Med Oncol (2014) 31:140 DOI 10.1007/s12032-014-0140-3
REVIEW ARTICLE
Biomarkers in prostate cancer: new era and prospective Amrallah A. Mohammed
Received: 1 July 2014 / Accepted: 15 July 2014 / Published online: 22 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Currently, most men are diagnosed with prostate cancer (PCa) after a prostate-specific antigen (PSA) test shows an elevated level of the PSA protein. An elevated level suggests cancer may be present. If an elevation is detected, a biopsy to detect cancer is followed. But the PSA test is controversial. An elevated level does not always mean there is cancer present. The test often leads men to having unnecessary biopsies and treatments. Even if cancer is found on biopsy, many of these cancers are slow growing and would not impact the lives of the men who have them. Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for PCa. The purpose of this review is to examine the advances in PCa biomarkers and implication for possible improving disease outcome. The future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, and metastasis and can serve as prognosticators, targets, and/or surrogate endpoints of disease progression and response to therapy.
Introduction Prostate cancer (PCa) is the second most common cancer in men worldwide. In the United States of America, approximately 240,000 men are diagnosed annually with PCa [1]. The clinical behavior ranges from a microscopic, welldifferentiated tumor that may never be clinically significant to an aggressive, high-grade cancer that ultimately causes metastases, morbidity, and death. The frequency of diagnosis of PCa is increasing. The reasons for this increasing incidence are not known, but both genetic and environmental factors have been implicated. The vast majority of men diagnosed with clinically localized PCa are treated with interventional therapies despite studies demonstrating that even without treatment, PCa-specific mortality is low [2, 3]. Several factors may influence overtreatment; however, the most important is the limitation of current clinical parameters in their ability to discriminate between aggressive and indolent forms of the disease in a significant number of men [4].
Keywords Prostate cancer Tumor markers New biomarkers Controversial PSA test
A. A. Mohammed (&) Oncology Center, King Abdullah Medical City-Holy Capital, Muzdallifa Streat, P.O. Box 57657, Mecca 21995, Saudi Arabia e-mail: [email protected] A. A. Mohammed Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
In 1994, prostate-specific antigen (PSA) was officially approved for PCa screening by the FDA, and 4.0 ng/ml was set as the upper limit of normal range. Following its prevalent use, PSA became the most frequent method of detecting PCa and has resulted in a considerable stage migration. However, considerable controversy remains about PSA screening, due to questions regarding survival benefit, cost effectiveness, and clinical factors such as the optimal age and total PSA at which to recommend biopsy [5], also increase in the levels of PSA is not as specific as it is sensitive for diagnosis. A rise in the PSA level can reflect
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the presence of cancerous cells, but can also be related to nonmalignant disorders such as benign prostatic hyperplasia (BPH), infection or chronic inflammation. Prostate-specific antigen can no longer be considered as a classical biomarker whose levels are directly correlated with increasing stage of the disease. Moreover, the relationship with tumor grade remains unclear [6] Also classical prognostic tools based on pretreatment PSA levels, such as Partin tables [7] and Kattan nomograms [8], have become less reliable because of the continuous shift toward earlier stages of the disease at diagnosis. According to Thompson et al. [9], there is no true PSA cutoff point for identifying PCa risk in that there are a significant number of men with PSA values \ 4.0 ng ml who actually have PCa [10]. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity, and assessment of various isoforms of PSA.
Med Oncol (2014) 31:140
supportive data to be beneficial biologically and clinically, and other potential candidates are still under investigation.
Selected PCa markers The prostate health index (PHI) The prostate health index is a new formula that combines all three forms (total PSA, free PSA, and p2PSA) into a single score that can be used to aid in clinical decision making [14]. Several large international studies have also reported on PHI, including the PRO–PSA Multicentric European Study, among 646 European men from five centers under going prostate biopsy for a PSA of 2–10 ng/ ml or suspicious DRE. Lazzeri and colleagues showed that using p2PSA or PHI significantly improved the prediction of biopsy outcome over total and free PSA [15]. PHI also predicts the likelihood of progression during active surveillance, providing another noninvasive modality to potentially select and monitor this patient population [16].
Biomarkers
Prostate cancer antigen 3 (PCA3)
The National Cancer Institute defines a biomarker as a substance found in tissue, blood, or other body fluids that may be a sign of cancer or certain benign (noncancerous) conditions. Most tumor biomarkers are made by both normal cells and cancer cells, but they are made in larger amounts by cancer cells. Like all respective biomarkers correlated to their respective cancers, prostate biomarkers exhibit some or all of these abilities: prognostic, predictive, and pharmacodynamic. Prognostic biomarkers predict the natural course of the cancer to distinguish the tumor’s outcome. They also help determine whom to treat, how aggressively to treat, which candidates will likely respond to a given drug, and the most effective dose. Predictive biomarkers evaluate the probable benefit of a particular treatment. Pharmacodynamic biomarkers assess the imminent treatment effects of a drug on a tumor and can possibly determine the proper dosage in the early stages of clinical development of a new anticancer drug [11]. Identification of disease-specific molecular biomarkers is a rational approach to addressing current clinical challenges of whom to biopsy, whom to offer certain interventional therapies, in whom to alter therapeutic strategies, and in whom to follow up treatment outcome [12, 13]. With recent advances in biotechnology, many potential blood biomarkers have been identified and are currently under investigation. In this review, we will discuss and list some of the biomarkers that have a substantial amount of
Around 1995, PCA3 was identified in collaborative research effort by Johns Hopkins Hospital, Baltimore and the Radboud University, Nijmegen, Netherlands [17]. PCA3 is a segment of noncoding messenger ribonucleic acid (mRNA) from chromosome 9q21-22 that has been shown to be elevated in [95 % of men with PCa. It can determine benign from cancerous prostate cells with an accuracy approaching 100 %. Unlike serum PSA, PCA3 is not affected by age, prostate volume, or other prostatic diseases (e.g., prostatitis) [18].Furthermore, no PCA3 transcripts have been detected in extraprostatic tissues, demonstrating that PCA3 is the most specific PCa biomarker identified [19]. In 2012, FDA approved urine test that detects the overexpression of the PCA3 gene, which is specific to PCa and an accurate predictor of whether cancer may be present. PCA3 is also considered to be helpful in deciding when to re-biopsy in the follow-up of patients under active surveillance [20].
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Confirm MDx It is an epigenetic assay ordered by Crawford and released in May 2012 and uses an epigenetic field effect (‘‘halo’’) to determine the risk of cancerization at a DNA level. The innovative test can help to single out men without a risk of prostate cancer from undergoing unnecessary biopsies as well as identify patients who need treatment. It also helps to identify high-risk patients for further tests or treatment [21, 22].
Med Oncol (2014) 31:140
TMPRSS2–ERG It is a fusion between the transmembrane protease serine 2 (TMPRSS2) gene (located at 21q22.3) with the transcription factor genes ERG (21q22.2) and ETV1 (7p21.1) (One TMPRSS2 allele loses its promoter, and one of the ERG alleles gains it) [23]. It is a specific DNA arrangement found in half PCa and detected in about one quarter of patients with prostatic intraepithelial neoplasia. This urine test may help to identify a subset of aggressive PCa with high specificity, may play a role in monitoring the response to hormonal or other therapies for predicting subsequent tumor behavior, and can help in better predicting the clinical outcome [24]. Phosphatase and tensin homolog gene (PTEN) The PTEN gene is tumor suppressor gene with four-protein signature that is commonly altered in PCa. It makes a protein that switches off the PI3 K/AKT/mTOR signaling pathway, which is responsible for cell growth, metastasis, and survival. A preponderance of evidence shows that PTEN mutation had a significantly greater Gleason score, poorer prognosis, and higher rate of metastasis [25]. Research on the PTEN gene is aimed at distinguishing between noncancerous enlargement of the prostate and PCa with subsequent appropriate therapy [26]. Oncotype DX The Oncotype DX PCa test measures the level of expression of 17 genes across four biological pathways to predict the aggressiveness. The test results are reported as a Genomic Prostate Score that ranges from 0 to 100 to determine the level of risk. It is similar to the Oncotype DX breast cancer assay used to determine the management of women with node-negative early breast cancer. The Oncotype DX PCa assay can determine whether men with newly diagnosed low-risk prostate cancer are appropriate candidates for watchful waiting or harbor more aggressive disease, thus helping in tailoring therapy [27, 28].
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predict the likelihood of relapse or progression during the 10 years following surgery; it is intended to estimate the risk of tumor recurrence and to guide the adjustment of therapy accordingly [29]. Decipher Decipher is a transformative genomic test, which measures the expression levels of 22 RNA biomarkers involved in multiple biological pathways across the genome that are associated with aggressive PCa. The study, titled ‘‘Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population,’’ revealed that over 70 % of high-risk patients had low genomic classifier (GC) scores and good prognosis, whereas patients with high GC scores had a cumulative incidence of metastasis [25 % [30]. When used in conjunction with conventional risk assessment tools, validation data indicate that Decipher is used to generate a patient’s tumor-specific risk of disease progression after radical prostatectomy and may have a financial impact on use of further therapy [31]. Circulating tumor cells (CTCs) The role of CTCs in PCa is rapidly evolving and providing a window into the hematogenous spread of cancer and can drastically improve oncologic understanding and patient care. Increased levels of CTCs in the blood of castrationresistant prostate cancer (CRPC) patients can predict worse outcomes. Evaluation of individual CTCs has allowed further prognostication of PCa [32]. CTC testing may help to guide treatment decisions and to optimize the frequency of other disease-monitoring tests, but approximately 50 % of patients have undetectable CTC levels based on current detection methods. With limited information regarding the prognostic value of CTCs in PCa, there is a need for prospective studies to confirm and validate the role of CTCs in CRPC [33]. Human glandular kallikrein (hK2)
Prolaris Prolaris is a gene signature test that assesses the cell cycle progression gene that has been validated in multiple cohorts and provides a risk assessment of PCa-specific progression and disease-specific mortality when combined with standard clinicopathologic parameters. Like Oncotype DX, Prolaris can identify which patients are ‘‘truly’’ at low risk and can be managed by active surveillance, potentially reducing overtreatment of prostate cancer. Prolaris has been extensively validated for use after prostatectomy to
Human kallikrein 2 is a serine protease very similar to PSA, sharing an 80 % sequence homology with PSA. Both hK2 and PSA are primarily expressed in the prostate gland. Despite these similarities, hK2 and PSA differ in their enzymatic activity [34]. The levels of hK2 in prostate, semen, and serum are less than 2 % compared with PSA. Within the last years, many studies have proven the value of hK2 to enhance the discrimination between PCa and BPH. It has been suggested that hK2 could differentiate between hK2 level in pT2 and pT3 PCa and between G2
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140 Page 4 of 6 Table 1 Selected serum markers
Med Oncol (2014) 31:140
Serum marker
Description
Biological role
Early prostate cancer antigen (EPCA) 1, 2 [36]
A nuclear matrix protein
Linked with early carcinogenesis
Found in precursor lesions and PCa tissue
Diagnostic value
The urokinase plasminogen activation (uPA) and receptor (Upar) [37]
Highly restricted serine protease
uPAR fragments were predictors on biopsy specimens
Transforming growth factor (TGF)-ß1 [38]
Growth factor involved in, cell proliferation, immune response, differentiation, and angiogenesis
Association with cancer progression and metastasis
Interleukin-6 (IL-6) and receptor [39]
Cytokine with variable effects on immune and hematopoietic mechanisms
IL-6 and IL-6R are associated with aggressive phenotype
Chromogranin A [40]
Part of the granin family of proteins, controlling cell growth, secreted by neuroendocrine cells in the prostate gland
Monitoring the treatment outcome and disease progression
PSP94 (h-microseminoprotein) [41]
One of the most abundant proteins in the semen
Ratio of PSP94/free PSP94 was independent predictors recurrence after radical prostatectomy
Prostate-specific membrane antigen (PSMA) [42]
Glycoprotein highly expressed in normal and cancerous epithelial prostatic cells
Corresponding with poor clinical
a-Methylacyl-CoA racemase (AMACR) [43]
Enzyme involved in fat metabolism
Diagnostic value by using monoclonal antibodies
Insulin-like growth factor (ILGF-1, -2) [44]
Growth hormone
Preclinical stage detection and outcome
Converts zymogen plasmin
uPA and uPAR might have a prognostic value
Suppresses tumor growth and metastasis
versus G3 PCa or Gleason scores \7 and C7 PCa. However, this finding was not validated by other authors [35]. The usefulness of hK2 for the preoperative staging of localized PCa therefore remains controversial. Table 1: shows some selected serum markers; description and biological function.
Discussion In spite of extensive research efforts, few PCa biomarkers have been successfully integrated into clinical practice. The recommendation by the United States Preventive Services Task Force against widespread PSA-based screening for PCa, because of the risk of overdiagnosis and overtreatment and the inability to detect a significant proportion of dangerous tumors. Multiple guidelines now endorse active surveillance for low-risk PCa. So, we need biomarkers carrying the promise of potentially avoiding unnecessary biopsy in men who do not have an aggressive or asymptomatic PCa. Early detection of PCa was made 20 years ago by the introduction of PSA in the clinical practice. However, PCa screening remains controversial. Furthermore, to date, there is no conclusive evidence that the use of PSA has reduced PCa-related mortality. Currently, biomarker research is focused on serum-, urine-, and tissue-based markers. Assays involving these biomarkers are being assessed to help patients avoid unnecessary biopsies, to reduce the use of interventional
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Outcome
strategies, and to enhance the risk stratification of organconfined tumors. There are many classifications for PCa biomarkers, but can be broadly categorized into three main buckets depending on their utility in PCa management: biomarkers that assist clinicians in determining (1) whom to biopsy, (2) when to re-biopsy, and (3) whom to offer therapy. See Table 2. Although several new biomarkers have shown promises in preliminary studies, no single biomarker is likely to have the desired level of accuracy. Combining biomarker assays may improve predictive accuracy compared with the use of individual markers, as the assessment of post-DRE urine TMPRSS2-ERG, in combination with urine PCA3, enhanced the utility of serum PSA level for predicting PCa risk and clinically relevant cancer on subsequent biopsy. At this time, the usefulness of genetic tests related to PCa screening, detection, and management is unclear because it has not yet been demonstrated that it actually improves outcomes. We expect that the widespread adoption of genetic tests would be a major paradigm shift in the management of men with newly diagnosed prostate cancer.
Conclusion The future of cancer profiling might rely on the combination of a panel of markers that can give accurate molecular diagnosis and staging and indicate the likelihood of aggressive behavior. However, while the overall data are promising, there is a need for appropriate clinical
Med Oncol (2014) 31:140 Table 2 Classification of PCa biomarkers Markers help in biopsy decision 1. Prostate-specific antigen (PSA) 2. Prostate health index (phi) 3. Prostate cancer antigen 3 (PCA3) 4. Human glandular kallikrein 5. a-Methylacyl-CoA racemase (AMACR) 6. Early prostate cancer antigen (EPCA) 1, 2 7. Insulin-like growth factor 8. PSP94 (h-microseminoprotein) 9. Early prostate cancer antigen (EPCA)1,2 10. Prostate-specific membrane antigen (PSMA) Markers help in re-biopsy decision 1. Confirm MDx 2. Prostate core mitomic test (PCMT) 3. TMPRSS2-ERG 4. PTEN gene Markers help in therapy decision 1. Oncotype DX 2. Prolaris 3. Decipher
guidelines and protocols to ensure a systematic and critical evaluation of each potential test prior to their introduction in patient care. Conflict of interest The authors certify that there is no actual or potential conflict of interest in relation to this article.
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REVIEW ARTICLE
Biomarkers in prostate cancer: new era and prospective Amrallah A. Mohammed
Received: 1 July 2014 / Accepted: 15 July 2014 / Published online: 22 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Currently, most men are diagnosed with prostate cancer (PCa) after a prostate-specific antigen (PSA) test shows an elevated level of the PSA protein. An elevated level suggests cancer may be present. If an elevation is detected, a biopsy to detect cancer is followed. But the PSA test is controversial. An elevated level does not always mean there is cancer present. The test often leads men to having unnecessary biopsies and treatments. Even if cancer is found on biopsy, many of these cancers are slow growing and would not impact the lives of the men who have them. Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for PCa. The purpose of this review is to examine the advances in PCa biomarkers and implication for possible improving disease outcome. The future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, and metastasis and can serve as prognosticators, targets, and/or surrogate endpoints of disease progression and response to therapy.
Introduction Prostate cancer (PCa) is the second most common cancer in men worldwide. In the United States of America, approximately 240,000 men are diagnosed annually with PCa [1]. The clinical behavior ranges from a microscopic, welldifferentiated tumor that may never be clinically significant to an aggressive, high-grade cancer that ultimately causes metastases, morbidity, and death. The frequency of diagnosis of PCa is increasing. The reasons for this increasing incidence are not known, but both genetic and environmental factors have been implicated. The vast majority of men diagnosed with clinically localized PCa are treated with interventional therapies despite studies demonstrating that even without treatment, PCa-specific mortality is low [2, 3]. Several factors may influence overtreatment; however, the most important is the limitation of current clinical parameters in their ability to discriminate between aggressive and indolent forms of the disease in a significant number of men [4].
Keywords Prostate cancer Tumor markers New biomarkers Controversial PSA test
A. A. Mohammed (&) Oncology Center, King Abdullah Medical City-Holy Capital, Muzdallifa Streat, P.O. Box 57657, Mecca 21995, Saudi Arabia e-mail: [email protected] A. A. Mohammed Medical Oncology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
In 1994, prostate-specific antigen (PSA) was officially approved for PCa screening by the FDA, and 4.0 ng/ml was set as the upper limit of normal range. Following its prevalent use, PSA became the most frequent method of detecting PCa and has resulted in a considerable stage migration. However, considerable controversy remains about PSA screening, due to questions regarding survival benefit, cost effectiveness, and clinical factors such as the optimal age and total PSA at which to recommend biopsy [5], also increase in the levels of PSA is not as specific as it is sensitive for diagnosis. A rise in the PSA level can reflect
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the presence of cancerous cells, but can also be related to nonmalignant disorders such as benign prostatic hyperplasia (BPH), infection or chronic inflammation. Prostate-specific antigen can no longer be considered as a classical biomarker whose levels are directly correlated with increasing stage of the disease. Moreover, the relationship with tumor grade remains unclear [6] Also classical prognostic tools based on pretreatment PSA levels, such as Partin tables [7] and Kattan nomograms [8], have become less reliable because of the continuous shift toward earlier stages of the disease at diagnosis. According to Thompson et al. [9], there is no true PSA cutoff point for identifying PCa risk in that there are a significant number of men with PSA values \ 4.0 ng ml who actually have PCa [10]. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity, and assessment of various isoforms of PSA.
Med Oncol (2014) 31:140
supportive data to be beneficial biologically and clinically, and other potential candidates are still under investigation.
Selected PCa markers The prostate health index (PHI) The prostate health index is a new formula that combines all three forms (total PSA, free PSA, and p2PSA) into a single score that can be used to aid in clinical decision making [14]. Several large international studies have also reported on PHI, including the PRO–PSA Multicentric European Study, among 646 European men from five centers under going prostate biopsy for a PSA of 2–10 ng/ ml or suspicious DRE. Lazzeri and colleagues showed that using p2PSA or PHI significantly improved the prediction of biopsy outcome over total and free PSA [15]. PHI also predicts the likelihood of progression during active surveillance, providing another noninvasive modality to potentially select and monitor this patient population [16].
Biomarkers
Prostate cancer antigen 3 (PCA3)
The National Cancer Institute defines a biomarker as a substance found in tissue, blood, or other body fluids that may be a sign of cancer or certain benign (noncancerous) conditions. Most tumor biomarkers are made by both normal cells and cancer cells, but they are made in larger amounts by cancer cells. Like all respective biomarkers correlated to their respective cancers, prostate biomarkers exhibit some or all of these abilities: prognostic, predictive, and pharmacodynamic. Prognostic biomarkers predict the natural course of the cancer to distinguish the tumor’s outcome. They also help determine whom to treat, how aggressively to treat, which candidates will likely respond to a given drug, and the most effective dose. Predictive biomarkers evaluate the probable benefit of a particular treatment. Pharmacodynamic biomarkers assess the imminent treatment effects of a drug on a tumor and can possibly determine the proper dosage in the early stages of clinical development of a new anticancer drug [11]. Identification of disease-specific molecular biomarkers is a rational approach to addressing current clinical challenges of whom to biopsy, whom to offer certain interventional therapies, in whom to alter therapeutic strategies, and in whom to follow up treatment outcome [12, 13]. With recent advances in biotechnology, many potential blood biomarkers have been identified and are currently under investigation. In this review, we will discuss and list some of the biomarkers that have a substantial amount of
Around 1995, PCA3 was identified in collaborative research effort by Johns Hopkins Hospital, Baltimore and the Radboud University, Nijmegen, Netherlands [17]. PCA3 is a segment of noncoding messenger ribonucleic acid (mRNA) from chromosome 9q21-22 that has been shown to be elevated in [95 % of men with PCa. It can determine benign from cancerous prostate cells with an accuracy approaching 100 %. Unlike serum PSA, PCA3 is not affected by age, prostate volume, or other prostatic diseases (e.g., prostatitis) [18].Furthermore, no PCA3 transcripts have been detected in extraprostatic tissues, demonstrating that PCA3 is the most specific PCa biomarker identified [19]. In 2012, FDA approved urine test that detects the overexpression of the PCA3 gene, which is specific to PCa and an accurate predictor of whether cancer may be present. PCA3 is also considered to be helpful in deciding when to re-biopsy in the follow-up of patients under active surveillance [20].
123
Confirm MDx It is an epigenetic assay ordered by Crawford and released in May 2012 and uses an epigenetic field effect (‘‘halo’’) to determine the risk of cancerization at a DNA level. The innovative test can help to single out men without a risk of prostate cancer from undergoing unnecessary biopsies as well as identify patients who need treatment. It also helps to identify high-risk patients for further tests or treatment [21, 22].
Med Oncol (2014) 31:140
TMPRSS2–ERG It is a fusion between the transmembrane protease serine 2 (TMPRSS2) gene (located at 21q22.3) with the transcription factor genes ERG (21q22.2) and ETV1 (7p21.1) (One TMPRSS2 allele loses its promoter, and one of the ERG alleles gains it) [23]. It is a specific DNA arrangement found in half PCa and detected in about one quarter of patients with prostatic intraepithelial neoplasia. This urine test may help to identify a subset of aggressive PCa with high specificity, may play a role in monitoring the response to hormonal or other therapies for predicting subsequent tumor behavior, and can help in better predicting the clinical outcome [24]. Phosphatase and tensin homolog gene (PTEN) The PTEN gene is tumor suppressor gene with four-protein signature that is commonly altered in PCa. It makes a protein that switches off the PI3 K/AKT/mTOR signaling pathway, which is responsible for cell growth, metastasis, and survival. A preponderance of evidence shows that PTEN mutation had a significantly greater Gleason score, poorer prognosis, and higher rate of metastasis [25]. Research on the PTEN gene is aimed at distinguishing between noncancerous enlargement of the prostate and PCa with subsequent appropriate therapy [26]. Oncotype DX The Oncotype DX PCa test measures the level of expression of 17 genes across four biological pathways to predict the aggressiveness. The test results are reported as a Genomic Prostate Score that ranges from 0 to 100 to determine the level of risk. It is similar to the Oncotype DX breast cancer assay used to determine the management of women with node-negative early breast cancer. The Oncotype DX PCa assay can determine whether men with newly diagnosed low-risk prostate cancer are appropriate candidates for watchful waiting or harbor more aggressive disease, thus helping in tailoring therapy [27, 28].
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predict the likelihood of relapse or progression during the 10 years following surgery; it is intended to estimate the risk of tumor recurrence and to guide the adjustment of therapy accordingly [29]. Decipher Decipher is a transformative genomic test, which measures the expression levels of 22 RNA biomarkers involved in multiple biological pathways across the genome that are associated with aggressive PCa. The study, titled ‘‘Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population,’’ revealed that over 70 % of high-risk patients had low genomic classifier (GC) scores and good prognosis, whereas patients with high GC scores had a cumulative incidence of metastasis [25 % [30]. When used in conjunction with conventional risk assessment tools, validation data indicate that Decipher is used to generate a patient’s tumor-specific risk of disease progression after radical prostatectomy and may have a financial impact on use of further therapy [31]. Circulating tumor cells (CTCs) The role of CTCs in PCa is rapidly evolving and providing a window into the hematogenous spread of cancer and can drastically improve oncologic understanding and patient care. Increased levels of CTCs in the blood of castrationresistant prostate cancer (CRPC) patients can predict worse outcomes. Evaluation of individual CTCs has allowed further prognostication of PCa [32]. CTC testing may help to guide treatment decisions and to optimize the frequency of other disease-monitoring tests, but approximately 50 % of patients have undetectable CTC levels based on current detection methods. With limited information regarding the prognostic value of CTCs in PCa, there is a need for prospective studies to confirm and validate the role of CTCs in CRPC [33]. Human glandular kallikrein (hK2)
Prolaris Prolaris is a gene signature test that assesses the cell cycle progression gene that has been validated in multiple cohorts and provides a risk assessment of PCa-specific progression and disease-specific mortality when combined with standard clinicopathologic parameters. Like Oncotype DX, Prolaris can identify which patients are ‘‘truly’’ at low risk and can be managed by active surveillance, potentially reducing overtreatment of prostate cancer. Prolaris has been extensively validated for use after prostatectomy to
Human kallikrein 2 is a serine protease very similar to PSA, sharing an 80 % sequence homology with PSA. Both hK2 and PSA are primarily expressed in the prostate gland. Despite these similarities, hK2 and PSA differ in their enzymatic activity [34]. The levels of hK2 in prostate, semen, and serum are less than 2 % compared with PSA. Within the last years, many studies have proven the value of hK2 to enhance the discrimination between PCa and BPH. It has been suggested that hK2 could differentiate between hK2 level in pT2 and pT3 PCa and between G2
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140 Page 4 of 6 Table 1 Selected serum markers
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Serum marker
Description
Biological role
Early prostate cancer antigen (EPCA) 1, 2 [36]
A nuclear matrix protein
Linked with early carcinogenesis
Found in precursor lesions and PCa tissue
Diagnostic value
The urokinase plasminogen activation (uPA) and receptor (Upar) [37]
Highly restricted serine protease
uPAR fragments were predictors on biopsy specimens
Transforming growth factor (TGF)-ß1 [38]
Growth factor involved in, cell proliferation, immune response, differentiation, and angiogenesis
Association with cancer progression and metastasis
Interleukin-6 (IL-6) and receptor [39]
Cytokine with variable effects on immune and hematopoietic mechanisms
IL-6 and IL-6R are associated with aggressive phenotype
Chromogranin A [40]
Part of the granin family of proteins, controlling cell growth, secreted by neuroendocrine cells in the prostate gland
Monitoring the treatment outcome and disease progression
PSP94 (h-microseminoprotein) [41]
One of the most abundant proteins in the semen
Ratio of PSP94/free PSP94 was independent predictors recurrence after radical prostatectomy
Prostate-specific membrane antigen (PSMA) [42]
Glycoprotein highly expressed in normal and cancerous epithelial prostatic cells
Corresponding with poor clinical
a-Methylacyl-CoA racemase (AMACR) [43]
Enzyme involved in fat metabolism
Diagnostic value by using monoclonal antibodies
Insulin-like growth factor (ILGF-1, -2) [44]
Growth hormone
Preclinical stage detection and outcome
Converts zymogen plasmin
uPA and uPAR might have a prognostic value
Suppresses tumor growth and metastasis
versus G3 PCa or Gleason scores \7 and C7 PCa. However, this finding was not validated by other authors [35]. The usefulness of hK2 for the preoperative staging of localized PCa therefore remains controversial. Table 1: shows some selected serum markers; description and biological function.
Discussion In spite of extensive research efforts, few PCa biomarkers have been successfully integrated into clinical practice. The recommendation by the United States Preventive Services Task Force against widespread PSA-based screening for PCa, because of the risk of overdiagnosis and overtreatment and the inability to detect a significant proportion of dangerous tumors. Multiple guidelines now endorse active surveillance for low-risk PCa. So, we need biomarkers carrying the promise of potentially avoiding unnecessary biopsy in men who do not have an aggressive or asymptomatic PCa. Early detection of PCa was made 20 years ago by the introduction of PSA in the clinical practice. However, PCa screening remains controversial. Furthermore, to date, there is no conclusive evidence that the use of PSA has reduced PCa-related mortality. Currently, biomarker research is focused on serum-, urine-, and tissue-based markers. Assays involving these biomarkers are being assessed to help patients avoid unnecessary biopsies, to reduce the use of interventional
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Outcome
strategies, and to enhance the risk stratification of organconfined tumors. There are many classifications for PCa biomarkers, but can be broadly categorized into three main buckets depending on their utility in PCa management: biomarkers that assist clinicians in determining (1) whom to biopsy, (2) when to re-biopsy, and (3) whom to offer therapy. See Table 2. Although several new biomarkers have shown promises in preliminary studies, no single biomarker is likely to have the desired level of accuracy. Combining biomarker assays may improve predictive accuracy compared with the use of individual markers, as the assessment of post-DRE urine TMPRSS2-ERG, in combination with urine PCA3, enhanced the utility of serum PSA level for predicting PCa risk and clinically relevant cancer on subsequent biopsy. At this time, the usefulness of genetic tests related to PCa screening, detection, and management is unclear because it has not yet been demonstrated that it actually improves outcomes. We expect that the widespread adoption of genetic tests would be a major paradigm shift in the management of men with newly diagnosed prostate cancer.
Conclusion The future of cancer profiling might rely on the combination of a panel of markers that can give accurate molecular diagnosis and staging and indicate the likelihood of aggressive behavior. However, while the overall data are promising, there is a need for appropriate clinical
Med Oncol (2014) 31:140 Table 2 Classification of PCa biomarkers Markers help in biopsy decision 1. Prostate-specific antigen (PSA) 2. Prostate health index (phi) 3. Prostate cancer antigen 3 (PCA3) 4. Human glandular kallikrein 5. a-Methylacyl-CoA racemase (AMACR) 6. Early prostate cancer antigen (EPCA) 1, 2 7. Insulin-like growth factor 8. PSP94 (h-microseminoprotein) 9. Early prostate cancer antigen (EPCA)1,2 10. Prostate-specific membrane antigen (PSMA) Markers help in re-biopsy decision 1. Confirm MDx 2. Prostate core mitomic test (PCMT) 3. TMPRSS2-ERG 4. PTEN gene Markers help in therapy decision 1. Oncotype DX 2. Prolaris 3. Decipher
guidelines and protocols to ensure a systematic and critical evaluation of each potential test prior to their introduction in patient care. Conflict of interest The authors certify that there is no actual or potential conflict of interest in relation to this article.
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