Review – Prostate CancerBiomarkers in the Management and Treatment of Men with Metastatic Castration-Resistant Prostate Cancer
Introduction
In 2010–2011, four systemic therapies demonstrated improved overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) and have become part of the therapeutic arsenal. These include the androgen synthesis inhibitor abiraterone acetate (AA) [1], the immunotherapeutic sipuleucel-T [2], and the taxoid cabazitaxel [3]. In addition, the receptor activator of nuclear factor κ-B ligand (RANKL) inhibitor denosumab demonstrated a delay in the onset of skeletal-related events (SREs) in this setting [4], and the radioisotope radium 223 (233Ra) has demonstrated a survival improvement in men with symptomatic bone metastatic CRPC [5]. Given this rapidly changing landscape [6], the expense of these treatment options, and the number of novel agents in development [7], major priorities for both clinical practice and research include the evaluation of biomarkers able to guide therapeutic decision making. In this review, we provide a framework for understanding and using existing biomarkers in CRPC in clinical practice and discuss methods for evaluating novel biomarkers in research settings to maximize clinical benefit.
A biomarker is defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [8]. Thus a biomarker can be a blood test, a response to a validated questionnaire, or radiographic measurements, and it is intended to guide patient management. Biomarkers can be prognostic, predictive, or surrogate in nature, or they can serve multiple roles. A prognostic biomarker provides evidence about a patient's eventual outcomes from a disease independent of a given therapy, whereas a predictive biomarker estimates the likelihood of response/benefit to a specific therapy in a specific context [9]. In metastatic CRPC, a host of prognostic factors have been reported (Table 1), but qualified predictive biomarkers have not been reported. An example of a predictive biomarker in oncology is overexpression of the HER2 oncogene in breast cancer, which is adversely prognostic and also predicts benefit with trastuzumab [10]. A surrogate biomarker goes further and is able to substitute as an intermediate for a clinically meaningful end point such as OS [11]. To fulfill criteria for surrogacy in oncology, a biomarker must satisfy several key statistical criteria described in detail elsewhere [11], [12], [13], [14] and must also be validated across multiple trials of a variety of mechanistically distinct agents [11], [12]. However, for a biomarker to become clinically useful, it must also directly inform and/or alter a medical decision and the treatment algorithm based on its result. Although prognostic markers can be helpful, predictive and surrogate biomarkers carry a greater degree of importance given their direct relationship with treatment decision making. In this paper, we review a selection of validated biomarkers in CRPC and discuss their utility in both the clinical and research settings.
Section snippets
Evidence acquisition
We conducted a literature search using PubMed and American Society of Clinical Oncology or European Society for Medical Oncology abstracts through September 2011 using the search terms for a given biomarker or therapy and prostate cancer with a focus on castration-resistant metastatic disease. Papers were synthesized by one of the authors (AJA), with input from the other authors as to inclusion or exclusion of relevant publications, and all the authors approved the final manuscript.
Evidence synthesis
The following sections focus on the evidence, rationale, advantages, limitations, and recommendations for use and evaluation of blood and urine biomarkers in CRPC rather than the broader landscape of imaging tests and qualitative outcome measures such as pain responses or quality-of-life changes, which are addressed elsewhere [15], [16]. Table 1 provides a synthesized list of currently validated prognostic and predictive biomarkers, and Table 2 provides a broad list of potential surrogate
Conclusions
The clinical utility of biomarkers in men with CRPC is context dependent, meaning that usefulness depends on the clinical/translational question (prognosis, prediction, surrogacy, treatment resistance, pharmacodynamic) and how a biomarker will have an impact on clinical decision making for a given systemic therapy. Currently all biomarkers in clinical use have prognostic implications when measured prior to starting therapy, but they have not yet been credentialed as predictive or surrogate
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