Genomics-guided Oncology

The approach to cancer treatment that bases treatment decisions on patient- or tumor-specific characteristics has changed our perspective on the combat and prognosis of cancer. Rapid developments in quality and availability of large scale molecular sequencing modalities have played a pivotal role in this context by providing extensive insights into the molecular environment of malignancies and the alterations that drive them. Consequently, the current landscape of cancer research is characterized by a focus on the development of a multitude of novel targeted molecules and immunotherapies. Unlike traditional chemotherapy, that exhibits cytotoxic effects in both healthy and cancerous cells, targeted therapies have the potency to specifically interfere with molecular signaling in cancer cells, thereby inhibiting growth or survival. Since their emergence, numerous targeted compounds have demonstrated remarkable effectiveness in specific tumor types and are now approved standard of care. However, although these large-scale sequencing modalities have proven effective in identifying patients that are suitable candidates for on-label targeted treatment, they have also exposed a limitation of our healthcare system in its current form: the inability to address the demand for a targeted agent beyond its label for patients that are molecularly similar, but histologically divergent from the registered population, and subsequently, as a medical society, being able to learn from the results. In an answer to this issue, worldwide, several precision oncology trials that study the effects of targeted and immunotherapies in off-label settings have been initiated. By applying a platform design, allowing for the incorporation of new drugs during trial course while discontinuing treatments that prove ineffective, this trial type facilitates accelerated clinical translation of novel insights into the use of anticancer drugs. In the Netherlands, the Drug Rediscovery Protocol has played a significant role in facilitating access to off-label treatments for patients that, from a biological perspective, could potentially benefit from them. Furthermore, the addition of obtaining pre-treatment biopsies for whole-genome sequencing (WGS) and RNA-sequencing to the protocol has enables elaborate biomarker studies to identify predictors of response or resistance. However, various challenges still hamper optimal execution of precision oncology. First, despite the expected positive effects based on mechanisms of action, not all patients treated derive benefit from targeted cancer treatment, while, like other anticancer treatments, these drugs are not exempt from potential adverse events. Second, beyond efficacy and safety matters, access to the most suitable drug still proves challenging in both on- and off-label settings, primarily due to stringent scientific legislation or lagging policy adaptations of healthcare systems. Treating the right patient with the right drug at the right time, or abstaining from treatment when the chance of benefit does not outweigh the risk of toxicity, therefore continues to be a complex matter. In this thesis, we focused on several aspects critical to enhance the efficacy of, and access to, genomics-guided oncology in the context of DRUP and beyond.