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Defining Translational Research and Personalised Medicine

Chapter 1 - Definition: Translational and Personalised Medicine, Biomarkers, Pharmacodynamics

The application of discoveries and technologies from the basic science research setting to the clinical setting is the basis for translational research that has facilitated the identification of novel drug targets and treatment strategies. This has ushered in a new era of a more individualised, or personalised, approach to cancer treatment, particularly in the metastatic setting. The standard of care for many patients with advanced malignancies is gradually evolving from empirical treatment based on clinical-pathological characteristics to the use of targeted approaches based on the molecular profile of the tumour. Fundamental insights into cancer biology gained from preclinical studies are used to design human clinical trials to test novel approaches to diagnosis or therapy. Results from phase III studies are then ultimately incorporated into everyday clinical practice. In designing clinical trials with novel targeted agents, patient selection is important, as agents targeted toward a particular genetic alteration are often inactive and even harmful in an unselected patient population. For example, initial phase III studies of epidermal growth factor receptor (EGFR) inhibitors in patients with metastatic colorectal cancer did not show a benefit for their use in an unselected population, but showed a survival benefit in patients with wild-type KRAS. In melanoma, the discovery of genetic alterations that drive tumour progression has led to a number of targeted therapies including drugs that target the BRAF V600E mutation. In patients with this mutation, treatment with the BRAF inhibitor vemurafenib induced tumour regression and led to improved overall survival when compared to chemotherapy.

Translational research in oncology has been greatly facilitated by rapid advances in molecular biology and histopathology techniques. For example, new methods for tumour acquisition and histopathology analysis can identify subpopulations of cells with unique mechanisms of sensitivity or resistance to specific therapies. Such interpatient and intrapatient tumour heterogeneity can influence prognosis and responses to systemic therapies. The term “personalised medicine” refers to the application of patient-specific genetic information (both germline and somatic) and molecular and/or cellular tumour characteristics to select the optimal treatment for individual patients with the goal of improved therapeutic efficacy and reduced toxicity. It involves the use of biomarkers that provide unique patient- and tumour-specific molecular information.

Biomarkers are molecular or cellular characteristics that indicate a normal or pathogenic process that can be used to aid in diagnosis, defining susceptibility for a particular disease, and determining clinical outcomes or response to a specific therapy or intervention. They can also be used to facilitate the development of rational drug combinations and to identify potential resistance mechanisms.

In addition, biomarkers provide clues about the mechanism of action of a particular drug and serve as a tool for selecting the most appropriate patients for enrolment in early phase clinical trials based on molecular characteristics of the tumour. The discovery of specific mutations that predict the efficacy of a particular drug in a molecularly defined patient cohort has greatly transformed drug development programmes in oncology, shifting the focus from the development of non-specific cytotoxic chemotherapies to molecularly targeted therapeutics.

Introduction Prognostic Biomarkers

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