Discoveries and application of prostate-specific antigen, and some proposals to optimize prostate cancer screening

Abstract

The discoveries and application of prostate-specific antigen (PSA) have been much appreciated because PSA-based screening has saved millions of lives of prostate cancer (PCa) patients. Historically speaking, Flocks et al first identified antigenic properties in prostate tissue in 1960. Then, Barnes et al detected immunologic characteristics in prostatic fluid in 1963. Hara et al characterized Y-semino-protein in semen in 1966, and it has been proven to be identical to PSA. Subsequently, Ablin et al independently reported the presence of precipitation antigens in the prostate in 1970. Wang et al purified the PSA in 1979, and Kuriyama et al first applied an enzyme-linked immunosorbent assay for PSA in 1980. However, the positive predictive value with a cutoff figure of 4.0 ng/mL appeared substantially low (∼30%). There are overdiagnoses and overtreatments for latent/low-risk PCa. Controversies exist in the PCa mortality-reducing effects of PSA screening between the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. For optimizing PCa screening, PSA-related items may require the following: 1) adjustment of the cutoff values according to age, as well as setting limits to age and screening intervals; 2) improving test performance using doubling time, density, and ratio of free: total PSA; and 3) fostering active surveillance for low-risk PCa with monitoring by PSA value. Other items needing consideration may include the following: 1) examinations of cell proliferation and cell cycle markers in biopsy specimens; 2) independent quantification of Gleason grading; 3) developing ethnicity-specific staging nomograms based on tumor stage, PSA value, and Gleason score; 4) delineation of the natural history; 5) revisiting the significance of the androgen/testosterone hypothesis; and 6) devoting special attention to individuals with a certain genetic predisposition. Finally, considering the uncertainty that exists in medicine, risk communication on PSA-based screening is indeed due.