ctDNA on the way to implementation in the Netherlands (COIN)

o RESEARCH QUESTION Success of expensive drug therapies critically depends on identifying the right patients to treat, thereby avoiding futile treatments with risk of adverse effects. An urgent need exists to molecularly profile tumors and their metastases before and during treatment, which could be achieved by cell-free circulating tumor DNA (ctDNA) testing. Yet ctDNA testing is lacking solid clinical validation and standardization for implementation into clinical care. o HYPOTHESIS ctDNA testing will improve effective cancer drug therapy. o STUDY DESIGN Part 1: Establish a generic multidisciplinary framework for standardized clinical validation and implementation of ctDNA diagnostics. Part 2: Run a ctDNA biomarker-driven intervention study in CRC. o STUDY POPULATION COIN focuses on NSCLC and CRC. o INTERVENTION Part 2: prevent under treatment in stage II colon cancer, in which adjuvant chemotherapy (ACT) is not standard. After surgery patients are randomized between: immediate ctDNA analysis (intervention arm: ctDNA-positive patients will be offered ACT) and post hoc ctDNA analysis (control arm: no ACT). o OUTCOME MEASURES Part 1: An established ctDNA clinical validation framework Part 2: Recurrence rate, quality of life (QoL), cost-effectiveness (CEA) of the ctDNA-based treatment and other parameters in post-surgery ctDNA-positive colon cancer patients receiving adjuvant therapy versus standard of care. o SAMPLE SIZE/DATA-ANALYSIS Part 1: Observational series n>5000. Part 2: Colon cancer n = 1320 Data will be analyzed by an intention-to-treat approach for the primary endpoint, standard survival methods and Cox’s proportional hazards models.