Hi, I’m Matt Binnicker, the Director of Clinical Virology and Vice Chair of Practice
in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Did you know that
aside from non-melanoma skin cancer, prostate cancer is the most common type of cancer among
men in the United States? Well, because of the significance of the disease, we need to have a good
understanding for how to screen for this disease, and in this month’s Hot Topic, my colleague,
Dr. Alicia Algeciras, will provide you with valuable information regarding the clinical utility
of the prostate-specific antigen test, and how the calculation of a prostate health index,
or phi, can help to stratify a patient’s risk for developing prostate cancer and reduce unnecessary
biopsies. I hope you enjoy this month’s Hot Topic, and I want to personally thank
you for allowing Mayo Clinic the opportunity to partner in your patients’ healthcare.
Thank you Dr. Binnicker for the introduction. My name is Alicia Algeciras-Schimnich. I am
an Associate Professor of Laboratory Medicine and Pathology and serve as Chair of the Clinical
Biochemistry and Immunology division at Mayo Clinic in Rochester, Minnesota.
I have received financial compensation from Beckman Coulter for speaking engagements.
Utilization management has become increasingly relevant for most medical institutions. While
viewing this presentation take some time to consider a few points including, how this
testing might be used in your practice, when should the test be ordered, and how the results
from this testing might impact patient management.
Other than skin cancer, prostate cancer is the most common type of cancer found in men in the United
States. In 2017 the American Cancer Society estimates that 161,000 new cases of prostate
cancer will be diagnosed. Prostate cancer is the third leading cause of cancer death
in American men, behind lung cancer and colorectal cancer, with an estimate of 26,000 deaths
in 2017. Although prostate cancer could be a serious disease, most men diagnosed with
prostate cancer will not die from the disease. Currently, more than 2.9 million men in the
US who have been diagnosed with prostate cancer at some point of their life are still alive.
The advances in prostate cancer diagnosis could be in part
attributed to the discovery of prostate specific antigen (PSA) in the 1970s. In the
1980s PSA was FDA approved for monitoring of patients diagnosed with prostate cancer,
later it was approved for the detection of prostate cancer and introduced as the screening
tool for prostate cancer. This led to a dramatic increase in the incidence rates for prostate
cancer driven by the widespread use of PSA. Overall, the early detection of prostate cancer
has led to a decrease in prostate cancer mortality. Today the mortality rate for prostate cancer
is approximately 45% lower than in 1992.
Today, the use of PSA for prostate cancer screening is highly controversial due to the
limitations of PSA. Particularly, PSA has a modest sensitivity and low specificity for
prostate cancer. For example, the specificity of PSA has been reported to be as low as 6%
at a sensitivity of 95%. An elevated PSA may not be indicative of clinically significant
cancer. The most common cause slight elevation of PSA is benign prostatic hyperplasia (or
BPH). The incidence of BPH increases with age. It is estimated that approximately 25%
of 40 year old men and 80% of 80 year old men have BPH.
The distinction between malignant and benign disease is particularly challenging in the
total PSA range of 2-10 ng/mL where there is significant overlap between men with benign
and malignant conditions. The low specificity of PSA has led to over-diagnosis of indolent
disease and over-treatment resulting in a high cost to manage patients with an elevated
PSA. A study that evaluated the cost of PSA screening in the US, estimated that the average
annual costs to Medicare in 2009 were approximately $500 million. 72% of the screening costs were
related to downstream biopsy-procedures with prostate cancer positive rate on the biopsy
ranging from 22-40%.
Research efforts has been directed at how can we make PSA a better cancer detection
tool? PSA can be found in circulation as various
isoforms. Total PSA immunoassays detect the PSA bound to Alpha 1-Antichymotrypsin as well
as the free form of PSA. Within the free PSA (fPSA) fractions there are multiple isoforms
including the precursor of PSA. The -7 proPSA represents the native precursor of PSA whereas
the -4 and -2 proPSA represent truncated forms of the -7 proPSA.
In prostate cancer, elevated concentrations of -2 proPSA have been described.
For many years laboratories have offer the free PSA test to help refine a man’s risk
for prostate cancer. Men with prostate cancer have a lower %fPSA when compared to men with
benign conditions. For example, when the %fPSA is less than 10% the probability of cancer
is around 56%; whereas %fPSA values greater than 25% represent a probability of cancer
of about 8%. %fPSA has been used to improve the sensitivity and specificity in men with
a PSA between 4-10 ng/mL. As I previously mentioned, the free PSA isoform
that have been shown to be elevated in prostate cancer is p2PSA. p2PSA has been shown to have
higher specificity than total PSA and free PSA for prostate cancer detection. More over
the higher the level of p2PSA the higher the probability of finding high grade prostate
cancer as defined by a Gleason score equal or greater to 7.
Clinically, p2PSA has been incorporated into the prostate health index (phi). This is a
mathematical formula that combines the results of total PSA, free PSA, and p2PSA to generate
a score that represents the probability of detecting prostate cancer at the time of the
biopsy. The higher the score the greater the probability of finding clinically significant
disease. A phi range between 0 and 26.9 corresponds to a probability of cancer of approximately
10% while a phi score greater than 55 corresponds to a 50% probability of finding cancer upon
biopsy.
phi has a higher specificity than total, p2PSA and % free PSA. This table summarizes the
results of a study that included 658 men with a total PSA between 4-10 ng/mL and a normal
DRE (digital rectal exam). 49% of patients included in the study had prostate cancer
on biopsy. This table shows the specificity of each marker for all prostate cancer and
high grade prostate cancer. The cutoff for each marker was selected to provide a 90%
sensitivity, meaning that 10% of cancers will be missed. Using this cut-off, phi showed
a specificity of 30% of men which will indicate that 30% with an elevated PSA in the 4-10
ng/mL range but with benign disease will have been spared from a biopsy. This will be the
case for both, all prostate cancer and men with significant prostate cancer. For comparison,
20% of cases would have been spared using % free PSA.
Overall, phi provides superior diagnostic accuracy and better risk stratification than
total PSA or % free PSA as shown by ROC above the curve analysis. At a 95% sensitivity using
phi for risk stratification will result in an improvement in the number of men with benign
disease that would be spared from a biopsy. phi specificity at 95% sensitivity was 16%
compared to 7 and 8% for total PSA and %fPSA respectively.
A meta-analysis published in 2014 evaluated the ability of %p2PSA and phi to discriminate
between aggressive and non-aggressive prostate cancer. Over 1,000 cases of prostate cancer
where included in the analysis with 431 cases having a Gleason score greater than or equal
to 7. The pooled sensitivity for the detection of prostate cancer with higher Gleason score
(greater than or equal to 7) was 90% while the specificity was 17% and a diagnostic odd
ratio of 3.1. In clinical practice phi could be used to fill the diagnostic gap between
PSA screening and a prostate biopsy. Combined with family and patient history, phi can be
used to tailor an individualized patient management plan. If the clinician determines that based
phi and other risk factors there is a low probability of finding prostate cancer upon
biopsy, a patient might be monitored closely instead of having a biopsy. On the other hand,
if the clinician determines that there is a higher probability of finding cancer, the
patient will likely undergo a prostate biopsy. Other Prostate Cancer Biomarkers During this
presentation, I also want to discuss other commercially available biomarkers that could
fill the same diagnostic gap as phi. The Prostate Cancer Antigen 3 (PCA3) assay is a urine test
for a noncoding prostate specific mRNA that is overexpressed in prostate cancer cells.
The reported result is a score based on the levels of PCA3 mRNA normalized to PSA mRNA
to account for the number of prostate cells present in the urine. It is important that
prior to the urine collection the patient undergoes a rigorous prostate massage to release
a sufficient number of prostate cells into the urine.
The 4K™score is a blood test that measures the serum levels of 4 biochemical markers:
total PSA, free PSA, intact PSA, and human kallikrein 2. The assay incorporates the results
of these tests into a proprietary algorithm that also takes into account the patient age,
whether nodules were detected during the DRE, and whether the patient had a prior negative
biopsy. The score provides the probability of finding high grade cancer upon biopsy and
similar to phi could help in the clinical decision on whether to proceed to a prostate
biopsy.
A limited number of studies are available comparing phi to PCA3 and/or 4K™score. In
the case of phi to PCA3 comparison 2 published studies have demonstrated similar performance
between assays. The first study included 110 prostate cancer cases and showed that PCA3
had a slightly higher diagnostic accuracy and specificity. The men included in the study
had an initial PSA concentration between 0.5-20 ng/mL which is a wider range than what is
considered the PSA diagnostic gray zone. The second study focus on the PSA diagnostic
gray zone and included 108 prostate cancer cases. In this study both assays showed similar
performance with a specificity of 40% at 90% sensitivity.
It is important to note that the FDA-approved indication for these tests is different. While
phi is FDA approved in men that haven’t had a prostate biopsy; PCA3 is indicated for
men who have had 1 or more negative prostate biopsy and a repeat biopsy is being considered.
Comparison between the 4K™score and phi was performed in a cohort of 531 men of which
271 were diagnosed with prostate cancer. Men had a total PSA between 3 and 15 ng/mL and
were undergoing a prostate biopsy for the first time. Similar ROC area under the curve
was found for phi and 4K™score regardless of whether all cases or only high grade cancers
were considered. Both assays showed superior performance than total PSA.
Using a cut-off of 10% for 4K™score, and 39 for phi, as predictors for prostate cancer
will have prevented 29% of biopsies on men with benign disease at a cost of delaying
the diagnosis for 15% of men with prostate cancer and 10% of the men with high-grade
prostate cancers. This study showed was that both tests performed
similarly and could both aid in decision making as to whether proceed with a prostate biopsy.
This is alignment with the National Comprehensive Cancer Network (NCCN) Guidelines for Prostate
Cancer Early Detection. Given that between 30-35% of men with a total PSA between 4-10
ng/mL will be found to have cancer, patients with a PSA on this range will benefit from
additional follow-up. The % free PSA, phi, or 4K™score are not recommended as first
line screening tests. However, in cases where the PSA levels might indicate the need for
a prostate biopsy, the use of these tests could be considered to further refine the
probability of finding prostate cancer at the time of the biopsy.
When you order phi through Mayo Medical Laboratories, testing starts with measurement of total PSA.
In order to promote proper ordering and utilization of phi, the other 2 tests require for the
phi calculation will only be performed when the total PSA is between 2-10 ng/mL. As shown
in this flow chart, if total PSA is less than 2 or greater than 10 ng/mL no further testing
will be performed. If the total PSA is between 2-10 ng/mL then free PSA and p2PSA will be
performed. The %fPSA and phi are calculated only in those cases with a PSA between 4-10
ng/mL which is the concentration range where the %fPSA and phi are most clinically useful.
This is a sample report for phi. When total PSA is between 4-10 ng/mL the total PSA, free
PSA and p2PSA will be measured and reported. Flagging will be performed for only the total
PSA portion of the test. For %fPSA and phi an interpretation table is provided for the
clinician to assess the probability of finding prostate cancer at the time of biopsy based
on the obtained scores.
To summarize, phi, is a blood test for prostate cancer risk assessment. It is currently FDA
approved and recommend by the NCCN Guidelines for Prostate Cancer Early Detection as a tool
to further refine the probability of finding cancer upon biopsy in men with an elevated
PSA. If used in the right population it could avoid approximately 30% of unnecessary biopsies.
phi is indicated in men with a total PSA is between 4-10 ng/mL and prior to performing
a prostate biopsy. Finally multiple studies have demonstrated a superior diagnostic accuracy
for phi when compared to total PSA and % free PSA.