PhD Defense: Genomics-guided Oncology; Advancing Efficacy and Access

Traditionally, cancer treatment has been based on the principle that patients with the same type of cancer are uniformly treated with the same therapy. However, the effectiveness of this approach, primarily centered around chemotherapy, has remained suboptimal despite advances from monotherapy to combination treatments, highlighting the ongoing need to reconsider and optimize treatment strategies. Insights into the human genome, the understanding that cancer arises from changes in it, the emergence of molecular diagnostics, and the subsequent development of targeted therapies and immunotherapies have paved the way for cancer treatment tailored specifically to the tumor genome of each patient.

While targeted therapies have the potential to intervene in molecular signaling processes, the strength of most immunotherapies lies in their ability to activate and enhance the immune system to eliminate cancer cells. Despite their different mechanisms, both approaches share the goal of exploiting patient- or tumor-specific characteristics, a concept known as "precision oncology" or "personalized oncology."

In recent decades, the development of next-generation sequencing methods, which allow for extensive study of tumor genomes, has made it possible to identify patients who are suitable candidates for precision oncology. At the same time, these methods have revealed a limitation of our current healthcare system: the inability to meet the demand for targeted drugs for patients who are molecularly similar but histologically different from the population for which the drug was approved, known as off-label use. To address this issue, various precision oncology studies have been initiated globally to investigate the effects of targeted and immunotherapies in off-label situations. In the Netherlands, since 2016, the Drug Rediscovery Protocol (DRUP) has facilitated access to off-label treatments for cancer patients who have no other treatment options and who may benefit from off-label treatments based on a biological rationale.

However, several challenges still hinder the optimal implementation of precision oncology. First, despite the expected positive effects based on their mechanisms, not all treated patients benefit from personalized cancer treatments, and these drugs, like other anti-cancer therapies, are not free of side effects. Second, timely access to the most appropriate drug remains a challenge, both in on-label and off-label situations, mainly due to strict regulations or delayed policy adjustments in healthcare systems. Treating the right patient at the right time, or deciding against treatment when the potential benefit doesn't outweigh the risk of toxicity, remains a complex issue. This thesis focuses on various aspects critical to improving the effectiveness and accessibility of precision oncology, both within the context of DRUP and beyond.