1. Nalley, Catlin

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Prostate cancer continues to be a leading cause of cancer mortality in men. An estimated 161,360 new cases of prostate cancer will be diagnosed in 2017 and approximately 26,730 men will die from the disease this year, according to the American Cancer Society.

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Since the U.S. Preventive Services Task Force (USPSTF) issued a grade D recommendation against the use of PSA-based screening for prostate cancer in men of all ages based on data showing that PSA-based screening contributes to overtreatment and over diagnosis of prostate cancer (Ann Intern Med 2012;157:120-134), there has been an ongoing debate regarding the screening guidelines for the disease.


A recent study suggests a potential correlation between an increase in metastatic prostate cancer among older men and the change in prostate cancer screening guidelines recommending against routine PSA testing (JAMA Oncol 2016; doi:10.1001/jamaoncol.2016.5465). However, earlier research has suggested there is no significant difference in prostate cancer mortality between PSA testing and digital rectal examination compared to the current standard of care (J Natl Cancer Inst 2012;104:125).


While the discussion surrounding PSA testing continues, another screening option has become available, the Prostate Health Index (phi). Derived from the PSA test, recent research has confirmed its potential not only for assessing prostate cancer risk, but also helping patients avoid unnecessary biopsies and over treatment.


Understanding phi Testing

Approved by the FDA in 2012, phi is a multi-analyte prostate cancer blood test that calculates a score based on the combination of three separate tests: PSA, free PSA, and p2PSA. This phi score informs clinicians on the meaning of elevated PSA levels as well as the probability of finding prostate cancer on a biopsy.


"p2PSA is the primary form of proPSA in prostate cancer tissue and comprises a greater percentage of free PSA in the serum of prostate cancer patients," noted E. David Crawford, MD, Professor of Surgery/Urology/Radiation Oncology, and Head of Urologic Oncology at the University of Colorado, Denver Anschutz Medical Campus. "The Prostate Health Index is defined as p2PSA divided by free PSA times the square root of total PSA."


In 2014, the National Comprehensive Cancer Network (NCCN) recommended phi as a blood test to improve specificity for prostate cancer detection in its "Clinical Practice Guidelines in Oncology for Prostate Cancer Early Detection."


According to the most recent NCCN recommendations, phi should be considered for patients with PSA levels >3 ng/mL who have not yet had a biopsy as well as for "men who have had at least one prior negative biopsy and are thought to be at higher risk."


Assessing Risk

The Prostate Health Index helps distinguish between prostate cancer and benign disease and improves the specificity of prostate cancer detection in the PSA range of 2-10 ng/ml, explained Crawford.


According to recent research, the phi score is a better predictor of prostate cancer than the total PSA test alone or the free PSA test alone. Additionally, evidence suggests the Prostate Health Index predicts prostate cancer risk more accurately than the free PSA to total PSA ratio or the free PSA ratio.


The phi values significantly enhance the clinical specificity for prostate cancer detection in men with a normal prostate exam whose PSA was in the 2-10 ng/mL range (J Urol 2011;185(5):1650-1655). In this study, researchers determined that increasing phi levels was associated with a 4.7-fold increased risk of prostate cancer and a 1.16-fold increased risk of Gleason score 7 or greater disease on biopsy. Histopathological grade of this disease, assessed by the Gleason score, ranges from 6 to 10. Gleason score 6 is considered low-grade, and 7 and above are considered high-grade and aggressive.


Biopsy Reductions

In the wake of the 2012 USPSTF guidelines, which centered on eliminating the over diagnosis and over treatment of prostate cancer, the phi test has shown to help mitigate unnecessary biopsies.


Research supports the potential correlation between phi testing and an improved specificity for detecting clinical significant prostate cancer as well as a reduction in over diagnosis. "Clinically significant prostate cancer may include tumors with a Gleason score greater than or equal to 7 or with a volume greater than or equal to 0.5 cc," explained Crawford. One such study by Stacy Loeb, MD, of New York University, and colleagues, reported that phi outperformed its individual components in detecting clinically significant prostate cancer (J Urol 2015;193:1163-1169).


According to the researchers, utilizing a 90 percent sensitivity cutoff for significant versus insignificant prostate cancer (a phi threshold of 28.6) could potentially avoid 30 percent of biopsies with indolent or no prostate cancer compared with 21.7 percent using free PSA alone. "The Prostate Health Index is a simple blood test that we recommend for use as part of a multivariable approach to reduce unnecessary biopsies and over diagnosis," the authors concluded.


"The phi is associated with more aggressive disease, which helps reduce unnecessary biopsies and overtreatment for initial and repeated biopsy patients," emphasized Crawford.


Active Surveillance

The Prostate Health Index is a test that can be utilized among prostate cancer patients undergoing active surveillance. These patients have biopsy proven low-grade prostate cancer and are monitored by routine PSA testing and prostate biopsies. "Urologists can use phi to risk stratify patients for biopsy decisions," Crawford noted. "It also serves a helpful tool to improve candidate selection for active surveillance and predict the risk of biopsy reclassification during active surveillance.


"Many researches have shown that phi has the potential to improve prediction of the presence and aggressiveness of prostate cancer. For example, phi helps initial and repeat biopsy decisions during the course of active surveillance," he continued. "Increasing phi scores predict a higher risk of more aggressive cancer characteristic and recurrence after radical prostatectomy surgery."


Research has confirmed that pre-operative phi levels could predict early biochemical recurrence (BCR) in prostate cancer patients (Urol Oncol 2015;33(8):337.e7-14). Investigators examined the value among 313 patients with localized prostate cancer who had the phi test prior to operation and then underwent radical prostatectomy. Investigators determined that 82 was the phi cutoff value to differentiate between patients with and without BCR. According to study results, the 2-year biochemical-free survival rate was 98 percent in patients with a pre-operative phi level of less than 82 compared to 70 percent for patients with a phi level of 82 or above.


"According to our findings, phi level emerged as an independent predictor of BCR and was significantly more accurate than the currently used predictors of BCR, such as tPSA level, clinical/pathological category, and Gleason score, in both the pre-operative and the post-operative settings," the authors concluded.


Crawford noted the Prostate Health Index's significant correlation with BCR makes it a potential prognostic predictor after radical prostatectomy.


Practice Implications

With a growing body of evidence that suggests enhanced detection accuracy, a reduction in unnecessary biopsies, and improved prediction of aggressive disease, the phi test has significant implications for prostate cancer practices.


Does this mean the Prostate Health Index should be considered the standard of care? "Numerous studies have shown that phi is more specific for aggressive prostate cancer than existing reference methods of total PSA and %fPSA," Crawford noted. "However, there are a number of other tests that need to be compared to this test. Perhaps, utilization of multiple tests will aid in decision making-precision medicine."


Looking to the future, Crawford noted, "We expect to see more clinical evidence of phi in the active surveillance cohort and how it can guide urologists to monitor these patients in the long term." He concluded, "By incorporating phi into the clinical algorithm, physicians will be able to have more confidence in biopsy decisions and treatment prognosis."


Catlin Nalley is associate editor.


More on Prostate Research in This Issue

Read more about new research on prostate cancer released at the 2016 European Multidisciplinary Meeting on Urological Cancers. Turn to page 37 and 38 to learn about genomic testing after prostatectomy, and multimodality treatment in high-risk node-positive prostate cancer.