The Prostate Health Index (phi) in Prostate Cancer Risk Assessment

Expires August 2026


Alicia Algeciras-Schimnich

Alicia Algeciras-Schimnich, Ph.D., is Chair of the Clinical Biochemistry and Immunology Division within the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. She holds the academic rank of Associate Professor of Laboratory Medicine and Pathology.


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Transcript and References


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 its significance, it’s important that we understand how to best screen for this disease, and in this month’s Hot Topic, my colleague Dr. Alicia Algeciras will provide you with valuable information regarding the 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 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 be a partner in your patients’ health care.

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 for Mayo Clinic in Rochester, Minnesota.


I have received financial compensation from Beckman Coulter for speaking engagements.

Utilization Message

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 this test should be ordered, and how the results from this testing might impact patient management.

Prostate Cancer (PCa) Statistics: 2017

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 U.S. who have been diagnosed with prostate cancer at some point of their lives are still alive.

Advances in Prostate Cancer Diagnosis

The advances in prostate cancer diagnosis could be, in part, attributed to the discovery of the prostate specific antigen (PSA) in the 1970s. In the 1980s, PSA was FDA-approved for the monitoring of patients diagnosed with prostate cancer, and 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.

PSA Limitations

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 of 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 when considering 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 U.S. estimated that the average annual costs to Medicare in 2009 were approximately $500 million. And 72% of the screening costs were related to downstream biopsy procedures with a prostate cancer positive rate on the biopsy ranging from 22-40%.

PSA Isoforms in Serum

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.

PSA Isoforms in Prostate Cancer

For many years, laboratories have offered the free PSA test to help refine a man’s risk for prostate cancer. Men with prostate cancer have a lower %-free PSA (%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 has 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. Moreover, 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 Specificity for Men with PSA 4–10 mg/mL

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 digital rectal exam (DRE). From these 658 men, 49% of patients 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 cutoff, 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.

Prostate Health Index (phi)

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 who 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. More than 1,000 cases of prostate cancer were 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 a higher Gleason score (greater than or equal to 7) was 90%, while the specificity was 17% with a diagnostic odds 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 on 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's 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.

 phi vs. PCA3

A limited number of studies are available comparing phi to PCA3 and/or 4K™score. In the case of the "phi to PCA3" comparison, two published studies have demonstrated similar performance between the assays. The first study included 110 prostate cancer cases, and it 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 for the PSA diagnostic "gray zone."

The second study focused 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 who haven’t had a prostate biopsy, PCA3 is indicated for men who have had one or more negative prostate biopsies and a repeat biopsy is being considered.

phi vs. 4Kscore

Comparison between the 4Kscore and phi was performed in a cohort of 531 men of which 271 were diagnosed with prostate cancer. Men had a total PSA between 3–15 ng/mL and were undergoing a prostate biopsy for the first time. Similar ROC area under the curve was found for phi and 4Kscore regardless of whether all cases or only high-grade cancers were considered. Both assays showed superior performance than total PSA.

Using a cutoff of 10% for the 4Kscore 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 that both tests performed similarly and could both aid in decision-making as to whether to proceed with a prostate biopsy.

NCCN Guidelines for Prostate Cancer Early Detection

This is in 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 the 4Kscore 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.

Ordering phi

When you order phi through Mayo Medical Laboratories, testing starts with measurement of the total PSA. In order to promote proper ordering and utilization of phi, the other two tests required 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 the 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.

phi Report when Total PSA Is between 4–10 ng/mL

This is a sample report for phi. When the 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 National Comprehensive Cancer Network 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, phi could avoid approximately 30% of unnecessary biopsies. phi is indicated in men with a total PSA 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.


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Alicia Algeciras-Schimnich

Alicia Algeciras-Schimnich, Ph.D., is Chair of the Clinical Biochemistry and Immunology Division within the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. She holds the academic rank of Associate Professor of Laboratory Medicine and Pathology.