Volume 37 Number 6 | December 2023

Minh Kosfeld, PhD, MLT(ASCP)CM, ASCLS Today Volunteer Contributor

Minh KosfeldProstate cancer (PCa) is the second most diagnosed cancer in males worldwide and is first in the United States. Since 1994, an FDA-approved protocol for PCa screening for men aged 50 and older has used the Prostate-Specific Antigen (PSA) test and a digital rectal exam (DRE). PSA is a protein produced only by the prostate gland, and elevated blood levels can indicate prostate-related issues, including PCa. Unfortunately, this screening protocol has many limitations:

  • Poor specificity: Only 25 percent of people with elevated PSA levels are found on biopsy to have PCa. Others have benign conditions such as prostatitis, benign prostatic hyperplasia (BPH), lower urinary tract infections, age-related factors, or recent prostate biopsy, ejaculation, or vigorous exercise. Unfortunately, there can be significant morbidity associated with prostate biopsy, including pain, infection, bleeding, and urinary obstruction.
  • Overdiagnosis of PCa: Mass screenings increase the detection of low-risk PCa that, if left untreated, may never cause significant harm. Since we are unable to distinguish aggressive from indolent disease, treatment can, in some cases, lead to complications worse than the natural progression of the disease itself including impotence, urinary incontinence, and bowel dysfunction.

In the early 2000s, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial sponsored by the National Cancer Institute (NCI) found no difference in prostate cancer mortality rates among men with and without PSA screening. This impacted the U.S. Preventive Services Task Force (USPSTF) decision in 2008 to recommend against PSA screening in men 75 and older, and in 2012, against any PSA screening. However, recommendations changed when a significant flaw in that study was found, and when, following a period of stability, the incidence of metastatic prostate cancer rose after 2010.

Consequently, the USPSTF updated its recommendation statement for prostate cancer screening again in 2018, changing the rating from a “D” (not recommended) to a “C” (selectively offering PSA-based screening based on professional judgment and patient preferences) for men aged 55 to 69. Per these standards, men at higher risk of prostate cancer (black men, men with germline variants in BRCA2 or BRCA1, and men whose father or brother had prostate cancer), PSA screening should begin at age 40 or 45. No screening was recommended for men 70 years and older.

In hopes of reversing this disturbing rise in metastatic PCa incidence, the clinical laboratory has focused its efforts on improving the traditional PSA test specificity and identifying additional biomarkers, especially for aggressive or more advanced disease. Examples of a few of these methods include:

  • Super sensitive PSA assays that measure blood PSA levels in the picogram (pg/mL) range, which is more sensitive than standard PSA tests (ng/mL). They are useful in early detection of PCa or identifying recurrence after prostatectomy.
  • Free PSA (non-protein bound) is more specific for benign prostate conditions than total PSA. Total blood PSA levels of 4.0 ng/mL and lower are considered normal, and levels above 10 ng/mL are highly suggestive of prostate cancer. Between these ranges (the gray zone), a higher percentage of free PSA is associated with a lower likelihood of detection of prostate cancer on biopsy.
  • Pro-PSA: An inactive precursor of PSA called [-2] proPSA or p2PSA is more closely associated with prostate cancer than with BPH. Pro-PSA is often used in combination with PSA and free PSA to calculate the Prostate Health Index (PHI) for individuals with PSA levels of 4-10 ng/mL and a negative DRI (Digital Rectal Exam). A higher PHI score is associated with a higher likelihood of prostate cancer and is an indication for biopsy.
  • IsoPSA is a blood test for cancer-derived PSA isoforms. High levels of IsoPSA suggest an increased risk for developing high-grade prostate cancer, making it a valuable tool in identifying patients with PSA levels of 4-10 ng/mL who should undergo biopsy.
  • 4Kscore Test uses an algorithm incorporating results of four PSA-related blood tests (total PSA, free PSA, intact PSA, and human kallikrein 2), the patient’s age, DRE test results, and prostate biopsy history to provide a personal risk score that can be used to determine the need for a prostate biopsy.
  • Urinary biomarkers: Prostate cancer antigen 3 (PCA3) mRNA and the TMPRSS2-ERG gene fusion are more strongly associated with PCa than BPH and can be detected in urine after performing prostate massage. Together with serum PSA (MiPS), they can be used to assess the likelihood of the presence of PCa, and thus the need for biopsy. In addition, when used in combination with genes associated with aggressive disease (in SelectMDx with HOXC6, DLX1, and PCA3; and in EPI with SPDEF, PCA3, and ERG), they can assess the likelihood of the presence of high-grade PCa.
  • Tissue-based biomarkers are specific molecular markers that can be identified in prostate tissue samples. They help improve the precision of prostate cancer diagnosis, risk stratification, and treatment selection. Common tests include the Promark test, which measures eight protein biomarkers; the Oncotype DX Prostate Cancer Assay, which assesses expression of 12 carcinogen genes and five reference genes to gauge tumor aggressiveness and risk of recurrence following radical prostatectomy in men with low and intermediate-risk PCa; the Decipher, which determines the activity of 22 genes in PCa cells to predict the risk of metastasis in men with high-risk PCa; and the Prolaris, which evaluates RNA expression of 31 genes involved in cell cycle progression and 15 housekeeping genes to provide a prognosis and guide treatment.

So, efforts are underway to best achieve early detection of aggressive prostate cancer and initiate therapy that will increase life expectancy and improve quality of life in the long run, while limiting unnecessary biopsies and aggressive therapies in those with indolent disease. A short list of current diagnostic tests and genetic biomarkers for PCa are outlined above, but new technologies for its detection continue to be developed, as none yet perform ideally. In the meantime, several of these diagnostic methods can be used to provide patients with sound, personalized clinical advice.

  1. Preston, MA. Screening for prostate cancer. UpToDate, June 2023. https://www.uptodate.com/contents/screening-for-prostate-cancer
  2. Karen B. Disturbing Rise in Prostate Cancer. Association for Diagnostics & Laboratory Medicine, Apr 2023. https://www.aacc.org/cln/articles/2023/april/a-disturbing-rise-in-prostate-cancer
  3. Prostate-Specific Antigen (PSA) Test was originally published by the National Cancer Institute, Reviewed: March 11, 2022. https://www.cancer.gov/types/prostate/psa-fact-sheet
  4. Porzycki P, Ciszkowicz E. Modern biomarkers in prostate cancer diagnosis. Cent European J Urol. 2020;73(3):300-306. doi: 10.5173/ceju.2020.0067R. Epub 2020 Aug 7. PMID: 33133657; PMCID: PMC7587476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587476/#cit0033

Minh Kosfeld is Director/Associate Professor for the Medical Sciences (formerly IMS) Program in the Department of Clinical Health Sciences at Saint Louis University, in St. Louis, Missouri.