Liquid Biopsy: The Next Evolution In Personalized Prostate Cancer Screening

By Spencer Heaton, MD, MBA, chief medical and commercial officer, LynxDx

The prostate-specific antigen (PSA) blood test has long been the gold standard in prostate cancer diagnostics. Screening can help detect the disease at earlier stages, often before signs and symptoms (which are usually associated with more advanced disease) appear.¹ Additionally, research has shown that prostate cancer survival rates increase for those at higher risk when it is detected early.²

And now, new screening methods that provide a genetically driven, more personalized approach offer promise to enhance the efficacy of diagnostic results. Here, we’ll examine how noninvasive methods such as liquid biopsy can offer a more comprehensive view that will ultimately benefit patients and providers. 

Building Upon The Progress Achieved With PSAs

Since 1993, the prostate cancer death rate has declined by half due to earlier detection through PSA testing and advances in treatment, according to the American Cancer Society Cancer Action Network.² This progress cannot be overstated and speaks to why, in March of this year, Congress introduced the PSA Screening for HIM Act, which, if passed, would require insurance companies to cover prostate cancer screenings for those at high risk for the disease without out-of-pocket costs.³ This would not only remove financial barriers to screening but also help reduce racial inequities in prostate cancer caused by socioeconomic conditions.

While the introduction of the PSA Screening for HIM Act is laudable for its intent to remove cost barriers for those at high risk, more work remains to be done. The PSA blood test does not, on its own, serve as a black-and-white diagnostic method. As we know, PSA is a protein produced by both cancerous and noncancerous tissue in the prostate and is mostly found in semen, which also is produced in the prostate.⁴ Small amounts of PSA ordinarily circulate in the blood.⁴ And while high PSA levels may indicate the presence of prostate cancer, the Mayo Clinic notes that “many other conditions […] can increase PSA levels.” As a result, determining what a high PSA score means can be complicated and there is a lot of conflicting advice about PSA testing, the Mayo Clinic concludes.

The challenge is that PSA testing may result in false positives or false negatives for a variety of reasons. Advancing age, inflammation, infection, an enlarged prostate, recent ejaculation, and certain medications can all result in higher PSA readings.⁵ Similarly, not all prostate cancers will cause a rise in PSA levels. Overall, sensitivity (true positive results) of PSAs has been estimated to be about 70 percent to 80 percent, while the specificity (true negative results) is about 60 percent to 70 percent.⁶

Because of all the uncertainty and variables that come into play with prostate cancer screening and diagnosis, most experts recommend that decisions be made on an individual basis, as clinicians and patients work together to determine the best care plan for each person. The ability to customize diagnosis and treatment represents a powerful breakthrough in the fight against prostate cancer. 

New Screening Methods Provide New Options

“A major focus of research needs to be the development of new methods and markers which more clearly separate indolent (low risk) cancers from aggressive and potentially lethal ones, thus enabling conservative management of a much larger proportion of the cancers found,” according to study authors of a manuscript published in Lancet Oncology. “Ideally, this would be achieved by non-invasive and relatively cheap methods,” the authors note.⁷

Fortunately, advancements in technology and innovation have made such methods a reality. Liquid biopsy, which includes the analysis of circulating tumor material in the blood or urine, has emerged as a promising non-invasive tool in the management of prostate cancer.⁸ According to 2022 research, unlike traditional surgical sampling, liquid biopsies provide numerous tumor-specific biomarkers.⁸⁸ These biomarkers have the potential to provide patient-specific insights, especially in complex cases such as patients who are at higher risk due to race or those who’ve previously had negative biopsy results.

Urine testing may be particularly useful in prostate cancer screening. Research has shown that urine following a digital rectal exam (DRE) is enriched with prostate cancer biomarkers including prostate cancer cells, DNAs, RNAs, proteins, and other small molecules. ⁹ By providing a combined measurement of cancer markers PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after DRE, urine analysis offers a precision medicine screening method for men who are considered to have an increased risk for prostate cancer. In fact, in a study of 1,032 men presenting for first-time prostate biopsy without preexisting prostate cancer, where the primary endpoint was presence vs. absence of aggressive prostate cancer, researchers found that 42 percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy.¹⁰

And newer urine analysis tools currently in investigational studies can screen for even more cancer biomarkers. In a Journal of Urology study published in April of this year, researchers incorporated novel transcripts associated with high-grade cancer and externally validated a 17-marker urinary panel for detection of certain aggressive forms of prostate cancer. Compared with current clinically available urine biomarker tests, this investigative screening tool improved diagnostic accuracy by nearly 10 percent and increased specificity by 21 percent at clinically actionable, highly sensitive thresholds. ¹¹

Incorporating this level of personalization in care plans can have a significant impact on both patients and care providers. For patients, the advantages of liquid biopsy include convenience and a more favorable risk profile; for physicians, liquid biopsy can offer important insight into disease prognosis that may help guide treatment decisions.⁸ Analysis of urine biomarkers has the potential to provide care providers and patients with additional personalized information, beyond what PSA alone can offer. This can be particularly beneficial for high-risk patient populations. 

The landscape of prostate cancer screening and diagnostics continues to evolve, offering ever-more precise and accurate results. The combination of traditional testing methods paired with the latest innovations in diagnostics represents a shift toward precision medicine that could deliver meaningful impact for patients in the form of improved outcomes. 

References

1. American Cancer Society Cancer Action Network. Early detection for prostate cancer. fightcancer.org. https://www.fightcancer.org/what-we-do/early-detection-prostate-cancer. Accessed July 30, 2023
2. American Cancer Society Cancer Action Network. Congress introduces PSA screening for HIM act. fightcancer.org. https://www.fightcancer.org/news/congress-introduces-psa-screening-him-act. Accessed July 30, 2023.
3. Congress.gov. H.R.1826 - PSA screening for HIM act. congress.gov. https://www.congress.gov/bill/118th-congress/house-bill/1826?s=1&r=1. Accessed July 30, 2023.
4. Mayo Clinic. PSA test. mayoclinic.org. https://www.mayoclinic.org/tests-procedures/psa-test/about/pac-20384731. Accessed July 30, 2023.
5. University of California, Los Angeles. DRE and PSA test work together in prostate cancer screening. uclahealth.org. https://www.uclahealth.org/news/dre-and-psa-test-work-together-in-prostate-cancer-screening. Accessed July 30, 2023. 
6. North Carolina Family Medical Group. Prostate cancer screening. ncfmg.com. https://www.ncfmg.com/wp-content/uploads/2018/04/Prostate-Cancer-screening.pdf. Accessed July 30, 2023.
7. Cuzick J, Thorat MA, Andriole G, et al. Prevention and early detection of prostate cancer. Lancet Oncol. 2014 Oct;15(11):e484-92. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70211-6.
8. Ionescu F, Zhang J, Wang L. Clinical Applications of Liquid Biopsy in Prostate Cancer: From Screening to Predictive Biomarker. Cancers (Basel). 2022 Mar 29;14(7):1728. https://www.mdpi.com/2072-6694/14/7/1728.
9. Fujita K, Nonomura N. Urinary biomarkers of prostate cancer. Int J Urol. 2018 Sep;25(9):770-779. https://onlinelibrary.wiley.com/doi/10.1111/iju.13734.
10. Sanda MG, Feng Z, Howard DH, et al. Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. JAMA Oncol. 2017 Aug 1;3(8):1085-1093. https://jamanetwork.com/journals/jamaoncology/fullarticle/2627420.
11. Samora N, Zhang Y, Xiao L, et al. MP17-11 refinement and external validation of a novel multiplex urine test for high-grade prostate cancer. J Urol. Vol. 209, No. 4S, Supplement, April 2023. https://www.auajournals.org/doi/epdf/10.1097/JU.0000000000003237.11. 

About The Author:

Spencer Heaton, M.D., MBA, serves as the chief medical and commercial officer at LynxDx. A physician executive, he has a multifaceted background spanning healthcare delivery, medical research, venture capital, and innovative technologies. He has played a pivotal role in healthcare technology and the development of medical products and diagnostics.