Prostate specific antigen (PSA) is currently the most commonly used serum biomarker for prostate cancer screening; however, many experts agree that screening for PSA alone is not sufficient for early detection. Fortunately, recent advances in prostate cancer research have resulted in the discovery of new biomarkers, providing patients and doctors alike with the possibility of improved diagnoses.
Prostate cancer is the most commonly diagnosed non-cutaneous form of malignancy in Canadian men. In 2016, an estimated 21,600 Canadian men will be diagnosed with prostate cancer and 4000 will succumb to the disease. Prostate cancer has a relatively good prognosis if found at early stages, with survival rates of 100% after treatment, which may include tissue surveillance, prostatectomy and radiotherapy. However, if the disease progresses to later stages (III or IV) and spreads to other organ systems or lymph nodes, the estimated survival after treatment drops significantly, to only 28%. This striking difference in survival is the driving factor behind the current efforts in prostate cancer research, which aim to uncover better markers for early detection.
Based on recent estimates, about 1 in 8 Canadian men is expected to develop prostate cancer during his lifetime and 1 in 27 will die from it.”
Canadian Cancer Society
The difficulty in diagnosing prostate cancer early is its silent development. Prostate cancer is often asymptomatic early in the course of disease, as malignancies commonly develop in the peripheral portions of the gland. Symptoms do not present until these malignancies spread locally towards the urethra or neck of the bladder, or until metastases occur, by which time the disease has often developed to advanced-stage prostate cancer and is much more difficult to treat. At these stages, standard treatment such as radiation or hormonal therapy is much less effective and patients may need to undergo complete androgen ablation therapy by chemical or surgical castration in an attempt to achieve remission. Survival at end stage III or IV prostate cancer is further complicated by castration resistance. Castration resistance develops due to germline mutations in the androgen receptor (AR), which causes the patient to become refractory to any further hormone treatment, rendering chemical castration ineffective. Therefore, early detection of prostate cancer is instrumental in the survival of patients afflicted with this disease.
The most common clinical methods for the early detection of prostate cancer are the transrectal ultrasound (TRUS), digital rectal exam (DRE) and biomarker screening. Of the three methods, the use of biomarkers is favored by clinicians due to its lower cost and greater efficacy than TRUS or DRE. The field of prostate cancer biomarkers is quite extensive and a significant amount of research effort has gone into uncovering new markers. Historically, the first molecule considered as a biomarker for prostate cancer was prostatic acid phosphatase (PAP). PAP is present in a number of organs; however, its highest concentration is in the prostate where it is secreted by prostate epithelial cells. PAP initially showed promise as a potential biomarker when a study in 1938 showed PAP elevation in patients with prostate cancer. However, this promise quickly faded as subsequent studies showed a weak correlation between PAP elevation and prostate cancer.
Currently, the most common biomarker screened for prostate cancer is prostate specific antigen (PSA). PSA is a serine protease that was discovered in the 1970s in prostate tissue. It is primarily produced by the ductal and acinar cells of the prostate and is secreted into the seminal fluid where it functions to liquefy the ejaculate. PSA is produced by both normal prostatic tissue as well as cancerous prostatic tissue; however, what makes it such a lucrative marker is its physiological compartmentalization. Normally PSA is confined within the secretory ducts of the prostate gland or prostatic urethra. During conditions such as inflammation, hyperplasia and neoplasia, which occur as cancer develops, there is disruption of the physiological barriers within the prostate, which leads to increased permeability. The net result is increased leakage of PSA into the serum where it can be readily detected by screens. Therefore, it has the potential to identify prostate cancer early on in its progression, allowing for effective therapy.
Although the introduction of PSA as a biomarker has led to a significant increase in early prostate cancer diagnosis, there is still much controversy over the efficacy and reliability of PSA alone as a screening tool. One limitation of PSA screening is that it is unable to differentiate between patients with high risk and low risk prostate cancer, as these two groups often have similar PSA levels. Another major limitation of PSA is its lack of specificity. PSA is most highly concentrated in the prostatic transition zone of patients with benign prostatic hyperplasia (BPH), a non-cancerous enlargement of the prostate caused by hyperplasia of prostatic epithelial and stromal cells. Therefore, PSA screening has the potential to flag BPH patients for unnecessary invasive biopsies. It has also been suggested that PSA screening has issues of accuracy, with several studies stating that PSA screening misses 18-28% of early prostate cancers. For these reasons, there is a critical need for more research into prostate cancer biomarkers.
An ‘ideal’ blood test for prostate cancer should clearly distinguish men who have cancer from those who do not. Although PSA measurement is a useful test, it is not perfect.”
Dr. Roger Kirby, The Prostate Centre
Recently, this research has gone in novel directions. Listed on the next page are just some of the molecules that have been identified as potential prostate cancer biomarkers in the last few years. Additionally, several studies have utilized genomic screening as a tool for prostate cancer detection, with a major emphasis being put on altered DNA, RNA or epigenetic modifications associated with prostate cancer. The noncoding RNA SChLAP1 has been shown to be an effective biomarker for prostate cancer in both early detection as well as aggressiveness. Similarly, the noncoding RNA PCA3 is reported to be elevated in 90% of prostate cancer cases, and is currently under development as a potential diagnostic tool. Exosomes have also been explored as simple and non-invasive potential biomarkers. Tumour-specific antigens can be found within exosomes isolated from urine, making them an effective source of biomarkers. This technique was developed recently by Anders Øverbye and his colleagues at the Institute of Cancer Research at Oslo University Hospital. They published a study in 2015 that compared antigens in the exosomes of healthy patients and those with prostate cancer and found significant differences between the two. This study highlights urinary exosomes as a novel and exciting new source of biomarkers for prostate cancer detection.
To conclude, while PSA remains the current accepted method of prostate cancer screening, a significant amount of research effort is focused on identifying new and more effective markers. The search for novel markers is not only important to improve the detection and clinical management of prostate cancer, but also to gain better insight into the origins of prostate cancer and develop more effective therapies for this disease.
- American Cancer Society – Prostate Cancer.
- Azevado A, Cunha V, Teixeira AL & Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011; 2(12): 384-396.
- Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics. 2016.
- Cary KC and Cooperberg MR. Biomarkers in Prostate Cancer Surveillance and Screening: Past, Present, and Future. Therapeutic Advances in Urology. 2013; 5(6): 318–329.
- Chang AJ et al. “High-Risk” Prostate Cancer: Classification and Therapy. Nat Rev Clin Oncol. 2014; 11(6): 308–323.
- DeGraff DJ, Adam AA, and Sikes RA. Disease Evidence for IGFBP-2 as a Key Player in Prostate Cancer Progression and Development of Osteosclerotic Lesions. American Journal of Translational Research. 2009; 1(2): 115–130.
- Gregorakis AK, Holmes EH, & Murphy GP. Prostate-Specific Membrane antigen: current and future utility. Semin Urol Oncol. 1998; 16(1): 2-12.
- McGrath S. et al. Prostate Cancer Biomarkers: Are we hitting the mark? Prostate International. 2016; 4(4): 130-135.
- Pentyala S. et al. Prostate cancer markers: An update. Biomed. Rep. 2016; 4(3): 263-268.
- Trewartha D & Carter K. Advances in prostate cancer treatment. Nature Reviews Drug Discovery. 2013; 12: 823-824.