BERKELEY, CA (UroToday.com) - The public controversy over the widespread screening of asymptomatic men for prostate cancer with the prostate-specific antigen (PSA) test has garnered much coverage by the media recently. Often critical of prostate cancer management, these reports generally present only a partial perspective of prostate cancer screening and the goals toward which the medical community should strive.
At the outset of any prostate cancer screening debate, one must recognize that PSA screening of asymptomatic men detects cancers that are typically at an early stage. This has resulted in a dramatic decrease in the number of men whose clinical presentation is metastatic disease. PSA has also helped physicians to stratify patient risk for aggressive prostate cancer by using simple metrics (e.g., PSA >20 ng/mL typically suggests worse disease). PSA is useful for monitoring disease recurrence after initial local therapies (radiation, surgery).
However, despite these attributes, PSA is widely known to be a non-specific test, and approximately 66 - 75% of men with an elevated PSA (>4 ng/mL) do not have prostate cancer.[1] Yet, most of men with an elevated PSA will receive a biopsy, and if cancer is found, treatment. This clinical paradigm is worrisome, as there is no consensus that PSA screening reduces prostate cancer mortality[2,3] and radical prostatectomy for PSA-screened patients with prostate cancer does not provide a definitive survival advantage over watchful-waiting.[4] PSA therefore propagates a system in which too many men with asymptomatic, indolent cancers are treated and hundreds of thousands of men without cancer to undergo invasive biopsy procedures.
Overall, it is estimated that 50% of prostate cancers detected by PSA screening would never have become clinically significant or caused symptoms.[5] These indolent cancers should not be managed the same way as aggressive prostate cancers. However, a major problem is the lack of biomarkers to assess the potential for disease aggressiveness at an early stage. While high PSA levels (>20 ng/mL) associate with a poor prognosis, most prostate cancer patients have a PSA of 4 – 10 mg/mL on screening. In this setting, the prognostic (and diagnostic) utility of PSA is poor. Moreover, most PSA-detected prostate cancers are of low or intermediate grade, generally Gleason 6 or Gleason 7. Thus, the typical scenario is a prostate cancer patient with modestly elevated PSA and low/intermediate grade. Clinically, the majority of these patients have indolent disease and a subset have aggressive disease—indeed, while 1 in 6 U.S. men are diagnosed with prostate cancer, only 1 in 32 may die from it.
Therefore, we assert two major challenges for the prostate cancer community: 1) the development of screening biomarkers that are more specific for prostate cancer to reduce unnecessary procedures, and 2) the development of biomarkers that more accurately resolve risk of aggressive prostate cancer at the time of screening. Rather than eliminating PSA entirely as a diagnostic marker, new biomarkers may be “multiplexed” with serum PSA, providing for a more specific diagnostic approach.
The past decade has witnessed several major advances in these areas. Indeed, in 2012, the FDA has approved two new tests for prostate cancer diagnosis: PCA3, a prostate-specific long noncoding RNA measurable in patient urine, and the Prostate Health Index (PHI), a serum test that incorporates total PSA, free PSA (the fraction not bound by serum proteins), and [-2]pro-PSA (a molecular precursor to mature PSA protein). PCA3 is approved for diagnostic use in the setting of a previous negative biopsy, and the PHI is approved for men with gray-zone PSA values of 4 – 10 ng/mL. These two tests have been shown to improve the diagnosis of prostate cancer and reduce unnecessary biopsies. Similarly, newer tests, such as urine-based detection of the TMPRSS2-ERG gene fusion RNA, which results from a prostate-cancer-specific translocation, may further augment this panel of non-invasive assays in the future. Thus, a patient with elevated PSA but a favorable PHI score and low urinary PCA3 is at a low risk for cancer, whereas a patient with gray-zone PSA (4 – 10 ng/mL) but high PCA3 and a high PHI score is at a high risk for cancer. In time, these tests may replace or supplement PSA as more specific screening tests.
However, more accurate non-invasive diagnosis is only part of the problem. The prostate cancer community needs new biomarkers to predict prostate cancer risk at the time of screening. Here, we assert that non-invasive biomarkers that stratify aggressive prostate cancer at an early stage will be crucial for the future management of this disease, enabling physicians to target treatment for high-risk cancers and reducing biopsies and aggressive management for indolent cancers. Validation of potential biomarkers may be facilitated by multi-institutional consortia, such as the National Cancer Institute’s Early Detection Research Network (EDRN). Yet, non-invasive prognostic tests for prostate cancer are currently lacking.
PSA-based prostate cancer screening has been widely used without evidence that it reduces prostate cancer-specific mortality, resulting in numerous forums to advocate against prostate cancer screening and treatment. However, these perspectives ignore the fact that a minority of patients with prostate cancer has aggressive disease that may be lethal. The challenge ahead is to stratify these patients from patients with indolent disease at the time of screening so that disease management is rationally determined based upon a patient’s disease risk. Future clinical practice could then employ a multiplexed assay in conjunction with PSA to establish diagnosis and prognosis in a rational manner. Recent advances, such as PCA3 and the PHI score, provide encouragement that new assays can move the prostate cancer community forward.
References:
- Schroder FH, Carter HB, Wolters T, et al. Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics. Eur Urol 2008;53:468-77.
- Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360:1320-8.
- Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-9.
- Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203-13.
- Etzioni R, Cha R, Feuer EJ, Davidov O. Asymptomatic incidence and duration of prostate cancer. Am J Epidemiol 1998;148:775-85.
Written by:
John R. Prensnera, b and Arul M. Chinnaiyana, b, c, d, e as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aMichigan Center for Translational Pathology
bDepartment of Pathology
cDepartment of Urology
dComprehensive Cancer Center
eHoward Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Address correspondence to:
Arul M. Chinnaiyan, MD, PhD
Comprehensive Cancer Center
University of Michigan Medical School
1400 E. Medical Center Dr. 5316 CCGC 5940
Ann Arbor, MI 48109-5940
Phone: 734-615-4062; Fax: 734-615-4055
Email:
Conflict of Interest Statement: Arul M. Chinnaiyan serves as an advisor to Gen-Probe and is co-discoverer of the TMPRSS2-ERG gene fusion in prostate cancer.
Beyond PSA: The next generation of prostate cancer biomarkers - Abstract
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