Prostate cancer is recognized as the second-most common cause of cancer and the sixth-leading cause of cancer mortality among men worldwide. According to the American Cancer Society, there were an estimated 241,740 new cases of prostate cancer and about 28,170 deaths from the disease in 2012. The worldwide burden of prostate cancer is expected to grow to 1.7 million new cases and 499,000 new deaths by 2030, simply due to the growth and aging of the global population.1 Screening and diagnosis of prostate cancer play a crucial role in the prostate cancer landscape.
Limitations of current screening tests
Since the late 1980s, prostate-specific antigen (PSA) has been the only recognized screening test for prostate cancer. However, PSA has limitations and is not at all a perfect screening tool. PSA has a recognized lack of specificity, meaning a large number of elevated PSA results are not due to cancer. For example, infection and inflammation of the prostate gland can elevate PSA levels in the blood. Additionally, elevated PSA in the blood can be due to a benign enlargement of the prostate, called benign prostatic hyperplasia (BPH). While PSA is indeed specific for the prostate gland, it is not specific to prostate cancer.
In fact, PSA lacks sensitivity for detecting prostate cancer. The recognized screening cut-off of 4.0 ng/mL was established in the 1990s as the 95th percentile of a normal (no cancer) population. The cases where PSA fails to detect prostate cancer are mostly overlooked, with the reasoning being that the cancer will be detected at some (near) future date and/or that the cancer is most likely not an aggressive cancer.
Over-diagnosis and over-treatment have received much more criticism, with concerns raised about poorly spent healthcare dollars and the side effects of prostate biopsies, surgeries, and other treatments. Recognized side effects from prostate biopsies include rectal bleeding, local infection, and severe systemic infections that require hospitalization. Infections are increasingly common due to antibiotic-resistant bacteria.
Due to the lack of sensitivity and specificity of PSA, in June 2012, the U.S. Preventive Services Task Force (USPSTF) issued a “D” rating for PSA screening, meaning the Task Force discourages physicians from offering PSA to their patients for the purpose of detecting prostate cancer. The USPSTF issued the following statement: “Do not use prostate-specific antigen (PSA)-based screening for prostate cancer.”2
Despite decades of clinical research, no clear consensus has emerged on the benefits of PSA screening. It has become evident that further prospective studies are needed. There has been a great deal of focus over the years on alternate biomarkers to supplement or even to replace the PSA test as a prostate cancer detection tool.
The need for better tools and strategies
Depending on the clinical setting in which PSA is used, the typical prostate biopsy is positive for cancer in men with elevated PSA levels only 20% to 40% of the time—meaning that as many as four out of five prostate biopsies do not find prostate cancer. The result of this is that as many as 750,000 prostate biopsies are reported as negative every year in the U.S. alone. These negative biopsies come with significant cost to the healthcare system, as well as considerable medical risks to the patient, as mentioned earlier.
The key to better diagnosis of prostate cancer is finding more effective ways to use PSA as a screening tool—ultimately, making PSA a better prostate cancer detection tool in the modestly-elevated PSA range. PSA is very specific for prostate cancer over 10 ng/mL—it’s the gray zone of 4 to10 ng/mL where the lack of specificity is of concern. Strategically, an improved PSA could contribute in clinical situations, such as detecting aggressive prostate cancer, which would more likely affect a man’s quality or length of life, and in identifying indolent forms of prostate cancer, which probably would not affect a man’s quality or length of life.
Isoforms of free PSA
Recently, an isoform of free PSA has gained attention because of its increased specificity for prostate cancer, supplementing information from initial PSA test results. Even though it is not yet able to completely replace PSA as a screening tool, this marker does appear to provide significant additional information for clinicians when making patient management decisions for men with a modestly-elevated PSA in the 4 to 10 ng/mL range.
Figure 1. Graphical depiction of molecular features of PSA molecules
Source: Mikolajczyk. Urology. 2002;59:797-802.
Serum contains two distinct forms of PSA: one form (complexed PSA) that is irreversibly bound to the serine protease inhibitor, alpha-1-antichymotrypsin; and a second form (free PSA) that is present as a free “non-complexed” form. Free PSA is composed of three distinct forms of inactive PSA. One form has been identified as the proenzyme, or precursor form of PSA (proPSA), and is more associated with cancer than the other two isoforms (Figure 1).3
The proPSA isoforms are found in several molecular forms. Native proPSA has a seven-amino acid leader sequence on the amino-terminal end of the protein. Normally, these seven amino acids are cleaved off by activating enzymes to yield the enzymatically active PSA that is found in seminal plasma. Truncated forms of proPSA can be found as [-5]-, [-4]-, and [-2]proPSA molecules. Early research demonstrated the [-2]proPSA form to be the most cancer-specific, and it was localized to cancer tissue in immunohistochemical staining of prostate gland specimens.3 Further, the [-2]proPSA molecule is also the most stable form of proPSA, meaning it is the least susceptible to further degradation and cannot be converted to enzymatically active PSA. Figure 2 depicts the typical proportions of the isoforms in serum from men with prostate cancer.
A multi-marker approach
The [-2]proPSA molecule demonstrates better performance when combined with total PSA and free PSA in a multi-marker index. This recently developed index is a combination of these three biomarkers: PSA, free PSA, and a new assay which identifies the biomarker [-2]proPSA. The three assay results are combined by an immunoassay analyzer’s system software to calculate a risk of prostate cancer. The index is calculated using the following formula:
[-2]proPSA / free PSA) x sqrt PSA
In June 2012, the U.S. Food and Drug Administration approved [-2]proPSA when used as the multi-marker index for use as an aid in distinguishing prostate cancer from benign prostatic conditions. The approval was for prostate cancer detection in men age 50 and older with total PSA in the 4 to 10 ng/mL range and with digital rectal examination (DRE) findings that are not suspicious for cancer. Prostatic biopsy is required for diagnosis of cancer.
In a pivotal multi-center study4 that demonstrated the clinical efficacy of the new marker and index, 658 men were studied (324 with prostate cancer and 334 without). The study involved men who were recruited from seven medical centers, were 50 or older, and had a negative DRE and a histologically determined diagnosis by prostate gland biopsy examination. Most of the men (79.3%) were undergoing their initial prostate biopsy. The median age was 63 years for men in both the cancer and benign disease groups, and total PSA values did not differ between the groups. The study analysis compared the ability of the index to discriminate prostate cancer from benign disease in comparison to total PSA.
The researchers evaluated prostate biopsy results and compared them to results of PSA, free PSA, [-2]proPSA and their derivatives. Using receiver operating characteristic (ROC) curve analysis, the area-under-the-curve (AUC) was 0.708 for the index and 0.516 for total PSA, demonstrating the enhanced power of the index (Figure 3). Fixing the sensitivity at 90% (cancer detection rate), the specificity of the index was 31.1% compared to 10.8% for PSA (p < 0.001). This translates to a 2.9-fold greater specificity for [-2]proPSA as part of the index versus total PSA (Figure 4). This improved specificity may allow a substantial decrease in the number of prostate biopsies that are reported as negative for cancer. Table 1 represents clinical study data5 analyzed to estimate the probability of having detectable prostate cancer in an individual patient, based on results of the index.
Note: Interpretive criteria for the index are available for both the Hybritech calibration and the World Health Organization (WHO) calibration of PSA and free PSA. The corresponding risk numbers are different, but the clinical performance, based on ROC AUC analysis, is equivalent.
Further research and clinical utility
New clinical utilities for the [-2]proPSA and index will likely be identified in future research studies. For example, [-2]proPSA has been found to correlate with the Gleason Score (GS) on prostate biopsy–the probability of GS ≥7 increases as the marker increases.
There is a strong need for a better indicator of aggressive prostate cancer, and [-2]proPSA might be shown to fill that void. With more knowledge about the prostate cancer, a physician may, given evidence of a more dangerous cancer, recommend a more aggressive treatment strategy for an individual patient.
Alternatively,[-2]proPSA may find use as a “rule out” marker for aggressiveness. Hypothetically, a score above a certain number may be used to reassure a man with a GS 6 cancer that there is no immediate need for intervention and that waiting is a safe strategy. Active surveillance is a special type of “watchful waiting,” a prostate cancer management program where a known but low-grade cancer is followed with regular PSA testing and prostate biopsies—for example, once per year. There have been reports that [-2]proPSA may predict those patients who will fail active surveillance, and should be more closely monitored or never entered into a
surveillance program.
Finally, because PSA is sometimes poorly sensitive to post-radical prostatectomy recurrence of prostate cancer, [-2]proPSA may be a more sensitive and specific test with which to monitor for a prostate cancer returning.
These and other applications of this or any marker must be thoroughly investigated by researchers before physicians will consider using [-2]proPSA for these novel utilities in their patients.
To sum up, prostate cancer remains a common and challenging disease to detect and manage, even after many years of clinical experience and extensive research. PSA has long been the only recognized screening biomarker, even with its limitations. It is known that over-diagnosis and over-treatment of prostate cancer is very common. For now, PSA remains the most effective biomarker available for helping to detect prostate cancer; however, the recently approved index may make PSA a more effective marker for prostate cancer in the challenging PSA range of 4 to10 ng/mL. By increasing the specificity for prostate cancer by three times, [-2]proPSA and the index make PSA a better marker for prostate cancer and may spare some men from prostate biopsies that will result as negative, simultaneously saving healthcare dollars. Undoubtedly, future research will focus on ways to combine protein and nucleic acids markers to bolster screening information from total PSA. The combined role of imaging studies is another emerging strategy. PSA will remain as the primary tool for helping detect prostate cancer, but physicians will gain comfort in making decisions with these new tools.
About the Author
References
- Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008: v2.0, Cancer incidence and mortality worldwide. IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010.
- Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.
- Mikolajczyk SD, Millar LS, Wang TJ, et al. A precursor form of prostate-specific antigen is more highly elevated in prostate tissue. Cancer Res. 2000;60:756–759.
- Sanda MG, Wei JT, Broyles DL, et al. Evaluation of the prostate health index (phi) for improving prostate cancer detection and identification of clinically significant prostate cancer in the 4 to 10 ng/mL PSA range. Manuscript submitted for publication.
- Beckman Coulter Access Hybritech p2PSA Instructions for Use, A84987A.
