PCA3 and a novel pre-biopsy nomogram

There has been hope in some quarters that the prostate cancer gene 3 or PCA3 test would provide data so helpful that we could dispense with the need for PSA testing at all. However, The “New” Prostate Cancer Infolink has long suspected — for a variety of reasons — that this would not be the case. The development of a new nomogram that incorporates PCA3 test results along with existing data now shows that the addition of PCA3 data provides only a small (albeit statistically significant) risk assessment benefit compared to data that are already available.

Chun et al. set out to design and construct a decision-making aid (a nomogram) based on pre-prostate biopsy data from a multi-institutional cohort of 809 patients, to investigate whether the urinary PCA3 assay improves prostate cancer risk assessment.

The authors report the following results from their study:

  • PCA3 is a statistically independent risk factor of prostate cancer at biopsy.
  • Addition of a PCA3 assay improved the predictive accuracy for a positive biopsy compared to the base model by between 2 and 5 percent.
  • The highest increment in predictive accuracy resulted from a PCA3 assay cut-off threshold of 17, where a 5 percent gain in predictive accuracy was recorded, but this increase in predictive accuracy was only just statistically significant (p = 0.04).
  • Other analyses further corroborate the superiority of the PCA3 nomogram over the base model.

The authors conclude that the PCA3 test fulfills the criteria for a novel marker capable of increasing the predictive accuracy of multivariate biopsy models. They also claim that their novel PCA3-based nomogram better identifies men at risk of harboring prostate cancer and assists in deciding whether further evaluation is necessary.

However, The “New” Prostate Cancer InfoLink would like to see greater clarity over the type of risk that is being “better identified” — and in which patients. If the PCA3 test becomes used as an excuse to carry out saturation biopsies in even more men over the age of 65, who are then found to have tiny amounts of pathological disease with a high likelihood of indolence, is this data really helpful to patients in the long term? By contrast, if the PCA3 test can be helpful in identifying risk for prostate cancer that is likely to become clinically significant early in younger men, who can then receive lower risk forms of treatment if needed — but with curative intent, there may certainly be a higher value to the use of test.

We assume that this new nomogram still needs to be validated using an independent (probably European) data set, and the value of this nomogram in the USA is moot at this point because the PCA3 test is not yet approved in this country.

7 Responses

  1. We have used the PCA3 score in our clinic practice based in Windsor, UK. Like any test, the PCA3 score has to assessed in the context of other available risk factors. I have found it especially useful in patients who have either very small or large prostates, and in men with inflammation in the prostate.

    In men with small prostates, they may be reassured inappropriately because the PSA is supposedly low, but this is so because there is no BPH to support the PSA made by the cancer. In men with large prostates, the PSA may be high because of BPH and they may have quite indolent cancers. Clearly in men with a urinary infection, the PSA can be high for inflammatory reasons alone, and the PCA3 is far less affected or not affected at all, unlike PSA.

    When looking at the value of tests, ROC curves are often used, and these reflect the value overall. However, tests are often relevant in specific situations only and not others. The small difference quoted above does not reflect the clinical situation. The PCA3 in my opinion is a valuable new tool for us to predict which men are at risk of prostate cancer and, possibly, which men may have serious prostate cancer in whom an intervention at the appropriate time may improve their quality of life for the long term.

  2. Dear Dr. Lanaido:

    Thank you for these insights, which are helpful. Part of the problem to date has been “expectation management” with respect to the real utility of the PCA3 test. One might describe the situation here in America as one in which there has been an “over promise” about the potential of the PCA3 test and then “under delivery” against that promise.

    Patients need clearer guidelines about what should be expected from the PCA3 test. Your comments help to “improve expectations.”

    For the benefit of other readers, a receiver operating characteristic (ROC) curve is a graphical plot of the sensitivity of a specific test vs. (1 – the specificity of that test). Those who wish to get into the details of what ROC curves show, and how, are referred to the discussion of ROC curves on Wikipedia. (Be warned … it’s complicated!)

  3. A “Beyond the Abstract” commentary on the original paper has just been published on the UroToday web site by Dr. Felix Chun (the lead author of the original paper).

    Dr. Chun himself makes the point in this commentary that we have a way to go before we fully appreciate the best application of PCA3 testing.

  4. “By contrast, if the PCA3 test can be helpful in identifying risk for prostate cancer that is likely to become clinically significant early in younger men, who can then receive lower risk forms of treatment if needed — but with curative intent, there may certainly be a higher value to the use of test.”

    How do I fit the above in with the advice that you’ve given about the negative biopsies? How do we know which diagnostic results to take seriously and which to dismiss?

  5. Tracy:

    The truth is that I don’t think anyone really knows yet how best to apply PCA3 data to individual patients. It is one thing to be able to show probabilities based on large numbers of very varied patients. It is quite another to be able to apply such data with predictive accuracy to a single individual when a test doesn’t give a “black or white” result.

    As I see it, at the present time, your husband has had two biopsies and they have both been negative. His PSA is elevated, and he has had one potentially significant PCA3 result. Yes?

    The question I think you both want to ask yourselves is, “What are you going to do if he has the saturation biopsy and you find 1/36 cores positive for cancer with Gleason grade 6 and (say) 1 mm of cancer in the positive core?” (That’s about as minimal a cancer as one might find on biopsy.) I can tell you that many, many men of your husband’s age probably have such cancer in their prostates, and it is probably clinically insignificant in as many as half of those men. We know this from autopsy studies. It doesn’t mean it might not become clinically significant in 10 years time. It might well do that. But what would you do now if you got the biopsy result I describe? He could have treatment and recover completely, or he could have treatment and not recover completely, or you could decide to defer treatment by using active surveillance — and regardless of everything else, you are still going to have to make that decision whatever type of treatment he might have. At the end of the day, this is about making some really hard choices between one’s normal desire to live forever and one’s less normal desire to live as well as one can for as long as one has. I would choose the latter, but I can’t choose for you. These are hard, hard choices.

  6. Mike, I really do get “it.” I suspect that what we’re going to find is pretty much what you just described (and I also appreciate the news could be much, much worse). But if it’s significant in 10 years, he’ll still only be 54. Do we run the risk of an untimely death at 60 or 65 (with the last half decade to decade of his life cancer-treatment hell)? Or does he get treatment now and run the very real risk of “side” effects that greatly diminish the joys of our day-in-day-out lives?

    Or does he engage in active surveillance until he either has to pursue treatment such as it is and hope for the best? Or does he engage in active surveillance paying close attention to improvements in treatment, and treat it when they get better at minimizing side effects?

    His doctor is actually one of the folks working on focal surgical ablation. That is the one focal therapy that seems to make any sense to me. Other focal therapies don’t seem to be any better in the long run in terms of the “side” effects we’re trying to avoid …. So, why do radiation, HIFU/cryo, etc., if he’s going to end up impotent in the long run from them anyway, but they’re less effective as a potential “cure”?

    I earn a living doing research and trying to convince policymakers to use “evidence-based” practices and to use research to inform policy decisions. The quality of research available to inform our decision-making in this situation is just plain old unsatisfactory — deeply, deeply unsatisfactory.

    I don’t expect my husband to live forever, but I’m still hopeful that he’ll get a life expectancy consistent with the average of the cohort of men of his generation. I’m willing to put my shoulder towards moving heaven and earth to get him there. I need a lot more bad news than we’ve gotten to date to just step back and do nothing.

    And by the way, prostate cancer isn’t the only health condition that causes ED. My husband and I have been married only 5 years. I spent 15 years in a relationship with someone who turned out to have a (long undiagnosed) pituitary tumor that pretty much destroyed testosterone production. Sexless relationships are terrible for everyone involved. So, it’s not imagined, unrealized fear driving my anxiety. I’ve lived the emotional and physical cost of not having the interest or ability to be in an intimate physical relationship. The toll extends far beyond the bedroom.

    I get it that in this situation, NOW is the time we have to confront and try to affect this issue. If we wait, the likelihood of not being able to affect a negative outcome is much higher.

    Thank you for your kind words and insights,


  7. Tracy:

    See also the long message that Terry Herbert has left you on the saturation biopsies page. The only thing that I thing both of us are trying to tell you is that you just cannot yet apply the pricinciples of “evidence-based” science to individual decisions about prostate cancer diagnosis and management. We can tell you statistical probabilities, but those probabilities aren’t usually good evidence when it comes to individuals because there is still no good way to differentiate aggressive and clinically significant prostate cancer from indolent disease in the very early stages.

    You wrote, “Or does he engage in active surveillance until he either has to pursue treatment such as it is and hope for the best? Or does he engage in active surveillance paying close attention to improvements in treatment, and treat it when they get better at minimizing side effects?” My answer to that is that he does both at the same time, but it is his and your mindset in doing this that will be important. I believe you need the mindset of an athlete who has been told that (s)he has a weakened joint that may affect his/her career. The athlete is aware of the problem and shouldn’t do anything totally stupid that will have a high probability of further affecting the problem (an example in your husband’s case would be to start taking massive doses of testosterone or similar steroids). However, for the athlete to perform at the highest level and succeed in his/her career, (s)he cannot go into every event thinking about risks to the joint, (s)he has to just accept that the joint might get affected by something and live with that as background noise.

    If I was in your husband’s situation, I would get a PSA test every 3 months (abstaining from intercourse for 48 hours beforehand), and I would get a 12-core biopsy once a year if I and my doctor thought it was necessary. And I would tell you that I loved you and I appreciated that you would go on monitoring the prostate cancer literature to see if better knowledge became available, but that we needed to accept the current realities of poor evidence and just get on with life.

    You know that I know you have a very good doctor who you are working with. He will help you as best he can, but there is only so much that he can do given the current state of medical science. Medicine really is an “art” first and science second. That is why it is always better to think in terms of “managing” a patient and his/her condition (i.e., the whole patient) than in terms of treating a specific condition.

    I had long suspected that there was another factor driving your concern about the loss of intimacy. You have explained that above. It is part of the “whole patient” situation. You, your husband, and your doctor need to be addressing that concern very directly in “managing” a set of signs and symptoms that suggest the possibility of prostate cancer but very definitely include fear of loss of the intimacy you cherish a great deal because you had to go without it for so long.

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