Role of CTCs in Bone Metastases and Advanced Prostate Cancer
Role of CTCs in Bone Metastases and Advanced Prostate Cancer
Prostate-specific antigen (PSA) has been used for over two decades as a serum marker for adenocarcinoma of the prostate. Although PSA screening remains an important part of disease screening and monitoring in early prostate cancer (PC), its utility in monitoring disease progression in advanced PC is undetermined. Furthermore, the role of PSA monitoring in the management of patients with PC and bone metastases appears limited. The purpose of this review is to evaluate the role of circulating tumor cells (CTCs) as potential novel biomarkers in advanced PC. We present a review of CTC testing and the clinical data supporting the prognostic potential of CTCs in this setting. We propose that combination of CTCs and PSA velocity or doubling-time assessments may offer insights into the prognosis and management of advanced PC.
As the second most frequently diagnosed cancer in men worldwide, after lung cancer, prostate cancer (PC) remains a significant public health issue. Approximately 900,000 cases of PC have been diagnosed annually in recent years, and rates are expected to increase with the aging of the population. PC is associated with approximately 258,000 deaths each year. Worldwide, PC diagnoses are most prevalent in North America, New Zealand and parts of Europe (>80 cases per 100,000 population) and lowest in China, Taiwan and Thailand (<5 cases per 100,000 population). The wide variation – up to 25-fold – in worldwide incidence has been largely attributed to improvements in early detection with the adoption of prostate-specific antigen (PSA) testing and subsequent biopsy in developed countries, as well as genetic, environmental and behavioral differences between populations.
PSA testing was introduced almost 25 years ago as a serum assay for prostate growth, based on inferential evidence that elevated PSA levels were associated with occult disease. While its original use was to aid in the care of patients already diagnosed with PC, by 1994, PSA testing was approved by the US FDA, becoming the first, and to date only, blood test for PC screening. In addition to its role in screening, PSA (both as a protein and an mRNA transcript) has become an established marker for monitoring the early disease course of PC. As the use of PSA screening has become more widespread, mortality rates from PC have steadily decreased. However, some argue that the decreased mortality is owing to improvements in treatment rather than improvements in screening and the resulting earlier detection of disease.
Despite the tremendous insight offered by PSA testing in early disease, its use in the management of advanced PC and as a prognostic marker for overall survival (OS) remains limited. Historically, PSA monitoring used a cutoff of 4.0 ng/ml for suspected PC. However, PSA is now typically considered to be a continuous variable, and factors such as PSA transcripts and kinetics may now be considered in patient evaluations. Advances in PSA analysis, such as the emerging science of PSA kinetics, which includes PSA velocity and doubling time, have demonstrated some potential as a surrogate for predicting OS in castration-resistant PC (CRPC) metastatic to bone. However, the utility of tumor-derived factors, such as PSA, and measurements of secondary effects, such as through biochemical markers of bone metabolism, have yet to be validated in large-scale prospective trials in this setting.
Abstract and Introduction
Abstract
Prostate-specific antigen (PSA) has been used for over two decades as a serum marker for adenocarcinoma of the prostate. Although PSA screening remains an important part of disease screening and monitoring in early prostate cancer (PC), its utility in monitoring disease progression in advanced PC is undetermined. Furthermore, the role of PSA monitoring in the management of patients with PC and bone metastases appears limited. The purpose of this review is to evaluate the role of circulating tumor cells (CTCs) as potential novel biomarkers in advanced PC. We present a review of CTC testing and the clinical data supporting the prognostic potential of CTCs in this setting. We propose that combination of CTCs and PSA velocity or doubling-time assessments may offer insights into the prognosis and management of advanced PC.
Introduction
As the second most frequently diagnosed cancer in men worldwide, after lung cancer, prostate cancer (PC) remains a significant public health issue. Approximately 900,000 cases of PC have been diagnosed annually in recent years, and rates are expected to increase with the aging of the population. PC is associated with approximately 258,000 deaths each year. Worldwide, PC diagnoses are most prevalent in North America, New Zealand and parts of Europe (>80 cases per 100,000 population) and lowest in China, Taiwan and Thailand (<5 cases per 100,000 population). The wide variation – up to 25-fold – in worldwide incidence has been largely attributed to improvements in early detection with the adoption of prostate-specific antigen (PSA) testing and subsequent biopsy in developed countries, as well as genetic, environmental and behavioral differences between populations.
PSA testing was introduced almost 25 years ago as a serum assay for prostate growth, based on inferential evidence that elevated PSA levels were associated with occult disease. While its original use was to aid in the care of patients already diagnosed with PC, by 1994, PSA testing was approved by the US FDA, becoming the first, and to date only, blood test for PC screening. In addition to its role in screening, PSA (both as a protein and an mRNA transcript) has become an established marker for monitoring the early disease course of PC. As the use of PSA screening has become more widespread, mortality rates from PC have steadily decreased. However, some argue that the decreased mortality is owing to improvements in treatment rather than improvements in screening and the resulting earlier detection of disease.
Despite the tremendous insight offered by PSA testing in early disease, its use in the management of advanced PC and as a prognostic marker for overall survival (OS) remains limited. Historically, PSA monitoring used a cutoff of 4.0 ng/ml for suspected PC. However, PSA is now typically considered to be a continuous variable, and factors such as PSA transcripts and kinetics may now be considered in patient evaluations. Advances in PSA analysis, such as the emerging science of PSA kinetics, which includes PSA velocity and doubling time, have demonstrated some potential as a surrogate for predicting OS in castration-resistant PC (CRPC) metastatic to bone. However, the utility of tumor-derived factors, such as PSA, and measurements of secondary effects, such as through biochemical markers of bone metabolism, have yet to be validated in large-scale prospective trials in this setting.
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