From the Urologic Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland.

Presented at the continuing medical education symposium, “Urology: Frontiers 2000,” held on March 10, 2000, at Baylor University Medical Center.

Corresponding author: W. Marston Linehan, MD, Urologic Oncology Branch, Division of Clinical Sciences, National Cancer Institute, 10 Center Drive, MSC 1501, Building 10, Room 2B47, Bethesda, Maryland 20892-1501 (e-mail: linehanm@mail.nih.gov).

CURRENT EPIDEMIOLOGICAL DATEA ON PROSTATE CANCER

This year, it is estimated that 198,000 Americans will be diagnosed with prostate cancer and 38,000 will die of this disease.

In February 2000, the National Cancer Institute (NCI) received an update on prostate cancer incidence and mortality. A large increase in prostate cancer incidence was noted in the 1980s in both Caucasians and African Americans, due possibly to increased awareness and better screening tools for prostate cancer. The incidence subsequent to that time is dropping, and it is predicted that the incidence will continue along the course it was in the 1970s and early 1980s.

The incidence rates are dropping in nearly all age groups, both for Caucasians and African Americans. Rates are increasing only in men aged 50 to 59. Those men may be receiving earlier screening and earlier diagnosis. Interestingly, there is an unprecedented drop-off in the number of patients with advanced disease. A similar drop-off was present in the higher Gleason grades. Over the past 10 to 15 years, the number of patients diagnosed with moderately differentiated prostate cancer significantly increased, while the number of patients diagnosed with well-differentiated or poorly differentiated cancer decreased. This may be due to the widespread adoption of the Gleason grading scale.

Mortality rates due to prostate cancer have decreased significantly, both for Caucasians and African Americans. The drops are seen in every age group, including men >80 years of age. Although our population is aging, we're beginning to see a leveling off of the absolute numbers of patients who are diagnosed and a significant and unprecedented drop in the mortality of these patients.

A variety of explanations have been considered for the drop in incidence and mortality. Could it be a change in diagnosis? Could it be a balance to the huge increase in awareness of prostate cancer that occurred in the 1980s? How do you decide who has prostate cancer and who dies of prostate cancer? A branch at the NCI is devoted to deciding how people code for deaths. There is much variability, even in who makes such decisions--whether a medical examiner (who may or may not be a physician), a mortician, an emergency room physician or a family practitioner, a specialist, or even someone who works in the medical records department. Was the change in the 1980s appropriate or artificial? Did the incidence and mortality rates really change, or did more people ascribe prostate cancer death to prostate cancer than to other causes? Many feel that there may be some artifact in some of the data, but basically the mortality rates are real.

A number of practice pattern changes that may have improved the mortality rates have been considered. The earlier introduction of hormonal therapy was one practice change that some believe may have had an effect. Another possibility is the introduction of nerve-sparing prostatectomy in the 1980s. This innovation led to a significant change in practice patterns and made surgical therapy much more palatable for many patients. The introduction of the prostate-specific antigen test and earlier detection of the disease also made it possible to treat more patients when the disease was localized. If you wanted to predict a change, you might say that it would take 10 or 15 years after introduction of a new therapy (such as nerve-sparing surgery) for changes in mortality rates to be evident. Practice patterns in the USA changed in the mid-1980s, and now, 15 years later, there is a change in mortality. It is not possible to say that the surgery and the drop in mortality rates are definitively correlated, but neither can one exclude the possibility. In the end, clinicians seem to be doing something that works. Of course, the change is probably multifactorial and may even include changes in diet.

USING GENETICS TO IMPROVE DIAGNOSIS AND TREATMENT

Physicians treating patients with prostate cancer have to choose among several treatment options, based on their best assessment of probabilities for disease spread and, later, recurrence. What tools do we have available to improve our methods for detecting early disease and for better understanding the patterns of disease in individuals?

I propose that our first tool is a better understanding of the cause of these cancers. All cancer is genetic. Some cancer is hereditary. When we understand the pathways of these cancers, we may be able, for example, to remove a small number of cells from a patient and develop a specific, highly accurate diagnosis that can lead us to choose the right treatment methods for that cancer. In my next paper I give examples of practical applications resulting from the discovery of kidney cancer genes (1).

Prostate cancer has some unique characteristics that could be better understood if we knew the cause of the disease. For example, in contrast to most cancers, which are solitary, prostate cancer manifests itself as an average of 6 independent events. Second, there is a remarkable incidence of prostate cancer. If an autopsy is done of a man in his 40s who dies of another cause, that man has a 35% to 40% chance of having a histologic diagnosis of prostate cancer. For a man in his 30s, there is about a 25% to 30% chance, and for a man in his 20s, a 15% to 20% chance. Why is it that only a small percentage of those men--about 8% or 9%--will develop clinical prostate cancer?

The Cancer Genome Anatomy Project

The Cancer Genome Anatomy Project (CGAP), a large, multi-institutional effort initiated by Dr. Klausner at the NCI, is now under way to identify all abnormal genes in prostate cancer. CGAP is a gene discovery engine, responsible for discovering a high percentage of all the genes identified in the world. Prostate cancer was one of the first cancers to go through this program.

CGAP works as follows. Prostate cancer removed in the operating room is microdissected, using a technique developed at the NCI to compare normal prostate tissue with cancerous tissue. Prostate cancer cells are pulled out and put through a number of steps to identify and sequence the genes expressed. Within 48 hours of identification of a new gene, the information is put on the Web site so everyone has access to it. Although we do not know the specific gene for prostate cancer yet, our group is focusing on an area on chromosome 8, which is one of the areas of highest abnormality. CGAP is one of the NCI's significant infrastructure efforts, which we hope will advance progress in prostate cancer research. We have several other initiatives as well, including research on the abnormal proteins expressed in prostate cancer (proteomics project) and karyotypic abnormalities in prostate cancer (Cancer Chromosome Abnormality Project, or CCAP).

The hereditary form of prostate cancer

It has been shown that men who have a first-degree relative with prostate cancer are at a higher risk of developing prostate cancer. Men with 2 or 3 first-degree relatives have up to an 11-fold risk. This has led to recommendations for increased screening and surveillance in these men. Knowledge of the gene for the hereditary form of prostate cancer will change how we practice--just as knowledge of the breast cancer gene has changed the way breast cancer is approached and treated. In addition, the gene for the hereditary form of prostate cancer may turn out to be the gene for the sporadic form.

Studying men with a hereditary form of prostate cancer is a very complex task. It is likely that >1 gene is involved. Currently the most likely candidates are thought to be on chromosome 1 and on the X chromosome.

Identifying targets for therapy

It is hoped that identification of the genes involved in prostate cancer will also lead to development of specific targets for therapy. We know, for example, that to progress prostate cancer needs angiogenesis and the production of angiogenic factors such as vascular endothelial growth factor. Clinicians are looking into the possibility of an anti-angiogenic strategy for patients with localized or locally advanced prostate cancer. Small molecules to block the pathway and receptor are another option.

LAPAROSCOPIC SURGERY

Increased use of laparoscopic surgery is another potential way to improve prostate cancer treatment and decrease morbidity. The NCI has had a very positive experience using laparoscopic surgery in patients with adrenal and kidney tumors, even very large tumors. Dr. McClellan Walter heads our laparoscopic team, and we recently sent 2 people to France to learn more about laparoscopic radical prostatectomies.

Although there is a learning curve for laparoscopic surgery, we've been amazed how it has revolutionized how we think and how we treat our patients. Patients are ambulatory <40 hours after surgery. We are doing very few open procedures now.

CONCLUSION

We are in an exciting era in the treatment of prostate cancer. As shown by the recent mortality data, physicians appear to be doing a good job treating this disease. With the tools available in molecular genetics, molecular biology, pharmacology, and genetic forms of therapy, I'm very optimistic that we'll see some significant changes in the next decade that will affect how we practice and improve patient outcomes (2-7).

1. Linehan WM. Molecular genetics of kidney cancer: implications for the physician. BUMC Proceedings 2000;13:368-371.
2. Vocke CD, Pozzatti RO, Bostwick DG, Florence CD, Jennings SB, Strup SE, Duray PH, Liotta LA, Emmert-Buck MR, Linehan WM. Analysis of 99 microdissected prostate carcinomas reveals a high frequency of allelic loss on chromosome 8p12-21. Cancer Res 1996;56:2411-2416.
3. Emmert-Buck MR, Vocke CD, Pozzatti RO, Duray PH, Jennings SB, Florence CD, Zhuang Z, Bostwick DG, Liotta LA, Linehan WM. Allelic loss on chromosome 8p12-21 in microdissected prostatic intraepithelial neoplasia. Cancer Res 1995;55:2959-2962.
4. Carlisle AJ, Prabhu VV, Elkahloun A, Hudson J, Trent JM, Linehan WM, Williams ED, Emmert-Buck MR, Liotta LA, Munson PJ, Krizman DB. Development of a prostate cDNA microarray and statistical gene expression analysis package. Mol Carcinog 2000;28:12-22.
5. Emmert-Buck MR, Strausberg RL, Krizman DB, Bonaldo MF, Bonner RF, Bostwick DG, Brown MR, Buetow KH, Chuaqui RF, Cole KA, Duray PH, Englert CR, Gillespie JW, Greenhut S, Grouse L, Hillier LW, Katz KS, Klausner RD, Kuznetzov V, Lash AE, Lennon G, Linehan WM, Liotta LA, Marra MA, Munson PJ, Ornstein DK, Prabhu VV, Prange C, Schuler GD, Soares MB, Tolstoshev CM, Vocke CD, Waterston RH. Molecular profiling of clinical tissue specimens: feasibility and applications. Am J Pathol 2000;156:1109-1115.
6. Emmert-Buck MR, Gillespie JW, Paweletz CP, Ornstein DK, Basrur V, Appella E, Wang QH, Huang J, Hu N, Taylor P, Petricoin EF III. An approach to proteomic analysis of human tumors. Mol Carcinog 2000;27:158-165.
7. Englert CR, Baibakov GV, Emmert-Buck MR. Layered expression scanning: rapid molecular profiling of tumor samples. Cancer Res 2000;60:1526-1530.