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Biomarker Selection and Validation

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

Most prognostic biomarkers are not routinely used in clinical practice, as they are generally developed in unfocused clinical studies composed of samples of heterogeneous patients with available tissues. These studies, which are not specifically designed to address the clinical significance of a prognostic biomarker, do not result in validated biomarkers with clinical utility. In order for a biomarker to be clinically useful, it should correlate with tumour behaviour and/or treatment outcomes. Its use in guiding treatment decisions should lead to improved clinical outcomes. Since a particular biomarker may be useful in one disease but not in another, it is also necessary to define the disease in which it should be used. Selected biomarkers used in routine clinical decision-making for advanced solid tumours are listed in the table below.

Selected Biomarker Tests Routinely Used in Clinical Decision-Making for Advanced Solid Tumours

Modified from Bedard PL, Hansen AR, Ratain MJ, et al. Tumor heterogeneity in the clinic. Nature 2013; 501:355-364.

Tumour type

Biomarker

Prognostic or predictive biomarker

Oligodendroglioma

1p and 19q co-deletion

Prognostic/predictive

Oligodendroglioma

MGMT promoter methylation

Prognostic/predictive

Medullary thyroid

RET mutation

Prognostic

Breast

ER expression

Prognostic/predictive

Breast

PR expression

Prognostic

Breast

HER2 amplification

Prognostic/predictive

Lung

EGFR mutation

Prognostic/predictive

Lung

EML4-ALK translocation

Prognostic/predictive

Gastric

HER2 amplification

Prognostic/predictive

Colorectal

KRAS mutation

Predictive

Melanoma

BRAF mutation

Prognostic/predictive

Gastrointestinal stromal

KIT mutation

Predictive

Gastrointestinal stromal

PDGFRA mutation

Predictive

In order to be clinically useful, a biomarker should be assayed in a specimen that is easily accessible in the clinical setting and can be readily obtained with standardised collection and processing protocols. Biomarkers that require serial assessments over a long period of time should be able to be collected in a minimally-invasive manner to be clinically feasible. The biomarker assay itself should be specific to the disease type tested and be reproducible, with appropriate cutoffs indicating the presence or absence of the biomarker. It is important for biomarkers to be validated in an independent clinical population that differs from the population used to develop the biomarker. Use of a particular biomarker should lead to a clinical decision that is linked to clinically meaningful outcomes, such as improvement in survival or quality of life or a decreased toxicity.

Predictive Biomarkers Pharmacodynamics and Drug Development

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