When I was a urology resident, my philosophy was that in going to medical school and doing your training, you could learn your trade like a plumber, a carpenter, or any other tradesman. You could go out and practice your trade, do a very good job, and take very good care of patients. But, for me, I thought it would be icing on the cake if I could also do research and discover something useful. I wanted to do something on my own.

When I was young—a medical student, a resident—I had a burning desire to join the contributors and be able to give something back to the field. In thinking about that and in talking to some of my wise professors, I decided that the best way to start would be to identify a problem that was common and that caused a lot of people suffering and death, and also a problem that the medical community was not doing a very good job in managing.

“Prostate cancer is an insidious disease that arises silently, passes through a curable phase silently, and becomes incurable silently.”

As I was a urology resident, prostate cancer seemed an obvious choice. It was the most common cancer of American men and the second-leading cause of cancer death. The only method available to detect it was a finger rectal exam, and most men would do anything to avoid having something inserted in their rectum in those days.

Prostate cancer is an insidious disease that arises silently, passes through a curable phase silently, and becomes incurable silently. If you wait for symptoms to signal its presence, it is too late to cure it. Accordingly, when prostate was detected, it was frequently advanced and, even when detected early, treatment rendered every man impotent and many incontinent of urine as well.

I trained at Johns Hopkins Hospital under Dr. Patrick Walsh, who is still a very inspirational person to me. He developed the nerve-sparing prostatectomy, which really helped a lot, in terms of being able to treat the patient successfully without such severe side effects. At first the nerve-sparing prostatectomy was controversial, and I would constantly work to refine the precise surgical technique over the years to maximize cure rates while minimizing side effects and complications. It did pay off, as after having performed more than 4,500 operations, my results are now better than ever.

From the beginning of my nerve-sparing prostatectomy series, I entered my patients into a prospective follow-up database and followed them indefinitely, recording information on their cancer control, potency, continence, complications, and any subsequent therapy. This provided me with the wonderful opportunity to remain involved in all aspects of their aftercare and become friends with many of them and their families throughout their lives. It also taught me a lot about the management of large patient databases that would later prove invaluable for my PSA and prostate cancer genetics studies.

The problem still was that we seldom detected prostate cancer early enough to catch it in a curable state, when we could do the nerve-sparing prostatectomy. In the late 1980s, the prostate-specific antigen (PSA) test came along. In 1988, there was a meeting in Prout’s Neck, Maine, funded by the NIH, to find a way to decrease the rate of death from prostate cancer by the year 2000. One way put forth was doing transrectal ultrasound scanning of the prostate gland as a screening tool for prostate cancer. I told my colleagues, "This is not going to work."

I had been performing PSA tests on my patients who had benign prostate disease and those with prostate cancer. I calculated the sensitivity, specificity, and positive and negative predictive values of PSA testing, and compared it with ultrasound scanning and with the digital rectal examination. I realized that, although far from perfect, PSA testing would be better than anything we had. It would offer the advantages over a rectal exam that it was non-invasive, objective, and it would give you a number. Men don’t like to have probes or fingers inserted in their rectum, but they would accept a simple test, like a cholesterol test. I told the group at the Prout’s Neck meeting that I believed the PSA test would be better than anything we had. I was kind of howled down: they said everyone knew that PSA was far too imperfect to be used as a screening test.

But a screening test for asymptomatic men was needed. Because of the insidious nature of prostate cancer, you have to be proactive about looking for it if you want to detect it in a curable stage.

When I returned home from the meeting, I was determined to initiate a PSA-based prostate cancer screening study to test my hypothesis. I started my study in 1989. I ultimately enrolled 36,000 men, and it ran for 12 years. By 1991, after enrolling the first 1,600 men in the study and analyzing the preliminary data, I wrote an article for the New England Journal of Medicine, showing PSA could be used as a first-line screening test for prostate cancer (Catalona WJ, et al., "Measurement of prostate specific antigen in serum as a screening test for prostate cancer," NEJM 324:1156-61, 1991 [published erratum, N Engl J Med 325:1324, 1991]). This paper received a lot of media coverage and really launched widespread PSA testing in the US and around the world.

I was just reading in the newspaper last week about prostate cancer death rates. They’ve been keeping records on death rates from cancer from the 1930s. Since 1995, the death rate from prostate cancer peaked and then started falling at an average of 4% a year for the past 10 years. It was very rewarding to feel that my mentor, Dr. Walsh, developed the nerve-sparing prostatectomy, and the PSA test that I had helped develop as a screening tool allowed physicians to detect cancer early enough before it had spread in the great majority of patients.

If you detect the cancer early and treat it with the nerve-sparing prostatectomy, patients end up after treatment being potent, continent, and cancer-free. What I consider a cure is to get the patient back to the way he was before he was diagnosed with cancer. If they end up potent, continent, and cancer-free, that’s great for the patient and his family.

In the 1990s, the so-called "genomic revolution" occurred with the Human Genome Project. It became apparent to me that all cancer is really genetic in origin, so cancer occurs because something goes awry with a patient’s DNA. Some of those changes could be inherited from parents, and others are acquired by exposure to the things we encounter in the world, but ultimately, it’s genetic. Until the Human Genome Project, the tools did not exist to capitalize on the genetic understanding of how cancer occurs.

When the Human Genome Project came along and I started seeing some of the things that were happening in research, I felt that having a very large practice of prostate cancer patients was a great opportunity because it could provide a necessary ingredient for cancer research. One of the real bottlenecks in research in prostate cancer was the lack of availability of blood samples and tissue samples from patients whose family histories and medical histories had been very carefully recorded in a database that could be easily interrogated.

I thought that if I were to collect tumor samples, blood DNA samples, and serum samples on my patients, and were to enter my patients’ medical histories into a prospective database that very carefully "annotated" their samples, that is, characterized their family history, their tumor characteristics, their treatments and their responses to these treatments, it would be a valuable resource for studying cancer. So, I always took a careful family history and, if they did have a family history of prostate cancer, I would not only get their samples but also would send away for tumor samples from their relatives treated at another hospital, if they were available.

Beginning in the 1980s, when I was doing my PSA screening program, I developed a large prospective database with thousands of my patients in it and collected samples in my biorepository. I established collaborations with genetic researchers, some of the best in the world, many working at other institutions. We studied the genetics of both familial and sporadic prostate cancer. I would say one of the most meaningful contributions of my collaborative research group is that when researchers first started studying the genetics of prostate cancer, they basically used two liability classes: either you had prostate cancer or you didn’t. When they performed the statistical analysis to find linkage signals in the genome where genes might exist, the statistical analysis was all based on cancer, "yes" or "no."

Many groups around the world performed studies and reported linkage signals in the genome where they thought there were prostate cancer susceptibility genes, but it was very hard to reproduce these linkage signals from one research group to another. Every group would come up with its own set of linkage signals. Part of the reason for this is that prostate cancer is so common that it is possible to have multiple cases occur in a family by coincidence alone and not as an inherited tumor. When this occurs, it has a profoundly adverse effect on the statistical analysis of genetic linkage signals.

Our group was the first to use a different classification. We used aggressive cancer versus less aggressive cancer or no cancer. When we did the analysis this way and focused on the aggressive cancer, which is really what causes suffering and death, we found signals that the linkage signals were more reproducible. We published several papers on that (e.g., Witte JS, et al., "Genomewide scan for prostate cancer-aggressiveness loci," American Journal of Human Genetics 67[1]:92-9, 2000). The field of prostate cancer genetics has pretty much gone on this path, focusing on the aggressive forms of prostate cancer.

At the present time, I have several major collaborations in prostate cancer research. One is the International Consortium for Prostate Cancer Genetics. This is a group of 20 or so medical centers from around the world, including the US, France, Germany, Sweden, Norway, England, Canada, and Australia—groups that are very interested in prostate cancer genetics. These groups pool their resources and merge their families and their data. This group has a grant funded by the US National Cancer Institute (NCI) under the leadership of William Isaacs, Ph.D., of Johns Hopkins. We’re now trying to focus in on some of the genetic linkage signals the group has discovered.

My second collaboration is also a multi-institutional group, recently funded by the NCI, called a SPECS (Strategic Partnering to Evaluate Cancer Signatures program) grant. There are SPECS grants for several of the most common types of cancer, including prostate cancer under the leadership of Dan Mercola, M.D., of the University of California, Irvine. We are looking at genetic signatures, patterns of gene expression, and characteristics of prostate cancer that would predict the prognosis, i.e., how aggressive the cancer is.

My third major collaboration is with a private company. This is a fascinating collaboration with deCode Genetics, based in Iceland. They’re a great company. The nature of that collaboration is that deCode has identified two genes that are associated with prostate cancer susceptibility and aggressiveness. They have validated these genes in two independent Icelandic populations. People in Iceland are mainly of Scandinavian and Irish descent, and deCode wanted to see if they could also validate these genes in a North American population. They came to me for this and, in a moderate-sized group of my patients, we’ve validated these genes. We’ve shown with additional samples from the Universities of Chicago, Pennsylvania, and Michigan that these genes increase the risk of prostate cancer. I sent them DNA samples from a group of my patients. They did the genotyping of the DNA in Iceland and we have verified what they’ve shown in two independent Icelandic cohorts.

To follow up, we’ve identified a smaller subset of patients that are carriers of these genes. We’re now taking a sample of their tumors and testing them with molecular genetic techniques to determine how being a carrier of these genes affects gene expression and protein production and function to determine how these genes could cause aggressive prostate cancer.

One of the genes that we and several other research groups have found to be most overactive in prostate cancer patients is hepsin. Hepsin is an enzyme of the protease category (it snips a protein) that sits on the cell surface. One reason it is exciting is that, because it sits on the cell surface, it’s "druggable." Another exciting feature is that it is a protease. One of the theories of how hepsin might cause cancer is that hepsin acts like a molecular scissors sitting on the cell surface, possibly converting inactive growth factor precursor proteins that surround the cell into active growth factors by snipping them to make them active. These growth factors then cause the cell to grow in an abnormal fashion.

One could imagine testing a population to see which people have hepsin overactivity. Since there’s a large pharmaceutical industry out there to manufacture protease inhibitors to treat HIV, it would be feasible to design a protease inhibitor specific for hepsin to treat prostate cancer. This could be effective, instead of surgery or radiation therapy, in treating patients with advanced prostate cancer, or patients with early cancers, or it might be possible to prevent prostate cancer in men who have inherited this genetic susceptibility. Currently, patients with chronic myelogenous leukemia and gastrointestinal stromal tumors are being treated with Gleevec, a molecule targeted to the genetic cause of the disease.

My guess is that there will be not just one, but also maybe a dozen or more genetic variations or mutations that could make a man susceptible to prostate cancer. Discovering what the variations are and going back to the tumors and doing functional studies to determine how these genetic alterations actually cause cancer will create new possibilities for more accurate early diagnoses, perhaps better and less invasive treatments with less associated side effects, or even the prevention of prostate cancer.

There are new forms of PSA that are more tumor specific. I’m embarking on studies to improve the PSA test. I am also collaborating with Dr. Brian Haab of the Van Andel Research Institute in studying the humoral immune response to prostate cancer antigens, hopefully to discover new serum markers for prostate cancer, and also working intensively on the genetics of prostate cancer from the angles previously mentioned.

One of the things that has allowed me to do this is that I have a large practice of prostate cancer patients. I usually perform eight radical prostatectomies per week. My research team and I obtain their informed consent them to provide tissues and blood samples for my research. My research team also records their medical information in a highly organized prospective database and keeps it updated on a regular basis. In this a way, my clinical practice provides critical and very valuable reagents for molecular genetic research.

It really is rewarding. Every day I usually see two new patients. This week, I’ve had a week of young men—two men in their early 40’s and two in their late 40’s. They were going about their business when they found out they had prostate cancer and now their world has been turned upside down. In the vast majority of cases, we’ll cure them. As they get older, they don’t want to have their sons and grandsons go through the same thing.

I have a private foundation called the Urological Research Foundation that is run by my patients. They raise money that helps support my research program. Some of my research has been supported by NIH funding or funding from other research agencies or industry collaborators, such as the Department of Defense, Prostate Cancer Foundation, and Beckman Coulter Incorporated, but much has been supported by my patients who want to support this kind of research in prostate cancer.

Many feel that the PSA test saved their lives. Some are celebrities who have gone public to increase awareness of prostate cancer issues. They didn’t ask to have prostate cancer or to have them and their family to be forced to deal with the issues, but now that it has come, they realize that if this kind of research is done, things really will be better for their children and their grandchildren, so they want to do their part to help now when help is most needed.

I had a patient today whom I had to inform that his biopsy came back showing prostate cancer. When I told him he said, "I saw my brother die of prostate cancer two years ago. I don’t want it to happen to me." In patients with a potentially aggressive prostate cancer, it’s a very bad, life-threatening situation.

Prostate cancer now kills almost 30,000 men in the United States every year, and nobody says very much about it. I often say that if 30,000 men were killed in a political conflict, the effect would be much more palpable to society and there would be a strong public outcry to stop it. In medical research, we are working together quietly—each contributing his or her individual talents and training—to try to end the unnecessary suffering and death from prostate cancer.