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By Kalli Spencer

For some time researchers have been searching for alternative prostate cancer blood tests. Prostate-specific antigen (PSA) is still the best test that is available. Even though it only detects changes in the prostate it is also affected by factors other than prostate cancer (PCa) such as infections and an enlarged prostate (benign prostate hyperplasia). This results in several unnecessary prostate biopsies in those with rising PSAs. A PSA isoform (Protein similar to PSA) called [−2]proPSA (p2PSA) has been shown to be more specific than PSA for PCa diagnosis. Prostate Health Index (phi) was derived from a formula incorporating p2PSA, total PSA (tPSA) and free PSA (fPSA). It was approved by the United States Food and Drug Administration (FDA) in 2012 for men aged 50 or above with PSA values of 4-10 ng/ml and a normal digital rectal examination (DRE) finding. Prostate health index density includes the prostate volume measured on ultrasound. Phi has been demonstrated to be superior compared to PSA, fPSA, and PSA density in predicting PCa. In patients with a negative systematic prostate biopsy, there is still a 15-30% risk of PCa diagnosed on repeated biopsy. For this reason, continued surveillance with a PSA and DRE is important in patients with initial negative biopsies. Patient selection for a repeat biopsy is also important in order to maximize cancer detection, while avoiding unnecessary biopsy related complications.

A study by Liu et al in 2021 investigated the relationships between initial phi and phi density level and the detection of PCa and high grade PCa (HGPCa) over time with a long follow-up period in patients with initial negative prostate biopsies1. They found that patients with an initially negative prostate biopsy, a higher baseline phi level predicted an increase in PSA as well as PCa and a HGPCa diagnosis over a median follow-up period of more than 6 years. It was also observed that a higher baseline phi was associated with a higher risk of PI-RADS 4 or 5 lesions detected on subsequent MRI of the prostate. PIRADS is a classification system to grade the severity of prostate cancer on MRI (PIRADS 4 and 5 indicates high grade cancer). In men with phi

This is the first study of its kind to investigate the role of baseline phi and phi density in predicting future PCa risk. Self reported limitations of the study include its retrospective nature. Not all men received a pre biopsy MRI so all biopsies at baseline were systematic TRUS biopsies which can lead to underdiagnosis of cancers in a proportion of men at initial biopsy. Not every man had a follow-up biopsy or MRI prostate, and undiagnosed cancers might exist in the cohort. The authors observed that men without a re-biopsy were mainly men in the lower baseline phi groups with static PSA over almost 6.5 years, and the risk of significant cancer in this cohort (with previous negative biopsy and a static PSA over a long time period) would be exceedingly low.

PHI is already a part of the European Association of Urology cancer guidelines and PHI density may have broader clinical utility in the near future. In summary men with a prior negative prostate biopsy, a higher phi (≥35) or phi density (≥1.2) will need closer follow-up and repeated investigation, while men with lower phi (

References

^{1. Liu AQ, Remmers S, Lau S et al. Initial Prostate Health Index (phi) and phi density predicts future risk of clinically significant prostate cancer in men with initial negative prostate biopsy: a 6-year follow-up study. Nature: Prostate Cancer and Prostatic Diseases 2021.}

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