chapter 98 Prostate Cancer Tumor Markers

The discovery and use of tumor markers have positively affected early detection, diagnosis, and staging for many malignancies. By improving early detection, tumor markers contribute to improved curative success rates. Optimal treatment and cure depend not only on accurate and early diagnosis but also on reliable follow-up for efficient detection of clinical recurrence. The identification of new markers and the development of sensitive tools to measure them will contribute to improved cure rates. Among urologic malignancies, prostate cancer has greatly benefited from the discovery and application of tumor markers. Since its discovery in 1979 until clinical application in the late 1980s through 1990s, the prostate-specific antigen (PSA) has evolved into an invaluable tool for detecting, staging, and monitoring prostate cancer in men (Sensabaugh, 1978; Wang et al, 1979, 1981; Papsidero et al, 1980; Kuriyama et al, 1981). The widespread use of PSA screening has generated greater awareness about prostate cancer. During the PSA era, cancers identified when confined to the prostate have improved cure rates using either radical prostatectomy or radiation therapy. Whereas the majority of prostate cancers in the 1980s and early 1990s commonly arose through finding an abnormal digital rectal examination (DRE) or elevated PSA, or both, today most prostate cancer arises as clinically nonpalpable (stage T1c) disease with PSA levels between 2.5 and 10 ng/mL. The evolving demographics and natural history of prostate cancer have resulted in a stage migration to nonpalpable, clinically localized (stage T1c) disease and a parallel reduction in mortality (Pound et al, 1997, 1999; Stephenson et al, 1997; Polascik et al, 1999). However, these PSA-detected T1c cancers are not homogeneous. Although PSA screening has improved survival, outcomes are not the same for all T1c-detected disease because some of these cancers may not pose a threat to survival (Gretzer et al, 2002). Methods for improved detection of clinically significant prostate cancer are needed. Despite routine application of PSA assays, limitations of specificity for this marker remain. Although PSA is widely accepted as a prostate cancer tumor marker, it is organ specific and not disease specific. Unfortunately, there is an overlap in the serum PSA levels among men with cancer and those with benign disease. Thus elevated serum PSA levels may reflect alterations within the prostate secondary to tissue architectural changes such as cancer, inflammation, or benign prostatic hyperplasia (BPH). Currently, serum PSA levels as low as 2.6 ng/mL are used as a threshold to perform transrectal ultrasound-guided biopsy. Although up to 30% of men presenting with an elevated PSA may be diagnosed following this invasive procedure, as many as 75% to 80% are not found to have cancer. In some instances the biopsy needle may fail to sample representative areas, thus failing to detect present cancer. To this end, application of PSA derivatives such as PSA density, PSA velocity, age-adjusted values, and, more recently, molecular derivatives have attempted to improve the performance of PSA (Christensson et al, 1990; Benson et al, 1992a, 1992b; Carter et al, 1992a, 1992b; Oesterling et al, 1993a, 1993b, 1993c; Riehmann et al, 1993; Seaman et al, 1993; Bazinet et al, 1994; Rommel et al, 1994; McCormack et al, 1995; Morgan et al, 1996; Lilja, 1997). We are in a midst of a PSA biomarker crisis because the specificities of PSA and its derivatives require supplementation to improve specificity and to differentiate cancer from benign diseases of the prostate. Research into the biochemistry of PSA is yielding advances that have the potential to contribute to the detection and management of prostate cancer. New understanding of the molecular biology of carcinogenesis and prostate cancer is beginning to yield a new era in prostate cancer tumor research. Exploiting the knowledge of molecular oncology and application of novel techniques has provided innovative tools for the discovery of new biomarkers. Application of these promising diagnostic tests may be instrumental not only for detection but also to aid in discrimination between aggressive and indolent cancers. This chapter reviews our currently used markers in tissue, blood and urine, as well as the cellular-based components, and describes some promising markers that may evolve from the improved knowledge and methods used to evaluate genomic alterations, epigenetic modifications, and protein expression.