Urologic Oncology

SLIDES & TRANSCRIPTS
Friday, December 5, 2003

EDRN Overview

Ian Thompson, M.D.

Slide 1:

I am Ian Thompson, and it gives me great pleasure to describe to you a wonderful resource that actually many of us are participating in and that all of you gave access to any number of ways, and it is called the Early Detection Research Network. The Program Director, Dr. Srivastava is here in the third row sitting behind us and just to give you a little overview of what is going on in the EDRN Dave Sidransky is the Chairman of the Steering Committee and how potentially you could become more involved with it and take advantage of some of its aspects.

Slide 2:

As you can see here the EDRN involves three specific organizations, biomarker development laboratories, biomarker validation laboratories as well as clinical and epidemiologic centers to really fulfill Dr. Von Eschenbach's vision of going from the laboratory directly to the clinic and ultimately popping out the other side biomarkers that you can take back and reliably use in your clinical practice.

Supporting this includes one of the world's finest data management coordinating centers at the Fred Hutchinson Cancer Research Network.

Slide 3:

There are 31 funded laboratories and centers, about 120 institutions and several hundred investigators who are participating in this.

Slide 4:

They are from all over the nation.

Slide 5:

Alan Partin is the Chairman of the Genitourinary Cancer Group and there are other groups that coordinate all of this effort.

This process is actually a stepwise process from the preclinical exploratory trials down to the concept validation and let us look at it. Why is it that you don't use some of the markers perhaps that Ed was talking about in your clinical practice? Part of that is the lack of the full validation of those markers so that you could be exceptionally confident that those markers will do exactly what you want them to do and that you can take care of the patients in the same fashion with less morbidity, potentially less cost than you are currently doing in your clinical practice, ultimately from a cancer control standpoint seeing a difference in the management of these patients.

Slide 6:

Biomarker discovery, and I am just going to give you a little brief tour of what is going on in the genitourinary component of this, Alan Partin is doing some really exciting work with isoforms of PSA to include pro-PSA

Slide 7:

and as you well know there are multiple isoforms of PSA that have different performance characteristics when you use them in your office

Slide 8:

and as Alan has demonstrated quite nicely maintaining sensitivity at 75 percent you can dramatically improve specificity.

Now, obviously all of us want what I call the free lunch. We want to improve specificity while maintaining sensitivity and ultimately that is the goal of our network.

Slide 9:

Much of this is involving leveraging new technologies for diagnosis and unlike other efforts we are using these technologies through this full validation stage so that when it pops out the other side and it receives the imprimatur of approval if you will of the research network you could feel very confident that you can take it to your clinical practice and change the management of the patients

Slide 10:

and I am following Chip and I am following David and so you will see some of these are repetitive but this is one of the technologies, one of the low-resolution technologies, surface-enhanced laser desorption and ionization which basically causes a fingerprint if you will of the protein profiles

Slide 11:

and Chip and others have shown quite nicely that it actually helps segregate patients.

I mean these are data from John Semmes who is leading the SELDI effort in the EDRN showing some very nice profiles of normal individuals and prostate cancer patients showing loss of some of these protein peaks in the prostate cancer patients and gain in other peaks and you put this in a neural net and there are a number of programs that allow you to analyze it and then potentially moving it forward into more high-fidelity systems, lower spectrum of mass ranges but higher fidelity systems like the QSTAR can take this forward and move this and enable you to take these sorts of data and then go forward and classify patients appropriately as to whether or not they have prostate cancer

Slide 12:

and your classification rates are really extraordinary as Chip pointed out.

His data and the EVMS data suggest that you could dramatically improve specificity while maintaining acceptable levels of sensitivity.

Slide 13:

Now, when you actually take this out and if you envision the concept that it is going to change your patient management, the steps in the validation are not just taking cases and controls. That is unacceptable. You have to be able to be assured that the technology platform is going to function in the same fashion in all locations and so this is the stepwise process of the SELDI trial within the early detection research network where actually we validate the technique and the portability, take the algorithm itself which is the neural net that kind of looks at the protein peaks and sorts patients into high probability and low probability and then validate it in a prospective clinical trial because really what we would like to be able to do is to go beyond PSA

Slide 14:

and unique to this trial and I am not sure if there are any other trials in prostate, is that we are segregating prostate cancers by prognosis and as one of the points that was made earlier the very high number of tumors that were detected in PCPT call into question whether we want to find all of these tumors and so the prognostic factor that we are using is segregating these by grade, so, to determine whether or not we cannot just find prostate cancers but find prostate cancers that would make a difference.

Slide 15:

Now, the process of this validation is not a case-controlled study. As you can see here all of these steps have to go through each one of these until ultimately on the other side of it it pops out. We are anticipating with the SELDI we should have an answer for you within the next 2 years or year and one-half. The nice thing about this is that we have already conducted the prospective clinical trial which is the PCPT. We have those samples available to us that relatively quickly could be analyzed to determine whether it is valid,

Slide 16:

ultimately getting down to the immunoassay development that will then be taken directly to the laboratory potentially in your office or your hospital that will enable you to have a biomarker that not just predicts the presence of disease but the presence of biologically consequential disease.

Slide 17:

As I was saying there are some other issues with regard to biomarkers and one of these is moving beyond the markers of disease but potentially to markers of prognosis and prognosis is perhaps, and for example, in prostate cancer and I think Michael Jewett who has touched on the subject of renal cell, the markers of prognosis for renal cell are going to be very important for us.

Ultimately we would like to be able to identify the man who is at risk for developing high-grade disease and then be able to apply the markers for the disease especially given the enigma of prostate cancer.

Slide 18:

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Slide 19:

One of the sites that we are running in San Antonio of the EDRN, it is one of the clinical and epidemiologic centers is involving a very large cohort, following individuals prospectively going beyond just individual markers of disease but markers of risk, family history, ethnicity, micronutrients, genetic variations, oxidative stress, inflammation and Elizabeth Platz will be talking about that later and integrating all of these to find out why it is some individuals with different kinds of exposure go on to develop no symptoms to individuals with the phenotype of aggressive disease.

Slide 20:

These sorts of studies require enormous investments of time and effort, ultimately 10,000 individuals in this cohort.

One of the advantages of some of the sites, for example, as ours is that we have about 47 percent of these individuals are ethnic minorities which gives you the opportunity to address issues like Ike Powell was talking about whether there are difference in risk or whether it is just differences in the way these patients are managed.

Slide 21:

Biorepositories have to be robust to be able to analyze these markers, not just including serum but DNA as Eric pointed out. You have to have toenails. So, you know something about senium exposure as well as biologic resources like prostatectomies

Slide 22:

and you have to have demographics, dietary information, symptom scores, medical-surgical history as well as history of medications.

Slide 23:

Some of the targets that we are looking at in the network as well as are being looked at in other components of the NCI program are some of the genetic variations that affect an individual's prostate cancer risk. SRD5A2 is only one of those that is fairly polymorphic and seems to be associated with an individual's risk.

Some of the upstream as well as downstream as well as the androgen receptors seem to confer a different risk.

Slide 24:

Here is SRD5A2. This is a slide Jurgen Reichardt who is collaborating with us, fairly highly polymorphic. The A49T is one of the most polymorphic of these and these are functional polymorphisms that affect the rate of DHT production.

Slide 25:

There is a 198-fold variation in the effect of these polymorphisms on the production of DHT, the efficacy if you will of 5-alpha-reductase

Slide 26:

and these variants not just confer your increased risk of disease but increase your risk as much as five-fold of aggressive disease, of high-grade disease.

Slide 27:

The androgen receptor itself if we go beyond markers just a serum test or a blood test we think of markers of prognosis, we all know that there are a number of polymorphisms, linked polymorphisms, for example, within the androgen receptor that are extremely common.

Slide 28:

This is just a sample from our population, extremely common in the population and these very long polymorphisms as opposed to the shorter ones have a functional significance in the function of the androgen receptor

Slide 29:

and already within some of these cohorts we found as much as a threefold increased risk in individuals with very short polymorphisms.

Slide 30:

Ultimately the goal is to validate these in clinical trials. A small clinical trial is ongoing currently in 300 individuals with a strong family history of prostate cancer, negative DRE, negative PSA and all of these individuals are ultimately biopsied to exclude the ascertainment bias that we see in the other types of studies, then being able to test these markers of prognosis, integrating these with these other mechanisms for example like SELDI can make a difference and I am going to skip forward through the microsatellite because that was covered earlier

Slide 31:

just to say to you that the difference in this kind of validation trial where we are taking individuals without disease but this group here as was pointed out earlier by David, this group includes individuals who have traditionally tested false positive with other markers like hematuria

Slide 32:

ultimately having deliverables so that you can see these sorts of new markers that will be able to be popped off the end of the pipeline of the EDRN to make a difference in the management of these patients,

Slide 33:

so, ultimately discovering new markers of disease and prognosis, validating these within rigidly designed and rigidly executed clinical trials to see if we can make a difference in the clinical practice of medicine.

Now, how can you become more involved? Recently released RFA for new biomarker laboratories,new competitive for clinical centers in 2004, perhaps the most widely available opportunity for involvement are associate memberships, and these associate memberships allow you to partner with biomarker discovery validation laboratories, clinical and epidemiological centers so if you have ideas for new markers or if you have opportunities to participate through large registries or biorepositories to become involved in this entire process to ultimately make a difference to our patients.

Thank you very much.