News

Using Biomarkers for Assessing Risk and Early Detection of Urinary Cancers

Urinary cancers, including bladder, renal cell, and upper tract urothelial carcinomas, are a significant public health challenge. In 2023, it was estimated that 82,290 adults in the United States would be diagnosed with bladder cancer. While current diagnostic methods, including cystoscopy and cytology, play an important role in oncology, they have limitations.

BRCA mutations are known to increase the risk of prostate and certain urinary cancers. BRCA mutations can be used in cancer risk assessment and management, but when it comes to urinary cancers, there are other tools that are more useful.

Biomarkers can help reduce the risks associated with certain treatments and increase cost savings. In this article, we will explore biomarkers, their importance, and their use in detecting and treating urinary cancers.

Overview of Urinary Cancers

Worldwide, bladder cancer is responsible for the majority of urinary cancer cases, with over 573,000 new cases and over 212,000 deaths annually. Renal cell and upper tract urothelial carcinomas are much less common. While variations exist from one region to another, developed countries bear a heavier burden.

Types

  • Bladder: The most common type. Smoking is the main risk factor.
  • Kidney (Renal Cell Carcinoma): Less common, with a higher mortality rate. Smoking and obesity are risk factors as well as a link to chronic kidney disease.
  • Upper tract urothelial (UTU): Relatively rare and aggressive. Shares risk factors with bladder cancer.

While mainly associated with breast and ovarian cancers, BRCA mutations are also associated with an increased risk of developing certain other types of cancers, such as prostate cancer and renal cell carcinoma.

Traditional Diagnosis

While traditional methods like urine cytology, cystoscopy, and imaging have long been the mainstays of urinary cancer diagnosis, they often fall short when it comes to accuracy, invasiveness, and early detection. For example, there is the potential for missed diagnoses in patients with BRCA mutations since their presence does not always indicate a specific urinary cancer:

  • Urine cytology: Non-invasive, low sensitivity.
  • Cystoscopy: Invasive, uncomfortable.
  • Imaging: May not differentiate benign/malignant.
  • Biopsy: Gold standard, but invasive.

Types of Biomarkers

Biomarkers are measurable indicators of specific biological states or conditions detected and quantified in biological samples like blood, tissues, or urine. They can help develop therapies used to treat many types of cancers, including urinary cancer. Biomarkers are often classified based on the way that they will be used. However, it’s important to remember that one biomarker can often fulfill multiple roles.

Common types of biomarkers include:

Diagnostic Biomarkers

Diagnostic biomarkers can detect or confirm the presence of a disease or identify the presence of a subtype of the disease. For example, NMP22 in urine is a reliable indicator of bladder cancer.

Monitoring Biomarkers

To monitor the progression of urinary cancers, urine cytology is often used, especially in bladder cancer. Regular examination of urine samples for abnormal cells can help determine the disease's course and the effectiveness of treatment.

Predictive Biomarkers

An example of a predictive biomarker in urinary cancers is the expression of PD-L1 (Programmed Death-Ligand 1) in urothelial carcinoma. The presence of PD-L1 can predict a patient's response to immunotherapies such as checkpoint inhibitors — monoclonal antibodies that target inhibitory pathways on T cells, resulting in anti-tumor activity.

Susceptibility or Risk Biomarkers

In urinary cancers, specific genetic alterations, like mutations in the FGFR3 gene, can act as susceptibility biomarkers, particularly in bladder cancer. They act as flags, signaling an increased risk of developing certain types of cancer.

Prognostic Biomarkers

Certain biomarkers play an important role in predicting the course of a disease and informing treatment decisions for patients with urinary cancers. Ki-67, a protein closely linked to cell proliferation, is a prime example. In bladder cancer, elevated Ki-67 expression serves as an indicator of aggressive disease.

Biomarkers and Approaches Used in Urinary Cancer Detection

Some of the most well-studied and clinically valuable biomarkers and approaches for identifying them in urinary cancers include:

Bladder Cancer

  • NMP22: Utilized to detect elevated protein levels that can indicate the presence of bladder cancer.
  • Urinary Cytology: Microscopic examination of urine used to detect atypical urothelial cells.
  • FGFR3 Mutations: Used to identify genetic alterations linked to non-invasive bladder cancers.

Renal Cancer


Upper Tract Urothelial Cancer


These biomarkers play a major role in the clinical management of urinary cancers, aiding in diagnosis, monitoring, and guiding treatment plans.

Applications of Biomarkers

Biomarkers unlock new possibilities for early detection, risk assessment, treatment plans, and personalized medicine for urinary cancers.

Using Biomarkers for Assessing Risk

Identifying people at high risk for developing urinary cancer allows for targeted screening and surveillance programs. Biomarker-based risk scores offer a more personalized assessment of risk than traditional methods. They can help identify those at higher risk.

Early Detection

Non-invasive tests may eventually replace or supplement cystoscopy, which can lead to earlier detection and better patient outcomes.

Prognosis and Treatment Response

Biomarkers like Bladder Tumor Antigen (BTA) for bladder cancer can be used to predict disease aggressiveness and the risk of recurrence. This can be used to guide treatment decisions and tailor therapy regimens for the best outcomes.

Personalized Medicine

By understanding a patient's unique biomarker profile, physicians can design treatment plans to target specific molecular pathways, leading to more effective and less toxic treatments.

Current Challenges and Future Directions

Limitations

While biomarkers hold great promise, there are some hurdles that still remain.

  • Tissue heterogeneity: Biomarkers may not always reflect how complex a tumor is, which can lead to potential misinterpretations.
  • Biological variability: Differences in the expression of a biomarker can make diagnosis difficult and complicate treatment decisions.
  • Limited predictive power: Biomarkers may not be able to fully track the progression of a disease and the response to treatment.
  • Ethical considerations: Data privacy and potential discrimination based on biomarker profiles must be considered carefully.

There are many ways that biomarkers will improve cancer detection and treatment:

  • AI and machine learning: Using AI to analyze complex biomarker data and improve the accuracy of diagnoses.
  • Liquid biopsy: Using tumor DNA circulating in the blood to improve monitoring and treatment personalization.
  • Development of novel biomarkers: Identifying new biomarkers with higher sensitivity and specificity for improved early detection and targeted therapies.
  • Clinical trials: To validate how useful a biomarker is and help determine the best way to integrate them into clinical practice.

Key Takeaways

Biomarkers make a big difference in urinary cancer management and offer improvements over traditional diagnostic methods. They can improve early detection and risk assessment and help personalize treatment. However, many challenges remain, such as developing standardizing tests and panels that can analyze and check for multiple components, are cost-effective, and are non-invasive. Future progress depends on continued research, collaboration, and integration into clinical, which can lead to improved patient care.

References

  1. Cancer.Net. (n.d.). Bladder cancer: Statistics. Retrieved from https://www.cancer.net/cancer-types/bladder-cancer/statistics
  2. Castro, E., & Eeles, R. (2012). The role of BRCA1 and BRCA2 in prostate cancer. Asian Journal of Andrology, 14(3), 409–414. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720154/
  3. Shah, A., Grimberg, D., Berg, H., Tan, W. P., & Inman, B. (2019). Should urothelial carcinoma be considered part of BRCA1 and BRCA2 cancer syndromes? Retrieved from https://suo-abstracts.secure-platform.com/a/gallery/rounds/1/details/509
  4. World Cancer Research Fund. (n.d.). Bladder cancer statistics. Retrieved from https://www.wcrf.org/cancer-trends/bladder-cancer-statistics/
  5. Califf, R. M. (2018). Biomarker definitions and their applications. Experimental Biology and Medicine, 243(3), 213-221. https://doi.org/10.1177/1535370217750088
  6. Yang Hyun Cho, Seung Il Jung, & Eu Chang Hwang. (2018). Novel and emerging surveillance markers for bladder cancer. In J. H. Ku (Ed.), Bladder Cancer (pp. 599-612). Academic Press. https://doi.org/10.1016/B978-0-12-809939-1.00031-X
  7. https://www.sciencedirect.com/topics/medicine-and-dentistry/nmp22
  8. Al Nabhani, S., Al Harthy, A., Al Riyami, M., Al Sinawi, S., Al Rashdi, A., Al Husseni, S., & Kumar, S. (2022). Programmed death-ligand 1 (PD-L1) expression in bladder cancer and its correlation with tumor grade, stage, and outcome. Oman Medical Journal, 37(6), e441. https://doi.org/10.5001/omj.2022.96
  9. May A, Roustio L, Hamilton ZA. The Role of Immunotherapy in Urologic Cancers. Mo Med. 2020 Mar-Apr;117(2):127-132. PMID: 32308237; PMCID: PMC7144716.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144716/
  10. Kacew, A., & Sweis, R. F. (2020). FGFR3 alterations in the era of immunotherapy for urothelial bladder cancer. Frontiers in Immunology, 11, 575258. https://doi.org/10.3389/fimmu.2020.575258
  11. Prognostic and clinicopathologic value of ki-67 and profilin 1 immunohistochemical expression in primary pT1 urothelial bladder cancer.
  12. https://pubmed.ncbi.nlm.nih.gov/12081583/#:~:text=Kidney%20Injury%20Molecule-1%20(KIM-1)%20is%20a,1%20is%20shed%20from%20cells
  13. NNMP22. Retrieved from https://www.sciencedirect.com/topics/medicine-and-dentistry/nmp22
  14. Urine Cytology. Retrieved from https://www.sciencedirect.com/topics/medicine-and-dentistry/urine-cytology
  15. de Martino M, Lucca I, Mbeutcha A, Wiener HG, Haitel A, Susani M, Shariat SF, Klatte T. Carbonic anhydrase IX as a diagnostic urinary marker for urothelial bladder cancer. Eur Urol. 2015 Oct;68(4):552-4. doi: 10.1016/j.eururo.2015.06.015. Epub 2015 Jun 30. PMID: 26138037. https://pubmed.ncbi.nlm.nih.gov/26138037/
  16. W, Sultana S. Role of VHL gene mutation in human renal cell carcinoma. Tumour Biol. 2012 Feb;33(1):9-16. doi: 10.1007/s13277-011-0257-3. Epub 2011 Nov 29. PMID: 22125026 https://pubmed.ncbi.nlm.nih.gov/22125026/#:~:text=The%20Von%20Hippel-Lindau
  17. Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002 Jul;62(1):237-44. doi: 10.1046/j.1523-1755.2002.00433.x. PMID: 12081583.https://pubmed.ncbi.nlm.nih.gov/12081583/#:~:text=Kidney%20Injury%20Molecule-1%20(KIM-1)%20is%20a,1%20is%20shed%20from%20cells
  18. Lin T, Liu Z, Liu L, Yang L, Han P, Zhang P, Wei Q. Prospective evaluation of fluorescence in situ hybridization for diagnosing urothelial carcinoma. Oncol Lett. 2017 May;13(5):3928-3934. doi: 10.3892/ol.2017.5926. Epub 2017 Mar 27. PMID: 28529600; PMCID: PMC5431676.
  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431676/#:~:text=Urine%20fluorescence%20in%20situ%20hybridization,17%20and%20the%20p16%20gene
  20. Guo, A., Wang, X., Gao, L., Shi, J., Sun, C., & Wan, Z. (2014). Bladder tumour antigen (BTA stat) test compared to the urine cytology in the diagnosis of bladder cancer: A meta-analysis. Canadian Urological Association Journal, 8(5-6), E347-52. https://doi.org/10.5489/cuaj.1668
  21. Purkayastha, K., Dhar, R., Pethusamy, K., Srivastava, T., Shankar, A., Rath, G. K., & Karmakar, S. (2024). The issues and challenges with cancer biomarkers. Journal of Cancer Research and Therapeutics, 19(Suppl 1), S20-S35.https://doi.org/10.4103/jcrt.jcrt38422
  22. Ferro, M., Falagario, U. G., Barone, B., Maggi, M., Crocetto, F., Busetto, G. M., Giudice, F. D., Terracciano, D., Lucarelli, G., Lasorsa, F., Catellani, M., Brescia, A., Mistretta, F. A., Luzzago, S., Piccinelli, M. L., Vartolomei, M. D., Jereczek-Fossa, B. A., Musi, G., Montanari, E., Cobelli, O., & Tataru, O. S. (2023). Artificial intelligence in the advanced diagnosis of bladder cancer-comprehensive literature review and future advancement. Diagnostics (Basel), 13(13), 2308. https://doi.org/10.3390/diagnostics13132308
  23. Crocetto, F., Barone, B., Ferro, M., Busetto, G. M., La Civita, E., Buonerba, C., Di Lorenzo, G., Terracciano, D., & Schalken, J. A. (2022). Liquid biopsy in bladder cancer: State of the art and future perspectives. Critical Reviews in Oncology/Hematology, 170, 103577. https://doi.org/10.1016/j.critrevonc.2022.103577
  24. Yang Hyun Cho, Seung Il Jung, & Eu Chang Hwang. (2018). Novel and emerging surveillance markers for bladder cancer. In J. H. Ku (Ed.), Bladder Cancer (pp. 599-612). Academic Press. https://doi.org/10.1016/B978-0-12-809939-1.00031-X
  25. Castaneda PR, Theodorescu D, Rosser CJ, Ahdoot M. Identifying novel biomarkers associated with bladder cancer treatment outcomes. Front Oncol. 2023 Mar 29;13:1114203. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10090444/
  26. Kamat, A. M., Apolo, A. B., Babjuk, M., Bivalacqua, T. J., Black, P. C., Buckley, R., Campbell, M. T., Compérat, E., Efstathiou, J. A., Grivas, P., Gupta, S., Kurtz, N. J., Lamm, D., Lerner, S. P., Li, R., McConkey, D. J., Palou Redorta, J., Powles, T., Psutka, S. P., Shore, N., Steinberg, G. D., Sylvester, R., Witjes, J. A., & Galsky, M. D. (2023). Definitions, end points, and clinical trial designs for bladder cancer: Recommendations from the Society for Immunotherapy of Cancer and the International Bladder Cancer Group. Journal of Clinical Oncology, 41(35), 5437-5447. https://doi.org/10.1200/JCO.23.00307
Blog