Prostate cancer biomarkers are either tissue, blood or urinary indicators which, when tested for and then factored against the microscopic diagnosis, may offer additional information as to the possible future behavior of that particular prostate cancer. For each prostate cancer diagnosis the microscopic appearances can be affected by subjective interpretation issues from the pathologist resulting in errors of grade estimation for that cancer. Therefore, biomarkers may provide an additional avenue for assessing the cancer’s biological potential and ultimate health-risk. Since most prostate cancers are readily diagnosed microscopically as low-grade and not requiring treatment or, high-grade and needing treatment, biomarkers may be more useful for trying to identify the risk-features of some high-volume low grade or, some mid-grade prostate cancers.
Prostate Cancer Progression and Upgrading Concerns Exaggerated
In reality, prostate cancer progression is more about the possible finding of a slightly increased amount of cancer on a subsequent biopsy because there was better tissue sampling of the multifocal disease rather than any true progression of the original Gleason 3+3=6 “cancer”. In addition, so-called prostate cancer upgrading or, grade progression to a slightly more aggressive pattern, is invariably due to pathology subjective interpretation differences amongst physicians or, even a difference of interpretation from the same pathologist over his previous reading. Furthermore, even if the confirmatory biopsy sometime after the initial biopsy suggests changes consistent with an “upgrading”, usually from the common 3+3=6 so-called cancer, then it will be invariably to a Gleason 3+4 cancer. This degree of upgrading is insignificant as the 3+4 (especially if the pattern 4 is less than 10%) behaves very much like the Gleason 3+3=6 “cancer”, a disease which LACKS the hallmarks of a cancer, is not a health-risk and does not require treatment. On the other hand, high-grade prostate cancers are usually diagnosed through the initial biopsy but, in the uncommon possibility of a de novo development of an area of high-grade prostate cancer elsewhere in the prostate in the future, persistent rises in serial PSAs will indicate the need for a repeat 12-core needle biopsy early enough to allow curative treatment if significant pattern 4 disease or above is detected. The goal then, is to detect validated pattern 4 disease (not pattern 3) as only prostate cancer with pattern 4 and above is potentially lethal. Primary pattern 4 (as in say, a 4+3) and above, has greater lethal potential than secondary pattern 4 disease (as in 3+4). However, even men with greater than 10% secondary pattern 4 disease can be managed without treatment after considering his tumor volume, his age and his comorbidities (other medical conditions) since most prostate cancers grow slowly. In fact, studies have shown that the prostate cancer cell doubling time is about 475 days so that from the time of initial cell mutation, it takes about 40 years for the tumor to achieve approximately 1 centimeter in diameter before it can be felt on a DRE (digital rectal exam). Pattern 4 cell division might be a little faster. Therefore, delays in detecting pattern 4 disease during active surveillance monitoring are unlikely to compromise curability by treatment undertaken through mpMRI targeting and focal therapy with HIFU, laser or, cryoablation.
Pre-Biopsy Biomarkers for Prostate Cancer Prediction
- The PSA (prostatic specific antigen), like the DRE of the prostate is standard practice but, highly unreliable when used for prostate cancer prediction. However, estimations of the total PSA, the percent free PSA, PSA density and PSA doubling time may help improve prediction of prostate cancer a little more than just using the total PSA.
- The phi (prostate health index) test measures three markers, total PSA, free PSA and the p2PSA and the combination of these 3 blood tests provides a phi score and, the higher the score, the greater the probability of a prostate cancer. The p2PSA assay is specific to measuring the pro PSA biomarker which is an isoform of free PSA and, which has been identified as prostate cancer-specific but, not necessarily cancer-grade specific.
- The 4k SCORE is a clinical decision aid that attempts to measure the probability of a prostate cancer by measuring 4 kallikreins in the blood stream. These are, total PSA, free PSA, intact PSA, human kallikrein-related peptidase 2 (hk2) along with age, findings of digital rectal examination and history of prior biopsy.
- mpMRI imaging. Obviously not a biomarker but, can also be useful in limiting unnecessary and risky prostate needle biopsies should there be concerns about an upward trending PSA. Furthermore, it appears that this imaging technique (in expert hands only) can detect fairly reliably just the important high-grade prostate cancers and leave the common Gleason 6 prostate pseudocancers undetected as these require no treatment whether focal or whole gland.
Post-Biopsy Tissue Stains for Prostate Cancer Detection
- Technically not a biomarker but, to ensure that there has been no handling error and that it is your biopsy reported on, there is a buccal swab test which can be done to accompany your prostate samples for a DNA match (Know Error).
- Typically, the prostate needle biopsy samples randomly, 2 cores in each of 6 areas of the prostate for about 0.10-.2% of its volume. The tissue then undergoes standard preparation and H+E staining prior to being examined under the low-power microscope. An additional stain, the triple immunohistochemistry stain can increase the diagnostic accuracy for detecting small foci of mostly nonlethal prostate cancer.
- Aside from pathologists adhering to a rigorous but very subjective (observer dependent) Gleason grading and scoring system for prostate cancer where interpretation errors by the pathologist can result in under or, over-reading of your Gleason grades and score, this grading system has undergone arbitrary evolution over time to the point where the current Gleason 3+3 grading does not equate with yesterday’s Gleason 3+3=6 score. Therefore, getting a second opinion on your pathology may provide a consensus and assurance regarding your diagnosis and, this may be a better option than getting an imperfect biomarker evaluation. Also, biomarker testing may not be approved by your insurance provider.
Post-Biopsy Prostate Cancer Tissue Biomarkers
Several genetic biomarker tests such as OncoType DX, Polaris, Decipher, ProMark, Confirm MDx, Mitomic and ProstaVysion are available, claiming to predict prostate cancer behavior for possible lethal potential. All are needle biopsy tissue-based and or, based upon postprostatectomy whole gland specimen tissue. The first three tests examine the activity of various genetic markers to try and predict biological potential while the ProMark uses an automated quantitative multiplex immunofluorescence method to measure the protein levels of 8 biomarkers directly on sections of prostate biopsy tissue. The biomarkers, attempt to predict whether the disease is truly indolent or has features interpreted as being more significant for possible upgrading or progression. The ConfirmMDx however, is a 3 gene methylation assay to detect an epigenetic field effect associated with the cancerization process at the DNA level. The Prostate Core Mitomic test can also identify a cancerization field by detecting mitochondrial DNA alterations in normal appearing tissue. Further, the ProstaVysion test attempts to provide a molecular analysis of prostate cancer biological potential through the pTEN/ERG biomarkers. The pTEN is a suppressor gene in prostate cancer and deletion of the pTEN occurs in 20-40% of localized prostate cancers. Also, the pTEN deletion is much higher in a Gleason 3 from a prostate with coexistent Gleason pattern 4. In addition, ERG gene fusion/translocations are found in 40% of prostate cancers so testing for both of these mechanisms may help predict prostate cancer aggressiveness.
Prostate Cancer Over-detection and Over-treatment
Prostate cancer remains as one of the most over-detected and over-treated cancers in healthcare mainly because of the prostate cancer industry’s disinformation programs such as “Prostate Cancer Awareness” and its many specious arguments for PSA-based screening to detect cancers which behave mostly as noncancerous. In fact one of the greatest healthcare dangers to men is to be treated for the common non health risk cancer like the Gleason 6 “cancer” with the toxic robotic prostatectomy and then be left with aftereffects worse than the disease itself. On the other hand, while the 15% or so of high-grade prostate cancers are a health-risk, potentially lethal, readily diagnosed and treated, some high volume Gleason 6 and some midgrade prostate cancers may benefit from biomarker evaluation before weighingup whether a treatment for some of these cancers could be beneficial. However, for the most part, prostate cancer biomarkers remain imperfect and may over or, underestimate risk. In addition, biomarkers appear to foster mainly the propaganda that most prostate cancers are a healthrisk and or, could progress to become a health-risk when the evidence is clear, not all cancers are equal and, most prostate cancers are not a health-risk since most behave as noncancerous.
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About Bert Vorstman MD, MS, FAAP, FRACS, FACS
Dr. Bert Vorstman is a Board Certified urological surgeon. Born to Dutch parents in Indonesia, he grew up in New Zealand. After training at the Otago Medical School in Dunedin, New Zealand he completed a urology residency at Auckland Hospital, Auckland, New Zealand. He Fellowship trained in Pediatric and Adult Reconstructive Urology at the Eastern Virginia Medical School in Norfolk, Virginia and, after NIH sponsored pioneering research on “Urinary Bladder Reinnervation”, he earned the honor of a Masters of Surgery Diploma from the University of Otago in 1988. Dr. Vorstman was a faculty member at the University of Miami, Jackson Memorial Hospital, Miami, Florida and then went on to found Florida Urological Associates, a busy urology practice in Coral Springs, Florida, USA.
Dr Vorstman’s passion and dedication is to help men and their spouses/partners understand fully the implications of their particular prostate cancer as well as the minimally invasive treatment options available in selected men with localized significant prostate cancer.
Dr Vorstman owns healthcare stock. He is the grandson of acclaimed Dutch author,
Amy Vorstman/Amy Groskampten Have.