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CAP Home > CAP Reference Resources and Publications > CAP TODAY > CAP TODAY 2009 Archive > Letters for November 2009
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November 2009

Prostate cancer biomarkers Prostate cancer biomarkers

Discovery and validation of new prostate cancer biomarkers is always a subject of considerable interest. In the informative report by William Check, PhD, in the June 2009 issue, a few novel candidate prostate cancer biomarkers are described (“New prostate markers waiting in the wings,” page 1). I would like to comment on the prostate cancer biomarker EPCA-2 discovered by Robert Getzenberg, PhD, and his colleagues. Their original paper was published in Urology (2007;69:714–720). Close examination of this paper reveals methodological and interpretative shortcomings, which were described in my letter to the editor of Urology soon after the paper was published. The editor, Alan Partin, MD, who was a co-author of this paper, withheld my letter for many months and, after repeated requests for a decision, informed me that he will publish my letter with a response from the authors. To date, he has not published my letter or a response. I then chose to publish a “Point” in Clinical Biochemistry on EPCA-2 (2007;40:1437–1439). Dr. Getzenberg’s group was invited to write a “Counter-point” but declined.

Dr. Getzenberg continues to advocate that EPCA-2 is a promising biomarker for prostate cancer. But how would the reader know if this test is really effective, as described in your report?

Highly promising biomarkers for cancer can now be validated effectively, and in a blinded fashion, through the Early Detection Research Network, or EDRN, of the National Cancer Institute. This organization is keen to validate promising cancer biomarkers, like EPCA-2, and provides all the necessary resources for such validation, including high-quality samples, blinded testing, and expert data interpretation. In fact, recently, a validation study of many candidate prostate cancer biomarkers has been conducted by the EDRN under the leadership of Daniel W. Chan, PhD (also from Johns Hopkins University and a co-author of Dr. Getzenberg’s paper), but EPCA-2 was not included, giving the impression that Dr. Getzenberg wishes to avoid a blinded and independent validation of his prostate cancer biomarker.

The scientific community needs better ways to establish if certain technologies that promise to revolutionize the practice of medicine really work. In therapeutics we have randomized controlled trials. For diagnostics, on many occasions, investigators appear to be more interested in getting publicity in newspapers and other informative publications such as CAP TODAY and less keen to subject their discoveries to rigorous validation by independent bodies to find out their actual performance. Others recently questioned the effectiveness of EPCA-2 (http://chronicle.com/article/Company-Says-Research-It/48319/ and http://contract. law360.com/articles/120488).

I conclude that EPCA-2 needs independent validation before it is considered a prostate cancer biomarker.

Science, in my view, should be argued not through letters or editorials but with data. At the same time, there are a number of factual inaccuracies in the letter Dr. Diamandis has written to CAP TODAY. He appears to have a personal bias against us and our work and has chosen to misrepresent facts to make a point that is, at best, speculative. Among the inaccuracies are the following: ? The letter submitted to Urology was not handled by Dr. Partin. Since he was an author of our manuscript, he recused himself and had the newly appointed editor of the journal make a decision about the letter. My understanding was that this letter was rejected for lacking scientific merit. Essentially the same letter was rejected by another international journal for the same reasons. ? The letter was later published in Clinical Biochemistry. Dr. Diamandis serves on the editorial board of this journal. To date, we never received a communication about his letter from this journal or anyone affiliated with it. We were not offered an opportunity to produce a “Counter-point.” ? Dr. Diamandis is unfamiliar with our studies and is not qualified to comment on their status. We have and continue to work with the EDRN in the testing of our biomarkers. Dr. Diamandis is also not aware of other serum biomarkers that use the same scientific backbone as EPCA-2. Investigation of these biomarkers is ongoing in our lab. For example, we have been able to identify colon cancer serum biomarkers (CCSA-2, CCSA-3, and CCSA-4) that have been reported in Cancer Research (2007;67:5600–5605) and Clinical Cancer Research (2008;14:1349–1354). One of these markers, CCSA-2, was recently validated independently by a group in Germany, and the findings were published in the Journal of Cellular Biochemistry (2008;104:286–294). This group recently completed the analysis of a blinded sample set and is now preparing the work for publication. In addition, we have successfully validated another colon cancer serum marker, CCSA-4, using a set of blinded samples provided by our collaborators at the University of Pittsburgh (results not yet published), and we recently completed the analysis of a set of blinded samples provided by the EDRN for CCSA-2 expression. We are now awaiting the results of this EDRN blinded study. Despite the relatively large sample sets that have been analyzed, we have continued to indicate that our findings regarding these serum biomarkers, including EPCA-2, are still at the proof-of-principle stage. As Dr. Diamandis is aware, developing and evaluating cancer biomarkers is a long process. In fact, with the exception of urine-based PCA-3, the other markers Dr. Check reported on in the June 2009 issue of CAP TODAY are at a similar stage as ours. We are not interested in publicity but only in bringing technologies forward that can help the many men suffering from prostate cancer. To this we have dedicated our lives. Ultimately, the science will speak for itself.

Eleftherios P. Diamandis, MD, PhD
Head of Clinical Biochemistry
Mount Sinai Hospital and University Health Network
Professor and Head
Division of Clinical Biochemistry
Department of Laboratory Medicine and Pathobiology
University of Toronto

Robert H. Getzenberg, PhD, Donald S. Coffey professor of urology and director of urology research in the Brady Urological Institute, Johns Hopkins Hospital, replies:

Science, in my view, should be argued not through letters or editorials but with data. At the same time, there are a number of factual inaccuracies in the letter Dr. Diamandis has written to CAP TODAY. He appears to have a personal bias against us and our work and has chosen to misrepresent facts to make a point that is, at best, speculative. Among the inaccuracies are the following:

  • The letter submitted to Urology was not handled by Dr. Partin. Since he was an author of our manuscript, he recused himself and had the newly appointed editor of the journal make a decision about the letter. My understanding was that this letter was rejected for lacking scientific merit. Essentially the same letter was rejected by another international journal for the same reasons.
  • The letter was later published in Clinical Biochemistry. Dr. Diamandis serves on the editorial board of this journal. To date, we never received a communication about his letter from this journal or anyone affiliated with it. We were not offered an opportunity to produce a “Counter-point.”
  • Dr. Diamandis is unfamiliar with our studies and is not qualified to comment on their status. We have and continue to work with the EDRN in the testing of our biomarkers.

Dr. Diamandis is also not aware of other serum biomarkers that use the same scientific backbone as EPCA-2. Investigation of these biomarkers is ongoing in our lab. For example, we have been able to identify colon cancer serum biomarkers (CCSA-2, CCSA-3, and CCSA-4) that have been reported in Cancer Research (2007;67:5600–5605) and Clinical Cancer Research (2008;14:1349–1354). One of these markers, CCSA-2, was recently validated independently by a group in Germany, and the findings were published in the Journal of Cellular Biochemistry (2008;104:286–294). This group recently completed the analysis of a blinded sample set and is now preparing the work for publication. In addition, we have successfully validated another colon cancer serum marker, CCSA-4, using a set of blinded samples provided by our collaborators at the University of Pittsburgh (results not yet published), and we recently completed the analysis of a set of blinded samples provided by the EDRN for CCSA-2 expression. We are now awaiting the results of this EDRN blinded study. Despite the relatively large sample sets that have been analyzed, we have continued to indicate that our findings regarding these serum biomarkers, including EPCA-2, are still at the proof-of-principle stage.

As Dr. Diamandis is aware, developing and evaluating cancer biomarkers is a long process. In fact, with the exception of urine-based PCA-3, the other markers Dr. Check reported on in the June 2009 issue of CAP TODAY are at a similar stage as ours. We are not interested in publicity but only in bringing technologies forward that can help the many men suffering from prostate cancer. To this we have dedicated our lives. Ultimately, the science will speak for itself.

 
 
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