Prostate-Specific Membrane Antigen Levels in Sera as a Possible Biomarker for Prostate Cancer

Abstract & Commentary

Synopsis: Prostate-specific membrane antigen (PSMA) was evaluated as a potential biomarker for the diagnosis and monitoring of patients with prostate cancer. While serum measurements of PSMA could be reliably made by Western blot analysis, this measurement was not shown to be a specific biomarker for prostate cancer.

Source: Beckett ML, et al. Clin Cancer Res 1999;5: 4034-4040.

Prostate cancer remains an extremely common disease. Projections for the year 2000 are that 180,400 new cases of prostate cancer will be diagnosed in American men. In addition, 31,900 American men are anticipated to die due to prostate cancer in the year 2000. These figures will make prostate cancer the leading cause of new cancers and the second leading cause of cancer deaths in American men for the year 2000 (the figures exclude basal and squamous cell skin cancers and in situ carcinomas).1 Thus, prostate cancer is a major health concern for American men.

Measurements of prostate-specific antigen (PSA) have been used for the diagnosis and monitoring of patients with prostate cancer.2-4 Current American Cancer Society recommendations include offering the PSA blood test and digital rectal exam (DRE) on an annual basis, beginning at age 50, to men who have at least a 10-year life expectancy and to younger men at high risk.5 However, no prospective, randomized study of PSA screening has been completed which uses prostate cancer-specific mortality as its endpoint. Thus, controversy remains regarding use of PSA as a routine screening test. Since PSA is prostate-specific but not cancer-specific, several non-malignant conditions of the prostate can cause an elevation of PSA values. These conditions include benign prostatic hypertrophy (BPH), as well as prostatitis, and physical exam manipulation of the prostate gland. Thus, it would be desirable to have a biomarker which could differentiate abnormalities of serum PSA due to benign conditions vs. elevations of serum PSA due to prostate cancer.

Several refinements have been proposed to improve the positive predictive value of elevated PSA for the identification of prostate cancer. These strategies include the use of age-specific reference ranges for serum PSA, as well as the use of a PSA density value. The PSA density refers to a quotient of serum PSA and prostate volume.6 Another strategy is to use serial measurements of PSA to identify a yearly rate of change in PSA values. This value, termed "PSA velocity," can also increase the positive predictive value of PSA measurements for prostate cancer.4,7 In addition, measurements of PSA can be obtained to identify free PSA vs. complexed PSA vs. total PSA. The percentage of free PSA is lower in serum samples from patients with prostate cancer than in serum samples from patients with non-malignant prostate conditions.8 Thus, measurements of free/total PSA values have been proposed as a useful measurement in patients with borderline elevations of PSA.

Prostate-specific membrane antigen (PSMA) is a transmembrane lipoprotein in prostate epithelial cells which has been proposed as a possible biomarker for patients with prostate cancer. Beckett et al used electrophoresis and Western blotting to measure PSMA levels in the sera of 236 normal individuals and cancer patients. Beckett and colleagues confirmed reproducible measurements of serum PSMA by Western blot analysis. Levels of PSMA were shown to be significantly elevated in men older than 50 years of age when compared with samples from younger men. However, measurement of serum PSMA was unable to distinguish early-stage prostate cancer from BPH, and measurement of PSMA was not more effective than PSA in monitoring prostate cancer patients. Beckett et al conclude that PSMA is not a specific biomarker for prostate cancer.

COMMENT By Mark R. Albertini, MD

The study reported by Beckett et al demonstrates a technique for measurement of serum PSMA in the sera of normal individuals and cancer patients. Values for PSMA were shown to increase with age, as serum values for men older than 50 years of age were greater than serum values of men younger than 50 years of age. Conditions such as benign prostatic hypertrophy and prostatitis did not increase values above age-adjusted comparison values. Values for patients with early stage (T1 and T2) prostate cancer were lower than those with a similar age control group, while patients with late-stage (T3) prostate cancer had a trend to an increased value over a similar age control group. However, values for patients with stages T2 and T3 disease were higher posttreatment (mean PSMA integrated intensity units: 6.06) than were values for a similar group of patients with T2 and T3 disease pretreatment (mean PSMA value of 3.09). The PSMA values for individual prostate cancer patients receiving treatment added no additional information above that available by measurement of PSA.

Sera from normal women and from breast cancer patients were also evaluated and shown to have detectable levels of PSMA. The source of PSMA in non-prostate tissues, including samples from women, remains unclear. Thus, the current assay for PSMA does not provide a specific biomarker for patients with prostate cancer. While further refinements of this assay may prove useful, additional evaluation with a larger number of patients in each diagnostic category will be required to evaluate its role for prostate cancer patients.

References

1. Greenlee R, et al. CA Cancer J Clin 2000;50(1):7-33.

2. Woolf SH. N Engl J Med 1995;333:1401-1405.

3. Oesterling J, et al. Cancers of the Genitourinary System, Cancer of the Prostate-Prostate Specific Antigen, in Cancer. In: DeVitaVJ, Hellman S, and Rosenberg S, eds. Principles and Practice of Oncology. Philadelphia, PA: Lippincott-Raven; 1997:1322-1386.

4. Scher H, et al. Prostate Cancer-Diagnosis and Screening. In: Abeloff M, et al, eds. Clinical Oncology. 2nd ed. New York, NY: Churchill Livingstone Publishing; 2000:1823-1884.

5. Smith R, et al. CA Cancer J Clin 2000;50(1):34-49.

6. Benson M, et al. J Urol 1992;147:815-816.

7. Gann P, et al. JAMA 1995;273:289-294.

8. Catalona W, et al. JAMA 1998;279:1542-1547.

Which one of the following statements about PSMA is true?

a. PSMA has been shown to be a specific biomarker for prostate cancer.

b. PSMA can be detected in serum samples from a healthy female population.

c. PSMA values are higher in serum samples from men younger than 50 years of age compared with serum samples from men older than 50 years of age.

d. Conditions such as benign prostatic hypertrophy and prostatitis have been shown to increase PSMA values above age-adjusted comparison values.