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PCA3 test: success story from laboratory to market place

Interview with Professor Jack Schalken of the Radboud University, Nijmegen (NL)

The number of prostate cancer cases is increasing rapidly. Fortunately not all these tumours need to be operated - some are slow-growing or indolent. The question remains: how do we reliably establish which tumour is aggressive and which is not? The answer may well be given by the PCA3 (Prostate Cancer Gene 3) test, commercially available for over a year now.

The genetic test was developed in the laboratory of the Radboud University in Nijmegen (NL) by a team headed by Professor Jack Schalken (see photo).

For those of you who do not know (or choose to forget…) what the prostate is and where it is located: it is an exocrine gland of the male reproductive system. It surrounds the urethra just below the urinary bladder. The prostate’s main function is to store and secrete a clear fluid that feeds and transports the spermatozoa; together they constitute semen. A healthy human prostate is slightly larger than a walnut.

Currently the early detection of prostate cancer (PCa) relies primarily on digital rectal examination (DRE) of the prostate and the prostate specific antigen (PSA) concentration in the blood. The outcome of both tests can result in a prostate biopsy to confirm the diagnosis of PCa. Each of these three measures has shortfalls that contribute to an increasing number of unnecessary biopsies, which are unpleasant for the patient. PCA3 (Prostate CAncer gene 3) is a new tool available in a simple urine test to help make better biopsy decisions in the diagnosis of PCa. It is available as the PROGENSA™ PCA3 assay in Europe. The PCA3 assay is the first gene-based diagnostic test to help solve the current challenges associated with the diagnosis of PCa.

The PCA3 gene was discovered by Dr. Marion Bussemakers while working with Jack Schalken at the University of Nijmegen (NL) and in the laboratory of Dr. William Isaacs at Johns Hopkins University in Baltimore (US). They discovered that the PCA3 gene is highly dominant in more than 95% of PCa tissue compared to normal or benign (i.e. non-malignant) prostate tissue of the same patients. In contrast to serum PSA, PCA3 is not only prostate-specific, but also PCa-specific. Prostate volume does not affect the PCA3 assay result, as is the case with PSA tests.

Professor Schalken spoke about the potential of PCA3 and his expectations.

Q: The PCA3 test means a breakthrough in the diagnosis of prostate cancer, since it is more specific for aggressive tumours. How much more specific is it?

Professor Schalken: “PSA is commonly elevated for reasons not related to cancer. As a result, PSA testing produces many 'false positive' results, which can lead to uncomfortable, expensive biopsies that ultimately prove unnecessary”. The PCA3 test has a specificity of over 80%, while the specificity of PSA testing is 25%. The PSA test is not at all selective for aggressive cancers while the cancers PCA3 detects are aggressive in 85% of cases.” It is also a sensitive test. The tumours that were missed had a Gleason score of 6 or less(a score which is given to prostate cancer based upon its microscopic appearance; cancers with a higher Gleason score are more aggressive and have a worse prognosis). 10 % of missed cancers had a score of 7 and were still fairly small. The test would probably have picked them up at a later stage. The final answer – is the PCA3 test an improvement for screening for prostate cancer - will have to come from an ongoing study. At the moment a screening study is being done in Rotterdam to compare the value of PCA3 tests with PSA tests. The results should be published in 2009.

Q: Will the PCA3 test be further refined or developed?

“No, the test is fully developed. ‘PCA3 has left the building’, i.e. our lab, a few years ago. It can, however, be the basis for a marker panel. Tumour markers are chemical substances that are produced by some cancers. Most of these substances can be found in the urine or bloodstream in small amounts even when cancer is not present. When cancers produce these substances, they are usually produced in very large amounts. In the next 2 to 3 years, additional markers will be added that give more information about the presence of a significant cancer”. “Molecular testing is going through revolutionary developments. In 5 years’ time, PCA3 testing may well be available as a point-of-care test, which means it can be done as a bedside test. This will have an enormous impact on the logistics and efficiency of any clinic; the patient comes in, gives urine and shortly after that you know the PCA3 value. The team can then immediately decide which treatment to offer the patient”, says Professor Schalken.

Q: What does the PCA3 test mean for the doctor’s daily practice?

“We will be able to change to a more rational biopsy schedule. It is a first small step towards more individualized medicine.At present it is standard practice to take another biopsy when a patient has had a negative biopsy but a positive test and not to take another biopsy when the patient had a negative biopsy and a negative test. But when the biopsy is negative and the PCA3 is very high, the patient may well have a potentially lethal cancer. This will lead to more imaging ((contrast enhanced) MRI, magnetic resonance spectroscopy, PET scan etc). That way cancers that are located in the ventral part of the prostate may be discovered and you can save lives. At the moment the use of PCA3 in active surveillance and screening is investigated. Therefore the place in the doctor’s daily practice could well expand to other indication areas.”

Q: Why was the promotion low key? After all, the PCA3 test is already on the market for a while.

”I believe the urologist should be informed first. This is a new and rather complex tool which should remain in the hands of experts for at least the first few years”. “There are 8 labs specialised in molecular diagnostics in Europe that provide this test; Noviogendix, the laboratory that performs the test in the Netherlands, is one of them. The tests are rather expensive and it takes qualified personnel to perform them. Thus, for reasons of quality, efficiency and costs it is best to have these tests done in specialised laboratories. I am convinced that this is the future for advanced diagnostics.”

Q: What do you expect from this publicity with regard to patients?

“The patient will no doubt actively seek PCA3 testing. The more the patient is aware of the uncertainties surrounding the diagnosis prostate cancer (a high PSA score does not necessarily mean prostate cancer but a low score does not give any guarantees either), the more a test that gives more certainty is welcomed. Patients will definitely try to avoid having to undergo a biopsy when it is unnecessary. Perhaps in time, the general practitioner (GP) will request a PCA3 test. The GP now refers a patient to the urologist based on an elevated PSA score, while he knows that in many cases treatment is not needed.”

Q: Doctors demand and sometimes invent new diagnostic methods. What is the influence of commercial companies, and where do they come in?

Schalken: “They play a pivotal role. In Nijmegen we have a translational research programme so we can bring the science that we develop in the laboratory to the bedside of the patient. We develop research tests; to turn them into a commercially viable product requires unique skills and expertise. In the case of the PCA3 test, it costs about $20-30 million to develop it into a test you can sell. Universities do not have the money, expertise or skills needed for production under Good Manufacturing Practice conditions, etc. Thus, a company is necessary.”

Q: Do you think this type of testing should be part of the national healthcare systems? Is it reimbursed at the moment?

“Reimbursement is an issue; it is different in every European country. However I am convinced that this is transient. The value of the test is such that it will get a place in the diagnostics reimbursement system. We should lobby more, both in Brussels and in local countries, to inform politicians of how important diagnostics can be. Less than 2% of the overall healthcare budget is spent on laboratory diagnostics, which is why people are less concerned about it. Diagnostics can, however, have a vast impact on treatment.” “One of the best examples is the HER2 test for breast cancer. It is only useful to give expensive therapy if the patient shows a dominant HER2 gene. This is crucial for healthcare programmes even though it is in conflict with the interests of pharmaceutical companies; they will sell less. The European Association of Urology (EAU), the urologists’ professional organisation, should develop a strategy in various countries to bring this conflict to the attention of healthcare providers. The EAU Research Foundation is already taking up the challenge. And PCA3 could lead the way here.”

For more information, please contact:

European Association of Urology Att. Ms. Lindy Brouwer l.brouwer@uroweb.org