8 Chapter 1 GENERAL INTRODUCTION Over the past decades, the landscape of oncology has evolved rapidly. Our knowledge on tumor biology has increased and as a result, many new targeted anticancer agents have been introduced. In daily practice, we encounter difficulties in selecting the right patient for the right drug and vice versa. Patients assigned to an ineffective treatment may experience unnecessary toxicity which impacts the prognosis and quality of life. Moreover, ineffective therapies delay effective treatment strategies that may influence patient’s prognosis and increase the costs for our health care system. Here, we provide an overview of current insight in tumor biology and the challenges we face regarding patient selection to steer anti-cancer treatment. Tumor heterogeneity Tumors are complex and heterogenous. Tumor heterogeneity can be used to describe 1) the differences between tumors of the same type in different patients (inter-patient heterogeneity), 2) between different tumors within one patient (inter-tumoral heterogeneity), and 3) between different cancer cells within one tumor (intra-tumoral heterogeneity). The evolutionary branching of cancer from a primary tumor to distant metastases contributes to heterogenous disease within individual patients1. Genome-sequencing studies have revealed considerable variations in the genetic make-up of tumor cells not only distinct anatomical locations but also distinct regions within the same tumor lesion2. This intra-tumoral heterogeneity is not limited to the genetic level, but encompasses also phenotypic, metabolic and secretory components3. These components are connected and evolve over space and time4. Another factor contributing to heterogeneity is the tumor microenvironment (TME), a dynamic system of interacting stroma cells, immune cells and host factors. Together with the different phenotypes of cancer cells, this creates a unique TME that is believed to explain differences in the course of disease within and between patients5. Drug and biomarker development In recent years, many clinical trials showed unprecedented (durable) response rates of novel targeted and immune therapies. This has led to expanding of the therapeutic arsenal for routine oncological clinical care for various tumor types6. In addition, numerous new drugs are in the pipeline. However, it is unlikely that all these drugs will succeed in getting a place in the current treatment plans. Therefore, it is important to focus on the development of biomarkers before or at least during the development of new drugs. This enables better patient selection to ultimately optimize treatment efficacy for the individual patient and limits the number of trials designed to study many other agents with the same target. A biomarker predictive for treatment response should accurately characterize (the complexity of) the TME, taken the tumor heterogeneity and dynamics into consideration. Conventional laboratory biomarkers of tissue function-based blood samples or tumor size measurements based
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