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New Biomarkers in Prostate Cancer
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New Biomarkers in Prostate Cancer
Review Article [1] | February 15, 2014 | Oncology Journal [2], Genitourinary Cancers [3], Prostate
Cancer [4]
By E. David Crawford, MD [5], Karen Ventii, PhD [6], and Neal D. Shore, MD, FACS [7]
In this article, we review recent advances in the discovery of prostate cancer biomarkers, their
integration into clinical practice, and implications for improving clinical management of the disease.
Introduction
In the United States (US), approximately 240,000 men are diagnosed annually with prostate cancer
(PCa).[1] Although effective treatment options are available for clinically localized PCa, the potential
burdensome morbidities and attendant healthcare costs[2] from overdiagnosis and overtreatment
have escalated the discussion and controversy regarding appropriate screening, diagnosis, and
optimal management of PCa.[3,4]
Although the lifetime risk of developing PCa is approximately 1 in 6 (~16%),[5,6] the risk of dying
from the disease is only ~2%.[6,7] The discrepancy between PCa incidence and lethality has led to
widespread scrutiny of prostate cancer patient management, particularly for low-grade, low-stage
(indolent) disease. 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.[8,9] Several factors may influence overtreatment; however, a very significant
reason is that current clinical parameters are limited in their ability to discriminate between
aggressive and indolent forms of the disease in a significant number of men.[10] Thus, clinicians and
patients may lack sufficient confidence to comfortably select and maintain an active surveillance
(active monitoring) strategy, for fear of missing a more aggressive phenotypic variant of the disease.
Given that PCa is both a biologically and clinically heterogeneous disease that develops amidst
diverse genetic and epigenetic changes,[11,12] 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, and in whom to alter therapeutic strategies.
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 strategies, when clinically appropriate; and to enhance the risk
stratification of organ-confined tumors. Markers are being developed to assist with the monitoring of
progression during “watchful waiting,” to detect micrometastatic disease (below the limit of
detection for imaging), and to better evaluate therapeutic responses to ongoing therapies.
PCa biomarkers can be broadly categorized into three main buckets depending on their role/utility in
PCa management (Figure 1): biomarkers that assist clinicians in determining (1) whom to biopsy, (2)
when to re-biopsy, and (3) whom to offer therapy.
Biomarkers That Help Clinicians Determine Whom to Biopsy
Prostate-specific antigen (PSA)
After its approval by the US Food and Drug Administration (FDA) in 1986, the PSA test revolutionized
the PCa screening and diagnosis landscape. It should be remembered that PSA testing is approved
for early detection along with digital rectal examination (DRE) in men over age 50.[13,14] In the US,
approximately 19 million men are screened annually with PSA testing, resulting in more than 1.3
million biopsy procedures and 240,890 new diagnoses of PCa.[1]
Nonetheless, there are inherent limitations to using the PSA test for PCa screening. First, the test
may give false-positive or false-negative results. Most men with an elevated PSA level (above 4.0
ng/mL)[15] are not found to have PCa; only about 25% of men who undergo a prostate biopsy due to
an elevated PSA level actually have PCa. Conversely, a negative result may give false assurances
that PCa is not detected, when in fact a cancer may exist. Also, early detection of PCa may not
reduce a man’s chance of dying from the disease.[15]
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The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was a large
population-based
randomized study designed and sponsored by the National Cancer Institute (NCI) to determine the
effects of screening on cancer-related mortality and secondary endpoints in men and women aged
55 to 74. After 13 years of follow-up in the PLCO trial, there was no evidence of a mortality benefit
for organized annual PCa screening vs opportunistic screening, which forms part of usual care, and
there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.[16]
However, Crawford and colleagues, in assessing men with no comorbidities in the PLCO study,
determined that screening did result in a survival benefit.[17]
Notably, however, 11-year follow-up results from the European Randomized Study of Screening for
Prostate Cancer demonstrated that screening does significantly reduce death from PCa.[18] A
potential reason for these different results is that in the US-based PLCO Cancer Screening Trial, at
least 44% of participants in the control arm had already undergone PSA testing prior to being
randomized into the study.[16]
To improve the sensitivity and specificity of serum PSA testing, several PSA derivatives and isoforms
(eg, PSA isoforms and PSA density) may be used. PSA density may be useful in determining the
presence of PCa.
Prostate health index (phi)
The phi (phi = [−2] proPSA/fPSA × PSA1/2; proPSA is a PSA subtype and fPSA is free PSA) has been
developed as an additional diagnostic biomarker in men with a serum PSA level of 2–10 ng/mL.
Previous studies have shown that elevated proPSA/fPSA ratios are associated with PCa. In a recent
prospective cohort of men enrolled into active surveillance for PCa, higher serum and tissue levels of
proPSA at diagnosis were associated with the need for subsequent treatment (Figure 2).[19]
Prostate cancer antigen 3 (PCA3)
PCA3 is a noncoding messenger RNA that has been shown to be elevated in > 90% of men with PCa,
but not significantly elevated in normal prostatic glands or in benign prostatic hypertrophy. PCA3 is
unique in that it can be measured in urine and adds to the diagnostic information obtained from the
PSA test, with higher area under the curve (AUC) values of 0.66 to 0.72, compared with 0.54 to 0.63
for serum PSA alone.[20] PCA3 complements the PSA test in men undergoing initial biopsy.[21] In
2012, PCA3 was approved by the FDA as a diagnostic test for PCa in the setting of a previous
negative prostate biopsy. PCA3 is also considered to be helpful in deciding when to re-biopsy and in
the follow-up of patients under active surveillance (Figure 3).[21] The mean PCA3 score was
statistically significantly higher in men with a positive biopsy, or those with atypical small acinar
proliferation (ASAP) and/or high-grade prostatic intraepithelial neoplasia (HGPIN), compared with
men who had a negative biopsy.[21]
Biomarkers That Help Clinicians Determine When to Re-biopsy
Up to 25% of men who undergo a prostate biopsy are misdiagnosed with a false-negative result.
Unnecessary prostate biopsies subject many men to undue risk. Surveillance, Epidemiology, and End
Results (SEER) Program data report that 6.9% of men are hospitalized in the 30 days following a
prostate biopsy. Associated complications include bleeding, infection, sepsis/bacteremia,
endocarditis, urinary symptoms/retention, and sexual dysfunction. Tests are needed to help
determine who needs to be re-biopsied.
ConfirmMDx
ConfirmMDx is an epigenetic assay to help distinguish patients who have a true-negative biopsy from
those who may have occult cancer. It detects an epigenetic field effect with the “cancerization”
process at the DNA level. This field effect around the cancer lesion can be present despite the
normal appearance of cells. Detection of field effects extends the coverage of the biopsy, helping to
rule in, or rule out, occult cancers. It provides actionable information to help men without PCa avoid
unnecessary repeat biopsies, with their inherent risk, and to identify men who require repeat
biopsies and potential treatment.[22,23]
The MATLOC (Methylation Analysis To Locate Occult Cancer) validation study demonstrated the
actionable and cost-effective nature of the ConfirmMDx test (also see the Cost vs Value section of
this article). MATLOC is a blinded multicenter study of an epigenetic test for prostate cancer
evaluating 483 men with initial negative biopsy followed by negative or positive biopsy. The real
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power of this test is in its negative predictive value of > 90% and its cost-effectiveness, as
demonstrated in studies done on 1 million lives (Figure 4).[24,25]
Prostate Core Mitomic Test (PCMT)
The PCMT identifies a large-scale depletion in mitochondrial DNA that indicates cellular change
associated with undiagnosed prostate cancer. It detects the presence of malignant cells in
normal-appearing prostate tissue across an extended area.[26]
TMPRSS2-ERG
TMPRSS2-ERG is a fusion between the transmembrane protease serine 2 (TMPRSS2) gene and the
v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene. This gene fusion is the
predominant variant in approximately 40% to 80% of PCa. Quantitative levels of urine TMPRSS2-ERG
appear to be associated with clinically significant PCa based on Epstein criteria, which stratify
disease aggressiveness using PSA density and characteristics of the patient’s biopsy (Gleason score
[GS], the percentage of tumor vs normal prostate tissue observed, and number of cores with
tumor).[27]
Combining biomarker assays may improve predictive accuracy compared with the use of individual
markers.[28] 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.[29]
The PTEN gene
Dysregulation of PTEN, a tumor suppressor gene involved in cell cycle regulation, is consistently
associated with poor prognosis in PCa. A preponderance of evidence shows that deletion of PTEN is
associated with higher Gleason grade, risk of progression, and recurrence after therapy. Additionally,
it is associated with advanced localized or metastatic disease and death.[30]
The PTEN assay is a prognostic fluorescence in situ hybridization (FISH) test typically ordered in
conjunction with prostate biopsy tests to indicate partial (hemizygous) or complete (homozygous)
deletions in the gene. For patients with a cancer diagnosis (for example, low-intermediate Gleason
scores of 6/7), the PTEN assay may help determine the rate of progression and subsequent
appropriate therapy. For patients with HGPIN or an atypical diagnosis, it is an effective screening tool
that allows clinicians to distinguish nonaggressive HGPIN or an atypical diagnosis from men at higher
risk of PCa.[31]
ProMark
ProMark is a prognostic biopsy-based PCa test. It uses immunofluorescent imaging analysis to
quantify biomarker expression and classify patients’ tumors. A clinical validation study demonstrated
ProMark can differentiate indolent from aggressive disease, based on data from standard
formalin-fixed, paraffin-embedded tissue.[32]
Prostate Biomarkers That Help Clinicians Determine Whom to Treat or Not
Treat
Given frequent uncertainty about the preferred course of treatment in many cases of early PCa,
accurate prognostic markers that supplement standard clinicopathologic parameters are needed.
Personalized risk assessment allows more informed treatment decision-making, given the variety of
options available for management of early-stage disease. A number of biomarkers are available to
guide clinicians through these challenging clinical situations.
Oncotype DX
Despite the fact that PCa remains a common cause of cancer death worldwide, many men will have
indolent disease that will not threaten their health during their natural life span, and overtreatment
of low-risk disease with radical therapy leads to significant morbidity and compromised quality of
life.
Because of early detection efforts, the vast majority of men with PCa are diagnosed with clinically
localized disease, yet are treated aggressively. However, studies indicate that even without
treatment, PCa-specific mortality remains relatively low. This aggressive treatment is due primarily
to the uncertainty around the malignant potential of many cancers. Improved prognostic tests that
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afford better stratification of patients based on their disease-specific risk of mortality and likelihood
of progression allow more indolent disease to be treated conservatively and more aggressive disease
to be treated more appropriately.
In men who have very low–, low-, and low-intermediate–risk PCa, Oncotype DX has been
prospectively validated as a biopsy-based predictor of adverse pathology. The Genomic Prostate
Score (GPS) adds independent predictive information beyond standard clinical and pathologic
measures (Figure 5). The GPS assesses underlying biology from very small biopsy tumor volumes,
addressing issues of tumor heterogeneity and biopsy under-sampling to more accurately predict
disease aggressiveness. Incorporation of the GPS enables more accurate identification of a larger
population of patients who can more confidently choose active surveillance as an initial management
strategy. This test has been validated from biopsy material and adds to other clinical parameters
such as National Comprehensive Cancer Network (NCCN) scores.[33,34]
Prolaris
Although overtreatment has garnered the majority of recent attention, under-treatment and
resulting mortality of men who harbor more aggressive cancer can also remain a significant problem.
These men may benefit from multimodality therapy, such as adjuvant radiation therapy, which may
result in decreased disease-specific mortality. A key distinguishing factor between cancerous and
noncancerous cells is the increase in cell cycle progression (CCP) gene mutations.[35] Prolaris is a
prognostic genomic assay that assesses the CCP gene signature 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. Prolaris has been validated to provide
personalized identification of both low-risk patients who can be managed with conservative options
and high-risk patients who may benefit from earlier definitive treatment.[35]
Decipher
Approximately 50% of men with PCa who receive radiotherapy after RP derive no benefit from this
intervention.[36] In men at elevated risk of recurrence following RP, only ~6% are found to have risk
factors suggesting that they will develop biochemical progression and metastatic disease after 5
years.[37] Decipher is a genomic assay that assesses the risk of disease progression after radical
prostatectomy. This assay has been shown to be independently prognostic of PCa death in a
high-risk surgical cohort. In a validation study, 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%.[37] This assay may better enable application of directed, multimodal
therapy for individual patients with high-risk PCa. The Decipher test is used to individualize the
management of high-risk patients (differentiating men who may have a treatment benefit from those
who may not) and may have a financial impact on use of radiation therapy or hormonal therapy
(Figure 6).[38]
Biomarkers Used to Assess the Therapeutic Response
PSA does not always accurately reflect response to therapy for castration-resistant PCa (CRPC).
Newer therapies, such as sipuleucel-T and radium-223, may improve survival without decreasing PSA
levels. For cytotoxic or hormonal therapies, PSA responses are not always indicative of clinical
response. Radiographic progression and symptomatology are still key parameters for consideration
of changing antineoplastic therapy. Discordance between PSA kinetics and clinical response and
progression of disease has been regularly observed. The need for biomarkers beyond PSA to predict
response to treatment is well recognized. Other helpful serologic tests include hemoglobin, alkaline
phosphatase, lactate dehydrogenase (LDH), and others. However, there is an unmet need for novel
biomarkers to better assist clinical evaluation of therapeutic response in metastatic CRPC.
Circulating tumor cells (CTCs)
The CTC assay is intended for enumeration of CTCs (CD45−, epithelial cell adhesion molecule
[EpCAM]+, and cytokeratins) in whole blood, which can be a biomarker for a therapeutic response to
antineoplastic regimens. Increased levels of CTCs in the blood of CRPC patients can predict worse
outcomes. Evaluation of individual CTCs has allowed further prognostication of PCa.[39] CTCs may
be useful for predicting treatment response and survival outcomes associated with cytotoxic and
hormonal therapies, but approximately 50% of patients have undetectable CTC levels based on
current detection methods.[40] CTC detection techniques with improved sensitivity are under
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investigation.
Implications for Clinical Practice Treatment Guidelines
Despite extensive research efforts, few PCa biomarkers have been successfully validated and
integrated into clinical practice (Figure 7). The serum-based PSA test therefore remains an important
biomarker for PCa detection and follow-up. One of the important lessons learned from the
popularization of PSA as a screening test is that biomarker development requires a priori deliberation
of the intended role of a particular biomarker. The recent decision by the United States Preventive
Services Task Force (USPSTF) to recommend against widespread PSA-based screening for PCa stems
from findings that, even without treatment, PCa-specific mortality remains low. The Task Force
concluded that the prevalence of overtreatment harms more patients than it benefits. The American
Urological Association (AUA) initially opposed the recommendation but has since modified its
position to partially align with that of the Task Force.
The potential complications associated with overtreatment have supported the introduction of active
surveillance as a management option. Multiple guidelines now endorse active surveillance for
low-risk PCa, although concerns regarding biopsy undersampling and under-staging have limited its acceptance. The development and validation of
biopsy-based genomic assays have been published and presented, demonstrating a more accurate
risk assessment at the time of diagnosis.
One reason for the current screening challenges in PCa is the lack of a genomic marker that helps to
determine the risk of disease progression at the time of initial diagnosis. Most urologists have
experience in treating men with apparent low-risk PCa who, upon RP, are found to have higher-grade
cancers, which are a surrogate for a higher risk of progression and death.
Prostate Cancer Awareness and Education
The 1980s and 1990s marked the founding of several national education and advocacy groups
focused on PCa screening and treatment. These include Patient Advocates for Advanced Cancer
Treatment, the Prostate Cancer Education Council, Man to Man, Us TOO! International, and other
groups.
A number of these are notable for their efforts to promote PCa screening: The nonprofit Prostate
Conditions Education Council (PCEC; www.prostateconditions.org), founded in 1989, is the leading
resource for information on prostate health in the United States. A consortium of physicians and
scientists, health educators, and prostate cancer advocates, the Council is the founder and
coordinator of the national Prostate Cancer Awareness Week Program, and with its Screening Site
Partners has screened about 5 million men for PCa across the US.
In the summer of 2000, Arlene Mulder, former Mayor of Arlington Heights, Illinois, founded the
Mayors’ Coalition for Prostate Cancer Awareness and Education, to further promote PCa awareness
and encourage screening. The same year, the United States Conference of Mayors designated
September as Prostate Cancer Awareness Month, the first major national organization to do so. To
date, 154 mayors have joined the coalition. In 2002, President George W. Bush officially designated
September as National Prostate Cancer Awareness Month.
Cost vs Value
A substantial clinical and economic burden is associated with the diagnosis and treatment of PCa in
the US and worldwide. All men diagnosed with PCa and their physicians face the challenge of
deciding whether to choose definitive therapy—which has a high cure rate but potentially significant
complications—or monitor the disease through active surveillance or watchful waiting. Among the
physician, payor, and healthcare system stakeholders in the US and globally there is widespread
concern that the rate of treatment for PCa is too high, especially since PCa in many men is often
indolent, with little malignant potential. However, there is no question that aggressive therapy is
indicated in a large subset of men with aggressive PCa. In our opinion, there is benefit to focusing
our treatment on men with high-risk PCa.
Appropriate incorporation of biomarkers into clinical practice can have a positive economic impact.
For example, a budget impact study of ConfirmMDx identified men who might avoid unnecessary
repeat prostate biopsies, thereby reducing overall healthcare spending.[25] By using the appropriate
biomarkers, we can reduce unnecessary biopsies and help men to make more effective clinical
decisions about their individual plan of care, which should translate into economic savings.
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Conclusion
PCa biomarkers hold tremendous promise for assisting clinicians in improving risk assessment,
reducing overtreatment, and providing more selective therapy for patients with high-risk disease. In
the last 2 years, a number of new, exciting biomarkers have emerged that offer the opportunity to
assist clinicians in determining when to biopsy, whom to re-biopsy, and how to assist patients in their
treatment decisions. If third-party payors are to support reimbursement, there will be a need to
demonstrate an actionable outcome that occurs and affects patient care.
Financial Disclosure: Dr. Crawford serves on the advisory boards of Dendreon, Ferring, Genomic
Health, Janssen, MDxHealth, and Myriad. He is also a speaker for Genomic Health, MDxHealth, and
Myriad. Dr. Shore is a consultant to Genomic Health, MDxHealth, and Myriad. Dr. Ventii has no
significant financial interest in or other relationship with the manufacturer of any product or provider
of any service mentioned in this article.
Figure 1: Biomarkers That Are Relevant to
Screening for Prostate Cancer
Figure 2: The Prostate Health Index (phi) Score
Correlates With the Pe...
Figure 3: Percentage of Men With Positive Biopsy
by Prostate Cancer An...
Figure 5: Assessing Individual Tumor Biology
Using the Genomic Prostat...
Figure 4: The Methylation Analysis to Locate
Occult Cancer (MATLOC) Va...
Figure 6: Risk Stratification of Prostate Cancer
Patients Using Deciph...
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Figure 7: The Prostate Cancer Diagnostic
Pathway, With a Focus on the ...
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Source URL: http://www.cancernetwork.com/oncology-journal/new-biomarkers-prostate-cancer
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/genitourinary-cancers
[4] http://www.cancernetwork.com/prostate-cancer
[5] http://www.cancernetwork.com/authors/e-david-crawford-md
[6] http://www.cancernetwork.com/authors/karen-ventii-phd
[7] http://www.cancernetwork.com/authors/neal-d-shore-md-facs
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