ReviewPredictive biomarkers for personalised anti-cancer drug use: Discovery to clinical implementation
Introduction
The advent of targeted anti-cancer therapies has highlighted the need to develop biomarkers to optimise drug development and clinical use.1 It is possible to adopt a generic definition of biomarkers as characteristics that can be objectively measured as indicators of a biological or pathological process or pharmacological response to a therapeutic intervention2 and in doing so identify biomarkers as of potential utility across the whole translational cancer research process. Accordingly, in drug development, biomarkers are being utilised in ‘go/no go’ decision making during the discovery stages, and in assessing the performance of drugs in pre-clinical and early clinical studies, collectively these can be referred to as pharmacological biomarkers.1, 3, 4 In the clinic, biomarkers can be used to facilitate precision and decrease invasiveness in cancer diagnosis; for patient selection for treatment based upon estimation of natural history of disease (prognostic biomarkers) or estimation of probability of response to a particular agent (predictive biomarker); or for detecting toxicity.5, 6 Such clinically useful biomarkers may also have potential value as surrogate end-points in clinical trials.
While there has been some success in the identification and development of diagnostic, prognostic and to a lesser extent toxicity and pharmacological biomarkers, there has been little progress in identifying clinically useful predictive biomarkers for solid tumours.7 Predictive biomarkers are potentially the most useful for clinical decision-making. Predictive biomarkers are distinct from prognostic biomarkers in that the latter provide an estimation of the natural history of a patient’s cancer independent of therapy, while the former produce an estimation of probability of response to therapy. In practice, many biomarkers have both predictive and prognostic impacts.
Biomarkers can also be classified according to modality of assessment, and this has implications for how particular biomarkers might be developed. The most common types of biomarkers according to this classification are provided in Table 1.
Herein we review the ‘state of the art’ and progress in the development process for predictive biomarkers and identify key challenges, problems and future directions. In particular the need for formulation of robust methodology for the biomarker development process from discovery to clinical implementation is identified and addressed.
Section snippets
Overview of the biomarker development process
The biomarker development process begins with discovery. Subsequent development of leads from discovery involves two key processes: the process of establishing a fit-for-purpose assay to objectively measure the biomarker, this can be defined as biomarker validation; and the evidentiary process of establishing a causal or correlative relationship between the biomarker and the clinical end-point or other biological or pathological end-point, this can be defined as biomarker qualification.8, 9, 10
Biomarker discovery
Biomarker discovery involves the comprehensive molecular characterisation of the clinical outcome of interest as assessed by an established clinical end-point.7, 11 For predictive biomarkers, the clinical end-point of interest is improved overall survival following treatment with the drug. Ideally, a causal mechanistic relationship between a particular molecular pathway and the clinical outcome in individual patients should be established. Due to molecular complexity and heterogeneity,
Biomarker validation
Validation of a biomarker involves a systematic evaluation to assure that the technique used to assay the biomarker is reliable to perform its task.9, 17 Biomarker validation is guided by the established principles of bio-analytical method validation.18, 19 However, as discussed below, not all these principles are directly transferable either in the context of ‘fit-for-purpose’ biomarker validation as already discussed or due to specific analytical challenges specific to biomarkers.9 In the UK,
General principles of qualification
Biomarkers must be qualified for a specified purpose prior to clinical implementation.26 The aim in the qualification of a biomarker is to define its sensitivity and specificity for clinical end-point determination and to prove its clinical utility.27 Use of unqualified biomarkers can lead to incorrect treatment decisions, which will impact adversely on patient health outcomes. Therefore, clinical studies must be conducted to properly assess the clinical utility of a biomarker.28
Although
Clinical Implementation of biomarkers
There are three key issues associated with implementing a biomarker test in the clinic. The first is the approval of the test by regulatory authorities, the second is the acceptability of the test by physicians and patients and the third is the impact of the biomarker test on the cost-effectiveness of anti-cancer treatments. Addressing these issues is essential when trying to implement a biomarker in the clinic.
Examples of successful predictive biomarkers
To illustrate some of the issues raised in this review, some specific examples from the published literature and clinical practice are now discussed. There has been a considerable increase in the number of published papers about predictive biomarkers since 2000 (see Fig. 5). Accordingly, the number of cancer predictive biomarkers being investigated or in development is rapidly increasing. There is significant attrition during predictive biomarker development, but no specific published data
Conclusions
While progress has been limited to date the potential benefits of predictive biomarkers to direct the use of systemic anti-cancer agents in individual patients are well recognised. Accordingly, there is significant motivation within the field to improve the biomarker development process. A key aspect would be the formulation of robust clinical biomarker development methodology with defined processes and acceptance criteria for ongoing development. Increasingly this is occurring and alongside
Conflict of interest statement
None declared
Acknowledgements
The authors are active in biomarker research in Oesophagogastric, Lung and Colorectal cancer work funded by NHS Grampian, Friends of the Aberdeen North Haematology, Oncology and Radiotherapy, Aberdeen Royal Infirmary Oncology Research Fund, and the Saudi Arabian Department of Cultural Affairs.
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