Prostate cancer

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Introduction:

The prostate is a gland in the male reproductive system, located between the bladder and the penis. It produces fluid that transports, nourishes and protects sperm. It pushes fluid into the urethra during ejaculation, leading to the release of semen (1). The prostate usually grows as a man gets older. Uncontrolled growth of cells in this gland can lead to prostate cancer (PCa) (2). Most PCa types develop slowly; however, some types can be fast growing. Eventually, the cancer cells may spread to surrounding areas of the body (2).

PCa is the most frequently diagnosed cancer, and the second leading cause of death among men in western countries. It is the third most common cancer worldwide (3).

The 5-year survival rate for men with local or regional PCa is nearly 100%. For men diagnosed with PCa that has spread to other parts of the body, the 5-year survival rate drops to about 33% (4) , highlighting the importance of screening and early detection of the disease.

Causes and Risk Factors:

There are several factors that can increase a person’s risk of developing PCa. Some include (1):

  • Age: Older men are more likely to develop PCa. About 6 in 10 cases of PCa are found in men older than 65.
  • Ethnicity: PCa is more frequent in black-African men in comparison to men of Asian descent or other races.
  • Family history: Men who have links to PCa in their family are at a higher risk of developing the disease, particularly if the disease was found at a young age.

Other risk factors may include geography, smoking, chemical exposure, inflammation of the prostate, sexually transmitted infections, vasectomy, diet and obesity. However, further research is needed to better understand the direct association with these factors and PCa.

Symptoms:

In early stages, PCa does not have many noticeable symptoms. Additionally, the condition may remain dormant in an individual for years, making detection challenging (1).

Some signs of PCa include (1):

  • Problems urinating
  • Increased urination especially at night
  • Blood in urine
  • Erection difficulties
  • Lower back pain
  • Enlarged or inflamed prostate

Screening and Detection:

Given that PCa has a long latency period and can be cured if detected early, efficient screening and characterization methods are critical (5). There are different methods to screen for the disease (1):

  • PSA test: The standard procedure to screen for PCa is to check for increased levels of Prostate Specific Antigen (PSA), a protein found in blood.

There are, however, limitations to the current PSA blood test. Other conditions like an enlarged or inflamed prostate, urinary tract infection, or trauma can also result in elevated PSA levels, making the test less reliable. Additionally, in some prostate cancer types, men do not display higher levels of PSA in the blood, resulting in some cancers being undetected (5):

- 65-70% of men with elevated PSA levels have a negative biopsy result.

- 15% of PCa patients do not have an elevated PSA level.

- PSA is not able to differentiate patients with aggressive PCa from those with indolent disease.

  • DRE: Digital rectal examination (DRE) involves a doctor directly inspecting the shape and size of the prostate by placing a finger through the rectum (1).
  • Biopsy: A biopsy involves inserting a needle into the prostate, typically through the rectum to obtain a tissue sample (1). Both DRE as well as a biopsy are invasive procedures and can cause discomfort to a patient.

Performing a prostate biopsy is mandatory for a final diagnosis (5). However, biopsies can lead to undesirable effects. Use of (unnecessary) repeated biopsies can be associated with significant morbidity, sepsis, bleeding, erectile dysfunction, infection, urinary retention, and hospitization (1,6). Further, two thirds of the biopsies performed are still unnecessary (7). Overtreatment and over diagnosis have broader implications, resulting in an increase in economic healthcare costs for the community. Additionally, it can cause psychological effects to a patient, including depression and anxiety (1,5).

Prostate Cancer and Urine Detection:

Due to limitations of the PSA test as well as invasive testing methods, researchers have been looking to find a more precise, non-invasive detection method for PCa.

As urine is an easily available sample type that can be collected non-invasively, it has the potential to be used for early detection and prediction of PCa. A recent study shows that urine is a promising source of biomarkers for PCa. Biomarkers include PCa cells, DNA, RNA, proteins and other small molecules. After manipulation of the prostate, these can be released into urine (8). PCA3 and TMPRSS2:ERG fusion RNA transcripts are two such specific markers (8,9,10).

To avoid dilution of markers, analyzing first-void or first-catch urine (first 20ml of urine flow), which contains higher concentration of prostate secretions, can be more effective than analyzing a urine midstream sample (3,7,9). One study showed that first-void urine was able to identify patients with PCa with 91% sensitivity and 69% specificity, while midstream urine was uninformative (11). Colli-Pee, a patented, award-winning, CE-labelled & FDA-listed device allows efficient and standardized capture of first-void urine. 

Urine also presents advantages over other bodily fluids, such as serum. Urine is easier to obtain and handle, needs less sample preparation, and contains higher amounts of metabolites. Further, biomarkers in serum are diluted through circulation and may be affected by the liver during metabolism. PCa biomarkers are diluted only in small volumes and immediately released during urination. Therefore, there is minimum proteolytic degradation through urine sampling, offering a stable proteome analysis (11).

Commercially available assays:

MDxHealth’s SelectMDx test measures two mRNA biomarkers in urine (DLX1 and HOXC6). It can help determine the risk of a patient developing prostate cancer (12).

ExosomeDx’s ExoDx Prostate test, is a simple urine test, which does not require prior prostate massage. It can be used as a  guidance in biopsy decision (13).

Diagnolita’s PCa test is suggested for men when the PSA concentration in serum is between 2 ng/ml and 10 ng/ml and PCa. Two PCa-specific RNA biomarkers are tested in patients to predict, in combination with clinical parameters the presence of PCa (14).

Assays in development:

ProCUrE is a non-invasive urinary methylation assay for the early detection of PCa. ProCUrE can support PSA testing to identify patients with clinically significant PCa (15).

EpiCaPture is a urine DNA methylation test for high-risk PCa. The test could help reduce the number of unnecessary biopsies to detect PCa (16).

Movember Foundation:

The Movember Foundation is the only global charity focused exclusively on men’s health. Since its establishment in 2003, the foundation has raised over £400 million to conduct work on men’s health, including PCa, testicular cancer, mental health and suicide prevention (17).

The Movember campaign is supported by people across the globe, where men grow a moustache during the month of November to raise awareness and funds for men’s health issues (17).

The Movember campaign focuses on several areas of prostate cancer (18):

  • Funding more research focused on prostate cancer
  • Improving the lives of men from diagnosis through to treatment and recovery
  • Raising and spreading more awareness about the disease, its causes, methods of prevention and treatment

References:
1. American Cancer Society Website - Key Statistics for Prostate Cancer - https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html

2. Prostate Cancer UK Website - About prostate cancer - https://prostatecanceruk.org/prostate-information/about-prostate-cancer

3. Dijkstra S, Birker IL, Smit FP, Leyten GH, de Reijke TM, van Oort IM, Mulders PF, Jannink SA, Schalken JA. Prostate cancer biomarker profiles in urinary sediments and exosomes. J Urol. 2014 Apr;191(4):1132-8. doi: 10.1016/j.juro.2013.11.001. Epub 2013 Nov 7. PubMed PMID: 24211598.

4. Cancer.Net Website - Prostate Cancer: Statistics - https://www.cancer.net/cancer-types/prostate-cancer/statistics

5. Lima AR, Bastos Mde L, Carvalho M, Guedes de Pinho P. Biomarker Discovery in Human Prostate Cancer: an Update in Metabolomics Studies. Transl Oncol. 2016 Aug;9(4):357-70. doi: 10.1016/j.tranon.2016.05.004. Review. PubMed PMID: 27567960; PubMed Central PMCID: PMC5006818.

6. Liss MA, Ehdaie B, Loeb S, Meng MV, Raman JD, Spears V, Stroup SP. An Update of the American Urological Association White Paper on the Prevention and Treatment of the More Common Complications Related to Prostate Biopsy. J Urol. 2017 Aug;198(2):329-334. doi: 10.1016/j.juro.2017.01.103. Epub 2017 Mar 29. PubMed PMID: 28363690.

7. Rigau M, Olivan M, Garcia M, Sequeiros T, Montes M, Colás E, Llauradó M, Planas J, Torres Id, Morote J, Cooper C, Reventós J, Clark J, Doll A. The present and future of prostate cancer urine biomarkers. Int J Mol Sci. 2013 Jun 17;14(6):12620-49. doi: 10.3390/ijms140612620. Review. PubMed PMID: 23774836; PubMed Central PMCID: PMC3709804.

8. Fujita K, Nonomura N. Urinary biomarkers of prostate cancer. Int J Urol. 2018 Sep;25(9):770-779. doi: 10.1111/iju.13734. Epub 2018 Aug 21. Review. PubMed PMID: 30129068.

9. Hessels D, Schalken J. Urinary biomarkers for prostate cancer: a review. Asian J Androl. 2013 May 6; 15(3): 333–339. Published online 2013 Mar 25. doi: 10.1038/aja.2013.6. PMCID: PMC3739649

10. Di Meo A, Bartlett J, Cheng Y, Pasic MD, Yousef GM. Liquid biopsy: a step forward towards precision medicine in urologic malignancies. Mol Cancer. 2017 Apr 14;16(1):80. doi: 10.1186/s12943-017-0644-5. Review. PubMed PMID: 28410618; PubMed Central PMCID: PMC5391592.

11. Theodorescu D, Schiffer E, Bauer HW, Douwes F, Eichhorn F, Polley R, Schmidt T, Schöfer W, Zürbig P, Good DM, Coon JJ, Mischak H. Discovery and validation of urinary biomarkers for prostate cancer. Proteomics Clin Appl. 2008 Mar 7;2(4):556-570. doi: 10.1002/prca.200780082. PubMed PMID: 19759844; PubMed Central PMCID: PMC2744126.

12. MDxHealth Website – Select MDx for Prostate Cancer - https://mdxhealth.com/selectmdx-prostate-cancer

13. Exosomedx Website - The ExoDx™ Prostate Test - https://www.exosomedx.com/

14. Diagnolita Website – Non-invasive diagnosis of prostate cancer -https://www.diagnolita.lt/en/

15. Zhao F, Olkhov-Mitsel E, Kamdar S, Jeyapala R, Garcia J, Hurst R, Hanna MY, Mills R, Tuzova AV, O'Reilly E, Kelly S, Cooper C, Brewer D, Perry AS, Clark J, Fleshner N, Bapat B. A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer. Clin Epigenetics. 2018 Nov 23;10(1):147. doi: 10.1186/s13148-018-0575-z. PubMed PMID: 30470249; PubMed Central PMCID: PMC6260648.

16. O'Reilly E, Tuzova AV, Walsh AL, Russell NM, O'Brien O, Kelly S, Dhomhnallain ON, DeBarra L, Dale CM, Brugman R, Clarke G, Schmidt O, O'Meachair S, Patil D, Pellegrini KL, Fleshner N, Garcia J, Zhao F, Finn S, Mills R, Hanna MY, Hurst R, McEvoy E, Gallagher WM, Manecksha RP, Cooper CS, Brewer DS, Bapat B, Sanda MG, Clark J, Perry AS. epiCaPture: A Urine DNA Methylation Test for Early Detection of Aggressive Prostate Cancer. JCO Precis Oncol. 2019;2019. doi: 10.1200/PO.18.00134. Epub 2019 Jan 14. PubMed PMID: 30801051; PubMed Central PMCID: PMC6383793.

17. Prostate Cancer Foundation Website - https://www.pcf.org/take-action/movember-pcf/

18. Movember Website – Prostate Cancer - https://ex.movember.com/about/prostate-cancer

Read our latest white papers on prostate cancer