25 The Drug Rediscovery Protocol MAIN The precision treatment of cancer holds great promise for patients in terms of life extension and quality of life1,2,4-7. However, early studies and experiences with genetically and molecularly informed decisions regarding treatment have also identified considerable hurdles, which may jeopardize the way in which we capitalize on precision medicine8-11. First, populations of patients who are eligible for specific treatments or trials become smaller and trials accrue slower, owing to pre-selection by targeted sequencing of candidate variants and to slow implementation of pre-selection tests. Second, these candidate variants can, in general, be appreciated only when their tissue context is taken into consideration. However, with regards to drug sensitivity, the importance of a given genetic or molecular variant is usually tested in the subtype of cancer that most frequently contains this variant. The importance of the same variant in other cancers often remains unknown. Third, as drug development is challenging for rare subtypes of cancer, this can create inequality in care12. Finally, with growing pressure from society to increase the success rate of drug-development trials13, there is hesitation amongst payers to reimburse large-scale sequencing efforts before they have proof that these efforts will make healthcare more sustainable. As a result, we are not using the full potential of rapidly expanding technological advances, knowledge of biomarkers and the spectrum of approved anticancer drugs for our patients. The Center for Personalized Cancer Treatment was founded in 201014 to address these issues. In this network (which now connects 45 hospitals in the Netherlands), patients with all types of metastatic cancer are offered the opportunity to undergo a fresh tumour biopsy for whole-genome sequencing (WGS) before starting systemic anticancer treatment. The WGS results are combined with treatment outcomes in a national, centralized database for research purposes, and returned to the physician who is treating the patient for future planning of treatment. This initiative has contributed to the identification of potentially actionable variants in cancers that are not routinely tested for these variants. To provide treatment opportunities for patients in whom such variants were identified (while simultaneously collecting clinical outcomes), we began the Drug Rediscovery protocol (DRUP), in which we seek to expand the use of targeted therapies that have been approved by the European Medicines Agency (EMA) and/or US Food and Drug Administration (FDA) beyond the approved indications of these therapies. The DRUP is an ongoing, prospective multi-drug and pan-cancer trial. Patients who are eligible are those who have progression of an advanced or metastatic solid tumour, multiple myeloma or B-cell non-Hodgkin lymphoma, and no suitable standard-treatment options. A potentially actionable genetic or molecular variant, which can be matched to one of the drugs available in the study (Extended Data Table 1), must have been identified via regular diagnostics or by the Center for Personalized Cancer Treatment. In recognition of the importance of tissue context, the trial design allows for an unlimited number of parallel cohorts (each defined by tumour type, molecular variant and study treatment) (Fig. 1). For selected variant categories (such as mutational load, microsatellite instabil2
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