Rising PSA After Negative Prostate Biopsy Part II: Can PCA3 Prevent Unnecessary Biopsies?

In my last post I discussed some PSA based tools that can be used to determine whether a rising PSA is due to prostate cancer or to other causes.  Such tools are very important because repeat biopsies for men with rising PSAs are positive for cancer in only 10-30% of cases, depending on how many biopsies are performed.  The yield (chance of cancer found) is less and less for every subsequent biopsy performed.  As a result, 70-90% of men may be undergoing these biopsies unnecessarily.  The problem with performing all of these repeat biopsies, aside from the pain and discomfort, is that they are not without risk (some more information about what to expect from prostate biopsies can be found in this previous post).  Unfortunately, the PSA tools I described, while helpful, are far from perfect.  The problem with these tests stems back to the basic problem with PSA: it is not only produced by prostate cancer but by normal prostate tissue.  As a result, PSA tests can be falsely elevated by other factors like infections, large prostates, and having sex.  Due to this limitation, PSA and PSA based tools can often overestimate the risk of prostate cancer in men with previously negative biopsies.  This, in turn, can lead to many unnecessary biopsies in men without prostate cancer.  Fortunately, a new test has recently been approved that may help determine which men really need to undergo a repeat biopsy in response to a rising PSA.  This test, called PCA3, may significantly decrease the need for repeat biopsies in select men with rising PSAs.  In this post, I will explain what PCA3 is, why it may be more informative than PSA, and how it may be used to prevent unnecessary biopsies.

What is PCA3?

Lets first discuss what PCA3 actually is.  PCA3 is a gene found within the DNA of human cells.  Like other genes, PCA3 serves as a code to produce a type of protein called mRNA.  It turns out that prostate cancer cells produce over 60 times more of the PCA3 mRNA than normal prostate cells.  In addition, no other tissue type in the human body produces this mRNA either.  Identifying this very prostate cancer specific protein, scientists then developed a test to identify and quantify it in men.  Unlike PSA, the PCA3 test is actually a urine, rather than blood, based test.  The test begins with a “prostate massage” by the physician.  Basically, this is a vigorous prostate exam that lasts for a few more seconds than a routine rectal exam.  After this exam, the patient then urinates and the urine is analyzed to look for and quantify the amount of PCA3.  The idea here is that the prostate exam causes the prostate to secrete the PCA3 protein into the urine, which can then be collected for quantification.

How is PCA3 better than PSA?

As I mentioned earlier, the major flaw of PSA is that it is not specific enough for prostate cancer.  In other words, way too many other things can cause PSA elevation aside from just prostate cancer.  PCA3, in contrast, is very specific for prostate cancer.  Neither infection nor sexual intercourse elevate PCA3.  In addition, unlike PSA, PCA3 is not proportional to the size of the prostate.  In other words, larger prostates do not produce more PCA3.  Finally, even urological procedures like prostate biopsies and cystoscopies, notorious for raising PSA, have no effect on PCA3.  I am sure that you are now starting to see the beauty of this new test.  Because it is so specific for prostate cancer, it may be able to prevent the unnecessary pain and risk of repeat biopsies in men with rising PSAs.  Lets see how this theoretical advantage pans out in practice.

PCA3 and the Prostate Biopsy Decision

Numerous studies have evaluated the utility of PCA3 in predicting prostate cancer.  One study evaluated the accuracy of PCA3 in predicting the extent and significance of prostate cancer.  The study obtained PCA3 tests from men with known prostate cancer about to undergo radical prostatectomy and then correlated the PCA3 level with the pathology findings from the surgery.  The study reported some very encouraging findings.  First, the study found that men with small amounts of cancer demonstrated significantly lower PCA3 values than those with large cancer volumes (PCA3 scores of 17 versus 47, respectively).  The study similarly found that men with insignificant or low risk prostate cancer also demonstrated substantially lower PCA3 scores than their counterparts with more substantial prostate cancer (PCA3 scores of 16 versus 45, respectively).

While PCA3 has, thus, been demonstrated to be a good predictor of significant prostate cancer, can this new test help predict the presence of prostate cancer and the need for prostate biopsy in men with a rising PSA after a previously negative biopsy?  Several studies have done just that.  A small study of 51 men, for example, performed a PCA3 test on men with a negative prostate biopsy who then underwent  a repeat biopsy for a further rising PSA.  The study reported that men with a positive repeat biopsy demonstrated substantially higher PCA3 values (median 50) as compared to those men with negative repeat biopsy (median 28).  A substantially larger study of over 1100 men undergoing repeat biopsies demonstrated a similar discrepancy of PCA3 values of 34 versus 17 for men with positive versus negative repeat biopsies, respectively.  This large study also reported that men with a PCA3 level greater than 35 had twice the risk of a positive biopsy as compared to those men with PCA3 less than 35.  Given this ability of PCA3 to differentiate prostate cancer from other causes of rising PSA, another study of 127 men reported that the PCA3 test can help avoid up to 73% of unnecessary repeat biopsies. 

Is there a downside to PCA3?

The main downside to PCA3 appears to be the lack of an accepted, definitive cutoff point above which the presence of prostate cancer is nearly certain.  While higher values of PCA3 are certainly more indicative of prostate cancer than lower values, there is no single magic number that can serve as a cutoff.  Numerous studies have used 35 as such a cutoff but with mixed results.  For example, one study evaluated using 35 as the PCA3 cutoff.  The study demonstrated that if only men with PCA3 over 35 were biopsied, 85% of previously undiagnosed prostate cancers would be detected while avoiding 50% of unnecessary, repeat negative biopsies in men without cancer present.  The study demonstrated that if a PCA3 cutoff of 44 is used to trigger a repeat biopsy, in contrast, only 75% of previously undiagnosed cancers would be detected while avoiding 73% of unnecessary, repeat negative biopsies. Still other studies have argued for lower cutoffs (such as 15 or 25), which identify larger percentages of previously undiagnosed cancers (95%) for the tradeoff of substantially more unnecessary biopsies.  So what is the magic number?  Is it more important to identify more cancers or prevent more unnecessary biopsies?  That is the million dollar question that is still being debated.  That is also a drawback of the test.

Take Home Message

For many years, urologists have been looking for a noninvasive test that can reliably predict the presence of prostate cancer in men with a rising PSA and a negative previous prostate biopsy. A rising PSA can often be misleading as its rise can be triggered by factors not related to prostate cancer such as an enlarging prostate, urinary tract infection, or even sexual intercourse.  A test was needed that can eliminate such extrinsic factors to determine if a man really does need a repeat biopsy or if he can safely avoid the risks and discomfort of this procedure. 

In many respects, PCA3 seems to be just such a test. It is only produced by prostate cancer and, so, is not affected by extrinsic factors.  It is fairly easy to obtain if you discount the discomfort of a “vigorous” rectal exam.  It appears to differentiate significant from relatively innocuous prostate cancer.  And it has been demonstrated through numerous studies to significantly reduce the number of unnecessary prostate biopsies while not substantially decreasing the ability to identify prostate cancer.  Is PCA3 the holy grail of prostate cancer diagnosis?  Of course not.  Is it without its limitations?  No.  However, it appears to be a valuable tool to be used in conjunction with the PSA tools I previously discussed to reliably determine which men really need a repeat prostate biopsy and which can avoid the risk and discomfort of a repeat procedure.

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This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician