Beyond PSA: the next generation of prostate cancer biomarkers

Abstract

Since the introduction of serum prostate-specific antigen (PSA) screening 25 years ago, prostate cancer diagnosis and management have been guided by this biomarker. Yet, PSA has proven controversial as a screening assay owing to several inherent limitations. The next wave of prostate cancer biomarkers has emerged, introducing new assays in serum and urine that may supplement or, in time, replace PSA because of their higher cancer specificity. This expanding universe of biomarkers has been facilitated, in large part, by new genomic technologies that have enabled an unbiased look at cancer biology. Such efforts have produced several notable success stories that involve rapidly moving biomarkers from the bench to the clinic. However, biomarker research has centered on disease diagnostics, rather than prognosis and prediction, which would address disease management. The development of biomarkers to stratify risk of prostate cancer aggressiveness at the time of screening remains the greatest unmet clinical need in prostate cancer. We review the current state of prostate cancer biomarker research, including the PSA revolution, its impact on early cancer detection, the recent advances in biomarker discovery, and the future efforts that promise to improve clinical management of this disease.

Figure 1. PSA clinical course and biomarker uses

In this model, PSA levels or increases suggest the presence of prostate cancer and can inform management decisions. Several types of PSA measurement can be employed, including total PSA, complexed and free PSA (cPSA and fPSA), PSA doubling time (PSADT) and velocity (PSAV), and PSA density. This cartoon plot illustrates the clinical course of some patients with recurrent prostate cancer, in which disease recurs following curative therapy. Hormonal therapy in this example leads to castrate-resistant prostate cancer (CRPC), in which the cancer becomes refractory to conventional hormonal therapies. The bottom segment of the plot indicates the type of biomarkers applicable for measurement for disease management.

Figure 2. Advances in prostate cancer biomarker uses

(A) The emerging clinical paradigm for prostate cancer biomarkers, including the combined application of imaging biomarkers and biomarkers found in serum, urine, and tissue. (B) Recent advances in molecular biology have enabled the robust detection of transcriptomic, proteomic, and genomic biomarkers in patient urine. PCA3 and TMPRSS2-ERG screening lend increased specificity for detecting cancer, resulting in fewer false positive test results. (C) Promising avenues of biomarker research are the isolation of circulating tumor cells (CTCs) and exosomes from patient serum. Molecular analysis of CTCs and exosomes for common genetic aberrations may further provide predictive information for prostate cancer.

Figure 3. Future challenges for prostate cancer biomarker research

Current clinical practice relies on PSA to help diagnose prostate cancer. New prostate cancer biomarkers should be targeted to addressing unmet clinical needs in prostate cancer management, including indicators for disease with low PSA values (<10ng/mL), prognostic markers to distinguish indolent from aggressive disease, and biomarkers for metastatic cancer.