Review
Predictive biomarkers for personalised anti-cancer drug use: Discovery to clinical implementation

https://doi.org/10.1016/j.ejca.2010.01.001Get rights and content

Abstract

A priority translational research objective in cancer medicine is the discovery of novel therapeutic targets for solid tumours. Ideally, co-discovery of predictive biomarkers occurs in parallel to facilitate clinical development of agents and ultimately personalise clinical use. However, the identification of clinically useful predictive biomarkers for solid tumours has proven challenging with many initially promising biomarkers failing to translate into clinically useful applications. In particular, the ‘failure’ of a predictive biomarker has often only become apparent at a relatively late stage in investigation. Recently, the field has recognised the need to develop a robust clinical biomarker development methodology to facilitate the process. This review discusses the recent progress in this area focusing on the key stages in the biomarker development process: discovery, validation, qualification and implementation. Concentrating on predictive biomarkers for selecting systemic therapies for individual patients in the clinic, the advances and progress in each of these stages in biomarker development are outlined and the key remaining challenges are discussed. Specific examples are discussed to illustrate the challenges identified and how they have been addressed. Overall, we find that significant progress has been made towards a formalised biomarker developmental process. This holds considerable promise for facilitating the translation of predictive biomarkers from discovery to clinical implementation. Further enhancements could eventually be found through alignment with regulatory processes.

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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