Scandinavian Journal of Clinical and Laboratory Investigation
ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
Risk stratification of prostate cancer 2016 Robert E. Reiter To cite this article: Robert E. Reiter (2016) Risk stratification of prostate cancer 2016, Scandinavian Journal of Clinical and Laboratory Investigation, 76:sup245, S54-S59, DOI: 10.1080/00365513.2016.1208453 To link to this article: http://dx.doi.org/10.1080/00365513.2016.1208453
Published online: 17 Aug 2016.
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Date: 20 August 2016, At: 02:27
SCANDINAVIAN JOURNAL OF CLINICAL AND LABORATORY INVESTIGATION, 2016 VOL. 76, NO. S245, S54–S59 http://dx.doi.org/10.1080/00365513.2016.1208453
ORIGINAL ARTICLE
Risk stratification of prostate cancer 2016 Robert E. Reiter Bing Professor of Urologic Research, Department of Urology, Institute of Urologic Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
ABSTRACT
ARTICLE HISTORY
Prostate cancer is a common malignancy in men, but its management is fraught with controversy owing to its variable biologic and clinical behavior. Despite evidence that PSA screening reduces prostate cancer specific metastasis and death, it has not gained acceptance by various health authorities. Nevertheless, recent advances in biomarker development potentially address many of the shortcomings of routine PSA testing alone, including improved specificity for the detection of clinically significant cancer, optimized risk stratification to aid clinical management decisions, and discovery of genetic variants that may guide optimized therapy of advanced disease.
Accepted 9 March 2016 Published online 12 August 2016
Introduction Prostate cancer is the most common cancer diagnosis in American and European men and the second most common cause of cancer-related death. Despite the high prevalence of the disease and the significant toll it takes on men, prostate cancer is a disease that has been fraught with controversy for decades. Particularly fraught has been the subject of prostate cancer screening. While large randomized prospective studies in Europe consistently demonstrate a 20% or greater reduction in prostate cancer-specific metastasis and death among men who are screened, screening has still not been recommended by national health associations [1]. In the United States, the US Preventive Services Task Force have given PSA testing a grade of D, indicating a recommendation against its routine use for prostate cancer screening and detection [2]. The major reason for this rejection of PSA testing was the concern for overdiagnosis and consequent overtreatment – that is, screening may lead to diagnosis of a large number of non-threatening, indolent tumors and that men risk unnecessary treatment associated with complications such as impotence, incontinence, and bowel injury. Concluding that the risks of overdiagnosis and overtreatment outweigh the potential benefits of early diagnosis, the task force opted to counsel against screening. In addition to the problems of overdiagnosis and overtreatment, PSA screening has also been criticized because of limitations of the PSA test itself, including its lack of specificity and the large number of biopsies required to diagnose a single cancer, among other issues. Whether a rejection of PSA is prudent health policy or not is debatable, but the controversy highlights a feature of prostate cancer that is increasingly recognized in many malignancies, including thyroid, breast and kidney CONTACT Robert E. Reiter [email protected] School of Medicine at UCLA, Los Angeles, CA, USA ß 2016 Medisinsk Fysiologisk Forenings Forlag (MFFF)
KEYWORDS
Decipher; fPSA; 4K score; mpMRI; PHI; oncotype Dx
cancers – the existence of significant disease heterogeneity that confers differential biological risk among men diagnosed with this malignancy. The recognition that the best solution to the prostate cancer conundrum is not to throw out PSA with the bathwater, but rather to improve our ability to discriminate between life-threatening and indolent tumors and treat accordingly. Luckily, technological advances in genomics, imaging and biology are yielding biomarkers that promise to stratify risk and improve clinical decision-making so that we might retain the benefits of prostate cancer screening while jettisoning some of the risks. New biomarkers are also advancing the management of men with high-risk and metastatic prostate cancer, rapidly changing the prostate cancer landscape.
Who to biopsy? Adjuncts to PSA PSA is a normal component of the make ejaculate and not a cancer antigen. For reasons that are not completely understood, PSA is released into serum more commonly in men with prostate cancer, leading to its use as a prostate cancer diagnostic test. However, PSA testing has low specificity. Anywhere from 60–80% of men with an ‘elevated’ PSA do not have cancer and undergo one or more negative biopsies. Attempts to improve the performance of PSA have had some success, including concepts such as PSA density (PSA divided by prostate volume, with density >0.15 being particularly predictive of both prostate cancer and clinically significant disease), PSA velocity (rate of change of PSA or an absolute increase of 8 ng/L/year, with velocities of 2 ng/L/ year associated with prostate cancer lethality), age specific cut-offs, etc. [3,4]. Likewise, the addition of PSA to clinical information such as family history, ethnicity, age, etc. can be
Bing Professor of Urologic Research, Department of Urology, Institute of Urologic Oncology, Geffen
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calculated using various risk calculators to aid decisions about the biopsy. Prostate health index and 4K score Recently, a number of additional derivatives of PSA and related proteins have entered the clinic with the promise of improving the specificity of PSA, reducing the number of unnecessary biopsies, and potentially reducing the overdiagnosis of indolent prostate cancer in favor of better selectivity for clinically significant disease. These tests are largely dependent upon the recognition that PSA is not a single entity but rather includes distinct protein forms such as proPSA (the propeptide of PSA), free PSA (unbound PSA in plasma), nicked PSA, and others. For unknown reasons, cancers release more proPSA and free PSA whereas benign prostate hyperplasia releases more nicked PSA [5]. Therefore, the ratios of these forms can improve the specificity of total PSA for diagnosing prostate cancer. Free PSA has been available for many years, and can reduce unnecessary biopsies by as much as 20% [3]. PHI (Prostate Health Index), defined by the equation proPSA pffiffiffiffiffiffiffiffiffiffi tPSA (1) PHI ¼ fPSA can reduce unnecessary biopsies by as much as 30% while missing only 10% of higher risk tumors [6–8]. Another new test, 4K, adds the human kallikrein 2 gene, another prostate specific kallikrein related to PSA, to the armamentarium. It has been reported to improve both the specificity of total PSA, reducing unnecessary biopsies by as much as 40%, while also being capable of identifying men with Gleason 7 or higher tumors more accurately [9–11]. Both tests have been validated in retrospective, and in the case of PHI at least, prospective studies, with somewhat varying results as can be expected. It remains to be seen whether these enjoy widespread uptake, as free PSA initially did, and whether they prove long term to reduce the number of biopsies and the overdiagnosis of prostate cancer. It is also not clear how much better these tests are when compared to simple tests such as PSA density or PSA velocity. Of particular importance is the rapidly changing landscape in which men with prostate cancer are being diagnosed, with the increasing use of multiparametric MRI (mpMRI) as a diagnostic test done in the setting of an abnormal PSA or high-risk individual followed by a targeted biopsy. mpMRI is anywhere from 80–90% sensitive for clinically significant cancer, has a high negative predictive value (i.e. a clean MRI is strong evidence that a high risk prostate cancer is not present), and has the potential to reduce radically the number of unnecessary biopsies [12].
Who to biopsy among men with prior negative biopsy? Conventional prostate biopsy is done in a systematic manner transrectally using a transrectal ultrasound probe to image
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the prostate. Generally, 12 cores – two each from the right and left apex, mid gland, and base of the prostate – are taken and then examined histologically. A problem with this technique is that it may miss as many as 30% of prostate cancers, particularly ones located in the anterior prostate away from the probe and needle’s reach. Therefore, there has been heretofore an unmet need to determine who might need a repeat biopsy or alternative biopsy strategy when the initial biopsy is negative but there is still a suspicion of cancer based on PSA and other risk factors. PCA3: PCA3 is a urinary assay designed to detect the untranslated mRNA PCA3 present in prostate cancer cells shed into urine upon vigorous digital rectal examination. PCA3 was first discovered as a differentially expressed gene in prostate cancer when compared to the normal prostate, and secondarily realized to encode a non-coding mRNA. Its strong preferential expression in the vast majority of prostate cancers led to the development of this test in which the PCA3 gene is amplified together with the control gene PSA (to control for the presence of prostate cells). Cut-offs developed through retrospective validation studies separated patients with and without cancer. PCA3 is approved for use in men with a prior negative biopsy and multiple studies have shown its ability to discriminate between men who do and do not have prostate cancer better than PSA alone [13–15]. Use of PCA3 can reduce second biopsies by as much as 50%, has a high negative predictive value, and has an estimated sensitivity of 50% and specificity of 75% as a single marker. When combined with risk calculators, PCA3 behaves even better, with high sensitivity and specificity. PCA3 has also been explored as a screening tool, but suffers from relatively low sensitivity compared to PSA and has not been approved as a screening tool. Recent attempts to improve upon this performance by adding prostate cancerspecific markers such as the TMPRSS2-ERG fusion genes has entered clinical testing and use but has not entered common practice yet [16]. Mitomics and confirm MDx Two additional tests to determine the need for repeat biopsy have been developed, with varying degrees of evidence and adoption. Confirm MDx is the better studied of the two and takes advantage of the fact that tissue adjacent to prostate cancers is not ‘normal,’ but rather contains epigenetic changes suggestive of a field effect in which cancers arise. These epigenetic markers – hypermethylation of specific genes including GSTPI, APC, and RASSF1 – can be detected in the negative biopsies of patients and is strongly prognostic for the presence of cancer. The assay tests for at least one of these epigenetic markers[17–19]. Reported PPV and NPV for this test are 30–40% and 80–100%, respectively. A 600-patient prospective randomized study comparing the number of repeat biopsies done using Confirm Mdx vs. standard of care will report in 2017. The Mitomics assay also exploits the concept of a field effect change in prostate and the observation of a 3.4 kb deletion in mitochondrial DNA associated with prostate cancer.
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Reports on this assay are early and prospective studies are lacking. Initial publications have reported negative predictive values of 80–90% [20,21]. As with PSA and markers for determination of the need for biopsy, the landscape for repeat biopsies is also changing rapidly. As noted, mpMRI can detect as many as 80–90% of significant tumors and has a high negative predictive value. Although its role prior to initial biopsy is still controversial, it has already gained widespread acceptance as an indicator for who needs a repeat biopsy (and as a guide for those biopsies) [22]. A patient with clinical risk factors for prostate cancer with a negative biopsy can undergo an mpMRI. The absence of a suspicious lesion is a strong predictor that there is no significant disease, while presence of a suspicious lesion has a high positive predictive value that correlates with the degree of suspicion. While studies comparing mpMRI, PCA3, Mitomics and Confirm MDx have not been completed, a wealth of data on mpMRI suggests that it may be superior, and that additional tests may only be warranted in unusual cases.
Biomarkers that may guide management of newly diagnosed prostate cancer – differentiating clinically significant from indolent disease Once a diagnosis of prostate cancer has been made, the major question facing clinicians and patients is whether the cancer is clinically significant and needs an attempt at curative therapy or whether it is indolent and might be managed expectantly – either by ‘active surveillance’ or ‘watchful waiting.’ Until recently, most cancers were treated aggressively, but increased recognition of the harms of overtreatment have prompted questions about the merits of prostate cancer screening and concomitant attempts to reduce the burdens of treatment in those who are least likely to benefit. While traditional clinic-pathologic features such as Gleason score, the percentage of biopsy cores involved by cancer, PSA density, PSA, age, and other risk factors (ethnicity, inherited predisposition) have long been used and stratify risk quite well, all have limitations that have impeded optimal patient selection. In addition, reliance on biopsy results is fraught because traditional biopsy fails to predict accurate clinical histopathology in as many as 30% of patients (i.e. a Gleason 3 þ 3 ¼ 6 cancer on biopsy is upgraded in 30% of men after radical prostatectomy). Because of these limitations, attempts have been made to develop molecular biomarkers that provide more biological and clinical information about a given patient’s cancer.
Oncotype dx GPS (genomic prostate score) GPS is a biopsy-based molecular assay that was developed to improve risk stratification of men with National Comprehensive Cancer Network (NCCN) very low, low and intermediate risk cancers (Gleason 3 þ 3 ¼ 6 and 3 þ 4 ¼ 7). The assay measures expression of 17 genes amplified from RNA harvested from the highest grade cancer in paraffin embedded biopsy specimens [23,24]. The genes represent
diverse biological pathways, including proliferation, stromal response, androgen response and cellular organization. In this way, it differs from its closest competitor, Prolaris (see below), which measures only proliferation. The resulting GPS score predicts the probability of adverse pathologic stage and grade. Specifically, the score predicts the probability for any given NCCN risk status that the cancer is Gleason grade 4 þ 3 ¼ 7 or higher and/or pathologic stage T3 or higher. So for someone with 1 mm of Gleason 3 þ 3 ¼ 6 cancer on biopsy, which is NCCN very low risk, the score signifies the likelihood that the pathology is the same, worse, or better than that predicted by that risk category. The worse the risk, the more likely the cancer is Gleason 4 þ 3 or has spread beyond the prostate. Although the test does not predict the probability of metastasis or death from cancer, the higher grade and stage of cancer that it does predict are associated with higher rates of clinical disease recurrence and death. Critically important, the test does not provide any information about the clinical significance of Gleason 3 þ 4 ¼ 7 that is still stage T2. Although it is now fairly well accepted that true Gleason 3 þ 3 ¼ 6 disease is biologically and clinically indolent even in young men, there is still poor understanding of the biological behavior of Gleason 3 þ 4 ¼ 7 disease and the risks of active surveillance of these men. GPS has been validated in a number of retrospective cohorts with matching biopsy and radical prostatectomy data and shown to predict adverse pathology as well as the ability to improve risk stratification for each NCCN risk category. Two recent studies have also demonstrated that the test can impact management decisions, reclassifying men in some cases from treatment to active surveillance, and in others from surveillance to active treatment. Additional prospective evaluations to correlate GPS with clinical decisionmaking and ultimate outcomes are underway. In my own practice, GPS helps to confirm that a given patient indeed does have low risk of adverse pathology and can allay the anxiety associated with a decision to be placed on active surveillance. In some cases, GPS has identified patients with high-risk disease even when the biopsy, clinical risk factors, and imaging suggested low risk disease. Prolaris Prolaris is a second molecular biomarker that can be used in newly diagnosed patients. Prolaris measures cell cycle progression (CCP) as manifested by expression of 31 cell cycle progression genes. Unlike GPS, CCP does not predict the likelihood of adverse pathology, but rather the likelihood of biochemical recurrence, metastasis and death [25–27]. There have been at least six clinical validation studies, some done using radical prostatectomies as the analyte, but others using biopsy tissue. While most correlated CCP with recurrence (which may not predict metastasis or death), one study evaluated the association of CCP with metastasis and two with prostate cancer specific mortality. In addition, studies have shown that CCP, like GPS, can add prognostic information for any given risk category, essentially stratifying very low,
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low, and intermediate risk cancers into a continuum of risk. However, the impact of Prolaris on clinical decision-making has not been evaluated, nor has the impact of the test on clinical outcomes. These await further prospective studies. Although these two new molecular assays offer novel methods by which to improve risk stratification of men newly diagnosed with low and low-intermediate risk cancers, their ultimate role in clinical management remains uncertain. First, neither test has been compared with mpMRI to determine if it adds information beyond that obtained by mpMRI. Second, neither test is particularly useful for the intermediate Gleason 3 þ 4 ¼ 7 cancers. Third, although the tests appear to impact clinical decision-making, the accuracy of such predictions and their impact on long-term outcome are not known.
Biomarkers that guide management decisions after primary treatment Another major challenge in the management of prostate cancer is whether to elect adjuvant or salvage therapy after primary therapy with radical prostatectomy or radiation therapy. Clinical factors that may impact such decisions include pathologic stage and grade, the presence or absence of positive surgical margins, and the development of a rising PSA. However, adjuvant and salvage therapy ultimately benefit only a subset of men with these features. Many men with positive surgical margins do not recur, nor are all recurrences metastatic or potentially lethal.
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progress and develop castration-resistant disease. The recent advent of effective second and third-line treatments for men with CRPC has made the need to refine treatment choices an urgent problem. Two recent biomarkers demonstrate the promise of genomics to guide treatment choice. AR V7 Prostate cancers are uniquely addicted to androgens. This requirement for androgen has led to the development of novel androgen synthesis inhibitors such as abiraterone and androgen receptor antagonists such as enzalutamide. However, approximately 15–20% of patients are refractory to these medications. ARV7 is one of a number of androgen receptor splice variants that lack the ligand-binding domain, which have been found in a subset of men with CRPC. Recent reports from Antonarakis et al. have suggested that the presence of AR V7 in circulating tumor cells of men with CRPC strongly predict response or lack of response to enzalutamide or abiraterone [31]. Moreover, men whose tumors express this variant, while resistant to androgen antagonism, may retain sensitivity to chemotherapy, suggesting that AR V7 could be used to stratify patients to next generation androgen antagonists vs. chemotherapy [32]. In fact, a recently opened clinical trial screens men for the presence of AR V7 as a selection tool for entry into a trial of a novel anti-androgen that appears to be active against AR lacking the ligand-binding domain. DNA repair gene mutations
Decipher Decipher is a 22-gene signature obtained by microarray analysis of prostate tissue. Currently, the test is primarily indicated for analysis of radical prostatectomy tissue, but the company recently made the test available for biopsies as well. The test is a prognostic test that predicts for the risk of metastasis and death from prostate cancer after radical prostatectomy (i.e. treated prostate cancer). In a series of patients from Johns Hopkins that did not receive any adjuvant or salvage radiation prior to metastatic progression, Decipher was shown to predict biochemical recurrence, metastasis and prostate cancer specific mortality in a continuous manner [28,29]. One small retrospective study suggested that patients with a high Decipher score (> 0.4) benefited from adjuvant radiation compared to salvage radiation, whereas men with scores below this threshold had equivalent outcomes regardless of the timing of radiation therapy [30]. Additional studies will be needed to determine how best to integrate the risk parameters obtained by Decipher in the management of patients after primary treatment or at the time of diagnosis.
Biomarkers that guide therapy in men with metastatic, castration-resistant prostate cancer (CRPC) Androgen deprivation remains the mainstay of treatment for men with metastatic prostate cancer, but virtually all patients
The genomic landscape of metastatic CRPC has been mapped extensively over the past few years. While the overall mutational load of prostate cancers remains lower than that in other malignancies, these studies have revealed patterns of genomic changes that provide potentially actionable information. One unexpected finding has been the relative abundance of changes in DNA repair genes such as BRCA 2, ATM and others, which are present in as many as 20% of sequenced tumors [33]. Indeed, it has long been recognized that men with germline mutations in BRCA 2 are susceptible to the development of lethal prostate cancer. Based on this information, a trial of PARP inhibition with olaparib in men with CRPC was conducted and recently reported, together with whole exome sequencing on all patients. Remarkably, 14/16 men with mutations in BRCA 2 and other related genes responded to olaparib, vs. only two who were biomarker negative [34]. Interesting, a number of these men had germline changes in BRCA 2 and ATM. Prospective biomarker-guided trials are now underway to confirm this result, but this remains perhaps the first such study in prostate cancer to demonstrate the power of actionable mutations to guide patient care.
Conclusion There has been an explosion in interest and development of biomarkers for the management of prostate cancer at all
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stages of the disease, ranging from improved diagnostic tests, ones that may reduce the burden of overtreatment, as well as ones that guide treatment decisions after primary and systemic therapy. Much remains to be learned, particularly how to use these biomarkers, in what sequence, and at what cost. Comparative and prospective studies are now urgently needed, particularly ones that can validate how any one or combination of these markers impact overall death and suffering from prostate cancer. Nevertheless, we are at the beginning of what promises to be a revolutionary change in how prostate cancer, like other solid tumors, is diagnosed and managed.
Disclosure statement
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The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
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ISSN: 0036-5513 (Print) 1502-7686 (Online) Journal homepage: http://www.tandfonline.com/loi/iclb20
Risk stratification of prostate cancer 2016 Robert E. Reiter To cite this article: Robert E. Reiter (2016) Risk stratification of prostate cancer 2016, Scandinavian Journal of Clinical and Laboratory Investigation, 76:sup245, S54-S59, DOI: 10.1080/00365513.2016.1208453 To link to this article: http://dx.doi.org/10.1080/00365513.2016.1208453
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Date: 20 August 2016, At: 02:27
SCANDINAVIAN JOURNAL OF CLINICAL AND LABORATORY INVESTIGATION, 2016 VOL. 76, NO. S245, S54–S59 http://dx.doi.org/10.1080/00365513.2016.1208453
ORIGINAL ARTICLE
Risk stratification of prostate cancer 2016 Robert E. Reiter Bing Professor of Urologic Research, Department of Urology, Institute of Urologic Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
ABSTRACT
ARTICLE HISTORY
Prostate cancer is a common malignancy in men, but its management is fraught with controversy owing to its variable biologic and clinical behavior. Despite evidence that PSA screening reduces prostate cancer specific metastasis and death, it has not gained acceptance by various health authorities. Nevertheless, recent advances in biomarker development potentially address many of the shortcomings of routine PSA testing alone, including improved specificity for the detection of clinically significant cancer, optimized risk stratification to aid clinical management decisions, and discovery of genetic variants that may guide optimized therapy of advanced disease.
Accepted 9 March 2016 Published online 12 August 2016
Introduction Prostate cancer is the most common cancer diagnosis in American and European men and the second most common cause of cancer-related death. Despite the high prevalence of the disease and the significant toll it takes on men, prostate cancer is a disease that has been fraught with controversy for decades. Particularly fraught has been the subject of prostate cancer screening. While large randomized prospective studies in Europe consistently demonstrate a 20% or greater reduction in prostate cancer-specific metastasis and death among men who are screened, screening has still not been recommended by national health associations [1]. In the United States, the US Preventive Services Task Force have given PSA testing a grade of D, indicating a recommendation against its routine use for prostate cancer screening and detection [2]. The major reason for this rejection of PSA testing was the concern for overdiagnosis and consequent overtreatment – that is, screening may lead to diagnosis of a large number of non-threatening, indolent tumors and that men risk unnecessary treatment associated with complications such as impotence, incontinence, and bowel injury. Concluding that the risks of overdiagnosis and overtreatment outweigh the potential benefits of early diagnosis, the task force opted to counsel against screening. In addition to the problems of overdiagnosis and overtreatment, PSA screening has also been criticized because of limitations of the PSA test itself, including its lack of specificity and the large number of biopsies required to diagnose a single cancer, among other issues. Whether a rejection of PSA is prudent health policy or not is debatable, but the controversy highlights a feature of prostate cancer that is increasingly recognized in many malignancies, including thyroid, breast and kidney CONTACT Robert E. Reiter [email protected] School of Medicine at UCLA, Los Angeles, CA, USA ß 2016 Medisinsk Fysiologisk Forenings Forlag (MFFF)
KEYWORDS
Decipher; fPSA; 4K score; mpMRI; PHI; oncotype Dx
cancers – the existence of significant disease heterogeneity that confers differential biological risk among men diagnosed with this malignancy. The recognition that the best solution to the prostate cancer conundrum is not to throw out PSA with the bathwater, but rather to improve our ability to discriminate between life-threatening and indolent tumors and treat accordingly. Luckily, technological advances in genomics, imaging and biology are yielding biomarkers that promise to stratify risk and improve clinical decision-making so that we might retain the benefits of prostate cancer screening while jettisoning some of the risks. New biomarkers are also advancing the management of men with high-risk and metastatic prostate cancer, rapidly changing the prostate cancer landscape.
Who to biopsy? Adjuncts to PSA PSA is a normal component of the make ejaculate and not a cancer antigen. For reasons that are not completely understood, PSA is released into serum more commonly in men with prostate cancer, leading to its use as a prostate cancer diagnostic test. However, PSA testing has low specificity. Anywhere from 60–80% of men with an ‘elevated’ PSA do not have cancer and undergo one or more negative biopsies. Attempts to improve the performance of PSA have had some success, including concepts such as PSA density (PSA divided by prostate volume, with density >0.15 being particularly predictive of both prostate cancer and clinically significant disease), PSA velocity (rate of change of PSA or an absolute increase of 8 ng/L/year, with velocities of 2 ng/L/ year associated with prostate cancer lethality), age specific cut-offs, etc. [3,4]. Likewise, the addition of PSA to clinical information such as family history, ethnicity, age, etc. can be
Bing Professor of Urologic Research, Department of Urology, Institute of Urologic Oncology, Geffen
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calculated using various risk calculators to aid decisions about the biopsy. Prostate health index and 4K score Recently, a number of additional derivatives of PSA and related proteins have entered the clinic with the promise of improving the specificity of PSA, reducing the number of unnecessary biopsies, and potentially reducing the overdiagnosis of indolent prostate cancer in favor of better selectivity for clinically significant disease. These tests are largely dependent upon the recognition that PSA is not a single entity but rather includes distinct protein forms such as proPSA (the propeptide of PSA), free PSA (unbound PSA in plasma), nicked PSA, and others. For unknown reasons, cancers release more proPSA and free PSA whereas benign prostate hyperplasia releases more nicked PSA [5]. Therefore, the ratios of these forms can improve the specificity of total PSA for diagnosing prostate cancer. Free PSA has been available for many years, and can reduce unnecessary biopsies by as much as 20% [3]. PHI (Prostate Health Index), defined by the equation proPSA pffiffiffiffiffiffiffiffiffiffi tPSA (1) PHI ¼ fPSA can reduce unnecessary biopsies by as much as 30% while missing only 10% of higher risk tumors [6–8]. Another new test, 4K, adds the human kallikrein 2 gene, another prostate specific kallikrein related to PSA, to the armamentarium. It has been reported to improve both the specificity of total PSA, reducing unnecessary biopsies by as much as 40%, while also being capable of identifying men with Gleason 7 or higher tumors more accurately [9–11]. Both tests have been validated in retrospective, and in the case of PHI at least, prospective studies, with somewhat varying results as can be expected. It remains to be seen whether these enjoy widespread uptake, as free PSA initially did, and whether they prove long term to reduce the number of biopsies and the overdiagnosis of prostate cancer. It is also not clear how much better these tests are when compared to simple tests such as PSA density or PSA velocity. Of particular importance is the rapidly changing landscape in which men with prostate cancer are being diagnosed, with the increasing use of multiparametric MRI (mpMRI) as a diagnostic test done in the setting of an abnormal PSA or high-risk individual followed by a targeted biopsy. mpMRI is anywhere from 80–90% sensitive for clinically significant cancer, has a high negative predictive value (i.e. a clean MRI is strong evidence that a high risk prostate cancer is not present), and has the potential to reduce radically the number of unnecessary biopsies [12].
Who to biopsy among men with prior negative biopsy? Conventional prostate biopsy is done in a systematic manner transrectally using a transrectal ultrasound probe to image
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the prostate. Generally, 12 cores – two each from the right and left apex, mid gland, and base of the prostate – are taken and then examined histologically. A problem with this technique is that it may miss as many as 30% of prostate cancers, particularly ones located in the anterior prostate away from the probe and needle’s reach. Therefore, there has been heretofore an unmet need to determine who might need a repeat biopsy or alternative biopsy strategy when the initial biopsy is negative but there is still a suspicion of cancer based on PSA and other risk factors. PCA3: PCA3 is a urinary assay designed to detect the untranslated mRNA PCA3 present in prostate cancer cells shed into urine upon vigorous digital rectal examination. PCA3 was first discovered as a differentially expressed gene in prostate cancer when compared to the normal prostate, and secondarily realized to encode a non-coding mRNA. Its strong preferential expression in the vast majority of prostate cancers led to the development of this test in which the PCA3 gene is amplified together with the control gene PSA (to control for the presence of prostate cells). Cut-offs developed through retrospective validation studies separated patients with and without cancer. PCA3 is approved for use in men with a prior negative biopsy and multiple studies have shown its ability to discriminate between men who do and do not have prostate cancer better than PSA alone [13–15]. Use of PCA3 can reduce second biopsies by as much as 50%, has a high negative predictive value, and has an estimated sensitivity of 50% and specificity of 75% as a single marker. When combined with risk calculators, PCA3 behaves even better, with high sensitivity and specificity. PCA3 has also been explored as a screening tool, but suffers from relatively low sensitivity compared to PSA and has not been approved as a screening tool. Recent attempts to improve upon this performance by adding prostate cancerspecific markers such as the TMPRSS2-ERG fusion genes has entered clinical testing and use but has not entered common practice yet [16]. Mitomics and confirm MDx Two additional tests to determine the need for repeat biopsy have been developed, with varying degrees of evidence and adoption. Confirm MDx is the better studied of the two and takes advantage of the fact that tissue adjacent to prostate cancers is not ‘normal,’ but rather contains epigenetic changes suggestive of a field effect in which cancers arise. These epigenetic markers – hypermethylation of specific genes including GSTPI, APC, and RASSF1 – can be detected in the negative biopsies of patients and is strongly prognostic for the presence of cancer. The assay tests for at least one of these epigenetic markers[17–19]. Reported PPV and NPV for this test are 30–40% and 80–100%, respectively. A 600-patient prospective randomized study comparing the number of repeat biopsies done using Confirm Mdx vs. standard of care will report in 2017. The Mitomics assay also exploits the concept of a field effect change in prostate and the observation of a 3.4 kb deletion in mitochondrial DNA associated with prostate cancer.
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Reports on this assay are early and prospective studies are lacking. Initial publications have reported negative predictive values of 80–90% [20,21]. As with PSA and markers for determination of the need for biopsy, the landscape for repeat biopsies is also changing rapidly. As noted, mpMRI can detect as many as 80–90% of significant tumors and has a high negative predictive value. Although its role prior to initial biopsy is still controversial, it has already gained widespread acceptance as an indicator for who needs a repeat biopsy (and as a guide for those biopsies) [22]. A patient with clinical risk factors for prostate cancer with a negative biopsy can undergo an mpMRI. The absence of a suspicious lesion is a strong predictor that there is no significant disease, while presence of a suspicious lesion has a high positive predictive value that correlates with the degree of suspicion. While studies comparing mpMRI, PCA3, Mitomics and Confirm MDx have not been completed, a wealth of data on mpMRI suggests that it may be superior, and that additional tests may only be warranted in unusual cases.
Biomarkers that may guide management of newly diagnosed prostate cancer – differentiating clinically significant from indolent disease Once a diagnosis of prostate cancer has been made, the major question facing clinicians and patients is whether the cancer is clinically significant and needs an attempt at curative therapy or whether it is indolent and might be managed expectantly – either by ‘active surveillance’ or ‘watchful waiting.’ Until recently, most cancers were treated aggressively, but increased recognition of the harms of overtreatment have prompted questions about the merits of prostate cancer screening and concomitant attempts to reduce the burdens of treatment in those who are least likely to benefit. While traditional clinic-pathologic features such as Gleason score, the percentage of biopsy cores involved by cancer, PSA density, PSA, age, and other risk factors (ethnicity, inherited predisposition) have long been used and stratify risk quite well, all have limitations that have impeded optimal patient selection. In addition, reliance on biopsy results is fraught because traditional biopsy fails to predict accurate clinical histopathology in as many as 30% of patients (i.e. a Gleason 3 þ 3 ¼ 6 cancer on biopsy is upgraded in 30% of men after radical prostatectomy). Because of these limitations, attempts have been made to develop molecular biomarkers that provide more biological and clinical information about a given patient’s cancer.
Oncotype dx GPS (genomic prostate score) GPS is a biopsy-based molecular assay that was developed to improve risk stratification of men with National Comprehensive Cancer Network (NCCN) very low, low and intermediate risk cancers (Gleason 3 þ 3 ¼ 6 and 3 þ 4 ¼ 7). The assay measures expression of 17 genes amplified from RNA harvested from the highest grade cancer in paraffin embedded biopsy specimens [23,24]. The genes represent
diverse biological pathways, including proliferation, stromal response, androgen response and cellular organization. In this way, it differs from its closest competitor, Prolaris (see below), which measures only proliferation. The resulting GPS score predicts the probability of adverse pathologic stage and grade. Specifically, the score predicts the probability for any given NCCN risk status that the cancer is Gleason grade 4 þ 3 ¼ 7 or higher and/or pathologic stage T3 or higher. So for someone with 1 mm of Gleason 3 þ 3 ¼ 6 cancer on biopsy, which is NCCN very low risk, the score signifies the likelihood that the pathology is the same, worse, or better than that predicted by that risk category. The worse the risk, the more likely the cancer is Gleason 4 þ 3 or has spread beyond the prostate. Although the test does not predict the probability of metastasis or death from cancer, the higher grade and stage of cancer that it does predict are associated with higher rates of clinical disease recurrence and death. Critically important, the test does not provide any information about the clinical significance of Gleason 3 þ 4 ¼ 7 that is still stage T2. Although it is now fairly well accepted that true Gleason 3 þ 3 ¼ 6 disease is biologically and clinically indolent even in young men, there is still poor understanding of the biological behavior of Gleason 3 þ 4 ¼ 7 disease and the risks of active surveillance of these men. GPS has been validated in a number of retrospective cohorts with matching biopsy and radical prostatectomy data and shown to predict adverse pathology as well as the ability to improve risk stratification for each NCCN risk category. Two recent studies have also demonstrated that the test can impact management decisions, reclassifying men in some cases from treatment to active surveillance, and in others from surveillance to active treatment. Additional prospective evaluations to correlate GPS with clinical decisionmaking and ultimate outcomes are underway. In my own practice, GPS helps to confirm that a given patient indeed does have low risk of adverse pathology and can allay the anxiety associated with a decision to be placed on active surveillance. In some cases, GPS has identified patients with high-risk disease even when the biopsy, clinical risk factors, and imaging suggested low risk disease. Prolaris Prolaris is a second molecular biomarker that can be used in newly diagnosed patients. Prolaris measures cell cycle progression (CCP) as manifested by expression of 31 cell cycle progression genes. Unlike GPS, CCP does not predict the likelihood of adverse pathology, but rather the likelihood of biochemical recurrence, metastasis and death [25–27]. There have been at least six clinical validation studies, some done using radical prostatectomies as the analyte, but others using biopsy tissue. While most correlated CCP with recurrence (which may not predict metastasis or death), one study evaluated the association of CCP with metastasis and two with prostate cancer specific mortality. In addition, studies have shown that CCP, like GPS, can add prognostic information for any given risk category, essentially stratifying very low,
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low, and intermediate risk cancers into a continuum of risk. However, the impact of Prolaris on clinical decision-making has not been evaluated, nor has the impact of the test on clinical outcomes. These await further prospective studies. Although these two new molecular assays offer novel methods by which to improve risk stratification of men newly diagnosed with low and low-intermediate risk cancers, their ultimate role in clinical management remains uncertain. First, neither test has been compared with mpMRI to determine if it adds information beyond that obtained by mpMRI. Second, neither test is particularly useful for the intermediate Gleason 3 þ 4 ¼ 7 cancers. Third, although the tests appear to impact clinical decision-making, the accuracy of such predictions and their impact on long-term outcome are not known.
Biomarkers that guide management decisions after primary treatment Another major challenge in the management of prostate cancer is whether to elect adjuvant or salvage therapy after primary therapy with radical prostatectomy or radiation therapy. Clinical factors that may impact such decisions include pathologic stage and grade, the presence or absence of positive surgical margins, and the development of a rising PSA. However, adjuvant and salvage therapy ultimately benefit only a subset of men with these features. Many men with positive surgical margins do not recur, nor are all recurrences metastatic or potentially lethal.
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progress and develop castration-resistant disease. The recent advent of effective second and third-line treatments for men with CRPC has made the need to refine treatment choices an urgent problem. Two recent biomarkers demonstrate the promise of genomics to guide treatment choice. AR V7 Prostate cancers are uniquely addicted to androgens. This requirement for androgen has led to the development of novel androgen synthesis inhibitors such as abiraterone and androgen receptor antagonists such as enzalutamide. However, approximately 15–20% of patients are refractory to these medications. ARV7 is one of a number of androgen receptor splice variants that lack the ligand-binding domain, which have been found in a subset of men with CRPC. Recent reports from Antonarakis et al. have suggested that the presence of AR V7 in circulating tumor cells of men with CRPC strongly predict response or lack of response to enzalutamide or abiraterone [31]. Moreover, men whose tumors express this variant, while resistant to androgen antagonism, may retain sensitivity to chemotherapy, suggesting that AR V7 could be used to stratify patients to next generation androgen antagonists vs. chemotherapy [32]. In fact, a recently opened clinical trial screens men for the presence of AR V7 as a selection tool for entry into a trial of a novel anti-androgen that appears to be active against AR lacking the ligand-binding domain. DNA repair gene mutations
Decipher Decipher is a 22-gene signature obtained by microarray analysis of prostate tissue. Currently, the test is primarily indicated for analysis of radical prostatectomy tissue, but the company recently made the test available for biopsies as well. The test is a prognostic test that predicts for the risk of metastasis and death from prostate cancer after radical prostatectomy (i.e. treated prostate cancer). In a series of patients from Johns Hopkins that did not receive any adjuvant or salvage radiation prior to metastatic progression, Decipher was shown to predict biochemical recurrence, metastasis and prostate cancer specific mortality in a continuous manner [28,29]. One small retrospective study suggested that patients with a high Decipher score (> 0.4) benefited from adjuvant radiation compared to salvage radiation, whereas men with scores below this threshold had equivalent outcomes regardless of the timing of radiation therapy [30]. Additional studies will be needed to determine how best to integrate the risk parameters obtained by Decipher in the management of patients after primary treatment or at the time of diagnosis.
Biomarkers that guide therapy in men with metastatic, castration-resistant prostate cancer (CRPC) Androgen deprivation remains the mainstay of treatment for men with metastatic prostate cancer, but virtually all patients
The genomic landscape of metastatic CRPC has been mapped extensively over the past few years. While the overall mutational load of prostate cancers remains lower than that in other malignancies, these studies have revealed patterns of genomic changes that provide potentially actionable information. One unexpected finding has been the relative abundance of changes in DNA repair genes such as BRCA 2, ATM and others, which are present in as many as 20% of sequenced tumors [33]. Indeed, it has long been recognized that men with germline mutations in BRCA 2 are susceptible to the development of lethal prostate cancer. Based on this information, a trial of PARP inhibition with olaparib in men with CRPC was conducted and recently reported, together with whole exome sequencing on all patients. Remarkably, 14/16 men with mutations in BRCA 2 and other related genes responded to olaparib, vs. only two who were biomarker negative [34]. Interesting, a number of these men had germline changes in BRCA 2 and ATM. Prospective biomarker-guided trials are now underway to confirm this result, but this remains perhaps the first such study in prostate cancer to demonstrate the power of actionable mutations to guide patient care.
Conclusion There has been an explosion in interest and development of biomarkers for the management of prostate cancer at all
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stages of the disease, ranging from improved diagnostic tests, ones that may reduce the burden of overtreatment, as well as ones that guide treatment decisions after primary and systemic therapy. Much remains to be learned, particularly how to use these biomarkers, in what sequence, and at what cost. Comparative and prospective studies are now urgently needed, particularly ones that can validate how any one or combination of these markers impact overall death and suffering from prostate cancer. Nevertheless, we are at the beginning of what promises to be a revolutionary change in how prostate cancer, like other solid tumors, is diagnosed and managed.
Disclosure statement
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The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.
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