative patients are randomized to a physician-driven therapy or a Wait&See strategy. The efficacy and effectiveness of this potentially ground-breaking new strategy of care will be measured via multiple outcomes, including safety and time to events variables, patient-reported outcome measures, and health-economics evaluation. Since colon cancer deaths are usually associated with metastases rather than local disease, MMRD will also reclassify how this disease is perceived by clinicians. This new prism will allow for treatment to be better matched against the tumor biology, also allowing for better monitoring – via ctDNA – to assess disease evolution in each patient, minimizing harm and maximizing the odds of cure. This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment.

Ventricular tachycardia (VT) is an unpredictable and potentially deadly condition and should be promptly treated with catheter ablation and medication, before irreversible and potentially fatal organ damage follows. Unfortunately, this combination of treatments does not prevent VT reoccurrence in 30-50% of VT patients and while they can undergo multiple invasive ablations, technical difficulties or refusal of the patient can lead to a lack of effective treatment options. A promising novel, non-invasive treatment option for VT is stereotactic arrhythmia radioablation (STAR). Besides being non-invasive, STAR can also be used to reach locations that are inaccessible for catheter ablation, which may potentially improve effectiveness of overall VT treatment. Small scale first in men/early phase trials have been performed for STAR, providing proof-of-concept for clinical safety and efficacy. However, patients with recurrent VT are not a homogenous group and each center deals with different inclusion criteria, imaging and/or target definition. Many questions remain and the available studies lack the power to clinically validate the approach and prepare for late stage phase III trials. The STOPSTORM consortium sets out to consolidate all current and future European efforts to clinically validate STAR treatment by merging all data in a validation cohort study, standardising pre-treatment and follow-up, in order to collect the data sets and statistical power needed to unanimously establish clinical safety, efficacy and benefit for STAR. The STOPSTORM consortium also sets out to refine protocols and guidelines, determine volumes of interest, define and model the optimal target region and target dose, also in relation to surrounding healthy tissues (i.e. organs at risk) and determine which patient population and underlying cardiopathies respond best to STAR. By doing so the STOPSTORM consortium paves the way to consensus and future late stage clinical trials for STAR.

MyPeBS addresses the crucial and timely question of the future of breast cancer screening in Europe. Indeed current standard mammographic screening, with entry stratified by age alone, has recently been largely questioned. Despite a demonstrated mean 20% reduction in breast cancer-specific mortality, together with reduction of late-stage disease in women older than 50, it is associated with potential harms including false positive recalls and over-diagnosis. Individual breast cancer risk estimation, through models including clinical variables, mammographic breast density and more than 100 genetic polymorphisms, now has substantial clinical and scientific bases. Personalized screening strategies, based on individual risk levels, could potentially improve the individual benefit/harms ratio of screening (earlier cancer detection and less intensive treatments in high risk women, less false positives and over-diagnoses in low risk ones), and increase the cost-efficacy for health insurances. MyPEBS will conduct an international randomized phase III trial to validate this hypothesis. It will primarily assess the ability of an individual risk-based screening strategy to be non-inferior, and possibly superior, to the standard of care screening, in reducing the cumulative incidence of stage II+ breast cancers. The trial, conducted in 5 countries (France, Italy, UK, Belgium and Israel) will include 85000 European women aged 40-70, all followed for 4 years. MyPEBS will also evaluate if an individual risk-based screening strategy, compared with the standard, reduces screening-related harms (unnecessary biopsies, overdiagnoses) in low-risk women, is overall at least as cost-effective as well as more accepted by women resulting in a larger screening coverage. After analyses of all components, the final objective of MyPEBS is to deliver recommendations for the best future breast cancer screening strategy in Europe.

Progress in biomedical research and healthcare requires profiting from the huge amount of data and knowledge that are generated. However, most of the potential users have no means to efficiently exploit this wealth of information. Up to now, many of the efforts done for developing bioinformatics methods and applications have not produced the expected societal impact for different reasons, including: 1) the deficit of integrative approaches that effectively combine different types of data from different sources; and 2) the lack of active involvement of the potential users (from experimental scientists to healthcare professionals) in the process of creating applications that mine, integrate, analyse and display biomedical information in a way that is immediately understandable and useful ('actionable') by the end users. The present project tries to overcome this issue by involving a multidisciplinary team of experienced bioinformaticians, and experimental and clinical scientists in the design and development of demanded bioinformatics applications. The bioinformaticians will develop medical-oriented integrative methods and applications (New Generation Genotype-Phenotype Explorations, Disease Biomarker Browser, Disease Trajectory Comorbidity Browser, Cancer Genome Interpreter, etc.), while the experimental and clinical partners will actively participate in the design and assessment of the applications, as well as in the curation of customized resources. The experimental and clinical partners belong to two completely different medical specialties (oncology and psychiatry), which have a big impact in citizens’ wellbeing. Moreover, the commonalities existing between the needs of these disparate specialties will facilitate the identification and design of applications likely to satisfy the needs of biomedical professionals in other areas. Finally, the project aims to setup a platform for the sustainable exploitation of the tools developed throughout its execution.

Colorectal cancer (CRC) ranks fourth in cancer deaths worldwide. Between 20% and 30% of patients with advanced CRC have liver metastases (CRLM). Liver cancer ranks second in cancer deaths worldwide, including hepatocellular carcinoma (HCC). Despite recent advances, liver resection offers the only chance of cure for patients with liver metastases. However, the recurrence rate of these tumours is high even after post-resection. The presence of positive margins in the remaining liver after resection correlates with increased local recurrence and decreased overall survival, the only factor where prognosis could be influenced by the performance of surgery. However, at present, the extent of an R-negative status remains debatable and varies widely from one publication to another. Currently, there are radiofrequency ablation studies that, based on preliminary retrospective human clinical trials, are able to correlate an additional coagulation of tumor margins with a reduction on local recurrence. However, there is no prospective and pragmatic controlled study that accurately measures this additional margin and its impact on oncological outcomes. The aim of LIVERATION is to conduct an ambitious, pragmatic multicenter clinical trial with 720 patients with CRLM and HCC at 24 clinical centres in 6 different countries to determine whether additional ablated margin produced by radiofrequency can decrease the recurrence rate and improve patient survival. We will also evaluate the patient-centredness of the intervention and its comparativeness with other therapeutic alternatives in terms of quality of life and patient experience in real-world settings. To this end, the consortium has been formed by highly experienced, highly qualified and multidisciplinary entities to carry out the project successfully. The results will not only have a major impact on a social and scientific level but also on an economic level for the EU. This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment’.