Old and newer tests and risks for prostate cancer; can you avoid inappropriate biopsy?

We now have five approved tests that can (at least in theory) help a man — and his doctors — to decide whether he is at sufficient risk for clinically significant prostate cancer that he should go get a biopsy. But how good are they really?

The first and oldest of these tests is the standard PSA test (based on serum levels of PSA in blood samples). All this test can really do is tell you and your doctor a number that, in a man with an intact prostate, might be anywhere between about 0.5 and > 1,000 ng/ml. If it is down around 0.5 ng/ml, then the chances are high (but not 100 percent) that you don’t have clinically significant prostate cancer. If it’s > 100 ng/ml, there a very strong likelihood that you do (and it may well be metastatic). There is no known PSA value, on its own, that can tell you you need a biopsy. However, if you are 55 to 70 years of age, the Prostate Cancer Prevention Trial or PCPT calculator can use PSA and other data to give you an estimate of likelihood that: (a) you have a Gleason score of 6 or less; (b) you have a Gleason score of 7 or more; (c) that the biopsy will be negative.

The second test is the percent free (%Free) PSA test (also based on serum PSA levels in blood samples). This can be helpful in trying to distinguish between risk for prostate cancer and risk for benign prostatic hyperplasia in a man with a PSA in the range from about 4 to about 10 ng/ml, a negative digital rectal exam, and no other clear indications of risk. The lower the %Free PSA level, the higher the potential risk for prostate cancer … but you can’t take these results as providing levels of “absolute truth.” men with low %Free PSA levels (e.g., 10 percent) have been found to have no sign of cancer and men with relatively higher PSA levels (> 25 percent) have been found to have prostate cancer on biopsy.

The third test is the PCA3 test — a test that is based on the presence of a biochemical known as prostate cancer antigen 3 in urine specimens taken after a “vigorous” digital rectal exam. Although the PCA3 test is generally considered to be “positive” for risk of prostate cancer if the PCA3 value is 35 or higher, it is also well known that prostate cancer can be found in men with lower PCA3 levels (down into the 20s) and not found in men with PCA3 levels of > 100.

More recently, Becton Dickenson gained approval to market the Prostate Health Index or phi test. This test uses a mathematical formula that combines total PSA, free PSA, and [-2]proPSA data to provide a Prostate Health Index level. In clinical trials among men with a standard PSA level between 2 and 10 ng/ml, the average (mean) phi scores were 34 for men who went on to have negative biopsies and 49 for men who went on to have positive biopsies, respectively. However, the chances of a false negative result or a false positive result from a phi test followed by a biopsy in individual patients are not well defined as yet. When used in significant numbers of patients, it is clear that this test can be used to reduce the total number of patients for who biopsy is recommended. But what we don’t know is how to interpret a phi test accurately in an individual patient … as with the three prior tests, all one gets is a set of probabilities.

And most recently of all we have the 4Kscore Test. According to the presentation by Lin et al. at the American Urological Association meeting in Orlando last week, the 4Kscore Test is able to give a more accurate prediction of risk for a Gleason score of 7 or higher on biopsy than the PCPT calculator. From that perspective it is (arguably) the most precise we have today for estimating the value of a biopsy. And the data on which this test has been assessed are, indeed, prospective data. In other words, all patients got a standard PSA test and a 4Kscore Test prior to having a biopsy. As with the phi test, when used in significant numbers of patients, this test can be used to reduce the total number of patients for who biopsy is recommended. However, again, we don’t yet know the chances of a false negative result or a false positive result from a 4Kscore test followed by a biopsy in any individual patient.

As a consequence, there is no way (yet) that anyone can tell any individual patient, with a very high degree of probability, that they should or shouldn’t have a biopsy any better than the probabilities based on their PSA level and the PCPT calculator. On the other hand, there is a different way to look at this.

If you are between 55 and 75 years of age, and you have a standard PSA test, and a repeat PSA test a month or two later, and then a phi test, and a 4Kscore test, and all four sets of data (combined with the data from the PCPT calculator in the case of the two PSA tests) all are strongly suggestive of risk for a Gleason score of 7 or higher on biopsy, then you would probably be wise to have that biopsy — and relatively soon. What we can not tell you yet is what happens if the phi test says “you need a biopsy” and the 4Kscore Test says “you almost certainly have low-risk disease with a Gleason score of 6 or less.” Then what do you want to do?

And on top of all of that, there is the question of the value of a multi-parametric MRI scan.

The “obvious” thing that needs to be done here is to run a prospective study in which 1,000+ men who are scheduled for biopsy on the basis of a total PSA test alone (i.e., symptom-free men with a negative digital rectal exam, and a PSA level of between, say, 2.5 and 15 ng/ml) are all given a repeat PSA test, a phi test, a 4Kscore test (which could all be run from blood drawn at a single sitting), and a multi-parametric MRI.  The tests could then be followed by a systematic, TRUS-guided, 12-core biopsy and an MRI/TRUS fusion-guided biopsy.

The data from such a trial ought to be able to give us some really great guidance about the relative accuracies of all of these potential strategies. Of course getting everyone to collaborate on the design and implementation of such a trial might be a much harder thing to accomplish than actually doing the study and analyzing the results.

5 Responses

  1. Nice post.

  2. I totally agree with the approach of exhausting all available tests before going through a biopsy. Unfortunately, the insurance company may not agree that all these tests are needed.

  3. The UK government-funded PROMIS trial should provide the information that we need. It is the very design — and probably more robust — that you were suggesting. We are recruiting well and about one-third of the way there for a target of about 700.

    Prostate Cancer UK is funding the associated biobank of blood and urine that will form a valuable resource for future use as well as attempting to validate existing biomarkers.

  4. I would like to meet the individuals that would submit to the full battery of tests suggested that include two invasive biopsies. Men are going through the same brutal invasion that women have endured for the years of breast cancer experimentation. From biopsies to “preventive mastectomies”. Truly, “the love of money is the root of all evil”! How many agencies and medical “associations” are needed to reach a conclusive decision? Does Hippocratic oath ever jingle a nerve?

  5. What does one do if one does not have known prostate cancer and there is a significant rise in the total PSA that has been double checked?

    One needs to sort this observation out and make sure one does not have prostate cancer. There could be other non-cancerous causes of the PSA elevation. But remember, once prostate cancer leaves the prostate, there is no cure for it. Also, more information has been forthcoming that prostate cancer looking low-risk initially can be more aggressive on closer examination (post-RP). There is now the Polaris [and other] genetic tests available that can be done on the prostate biopsy specimen to see if this prostate cancer is a potentially lethal one.

    Based on the available info from all the latest meetings, the steps one should take next are not a big mystery.

    The first thing one might consider is getting an estimate of the actual size of the prostate to calculate the prostate density by TRUS or MRI. If the PSA density is > 0.12 or 0.15 (depending on who you talk to), you might want to proceed to step 2. Even if the PSA density is < 0.12, prostate cancer is not excluded, so you might still want to proceed with step 2, particularly if there are significant risk factors, such as a positive FH, a family history of BRCA1/2-positive genetics, race, etc.

    Step 2 would be to go to a center that specializes in 3-T multiparametric MRI (mpMRI) of the prostate and MRI-guided prostate biopsy, and see if any thing suspicious shows up on the mpMRI. If there are one or more suspicious areas, then the thing to do would be to get a MRI-guided biopsy of these suspicious areas plus have random prostate biopsies at the same time. It is as simple as that.

    If one does not have an mpMRI and MRI-guided biopsy available, the next best thing to do would be to let them go ahead with a blind, 12-core TRUS biopsy, but insist on additional cores samples of the anterior prostate. This will require a longer needle, as normally the 12-core TRUS biopsy does not sample the anterior prostate. If the urologist is not able to do this extended TRUS biopsy with anterior prostate sampling, then a person needs to find a urologist that can do this sampling. It is as simple as that.

    Make sure you and the doctor doing the biopsy work together do everything possible to prevent a biopsy-related infection. You can search online for different ideas on what that might include, such as pre-biopsy rectal culture for ciprofloxacin-resistant organisms, when to actually start the pre-biopsy ciprofloxacin and for long after, special enema preps, parental antibiotics just before the biopsy, etc.

    Good luck!

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