Reports From Dr. Catalona's Follow-Up Studies
Prepared by Cecilia Lacks, PhD, from Presentation Proposals to the AUA prepared by William J. Catalona, MD and his research collaborators

Each year, Dr. Catalona and his research collaborators deliver their research findings at the annual meeting of the American Urological Association (AUA).

Although the information is technical, we feel that Quest readers would like to be familiar with the direction of the research and the vocabulary associated with it.

Some of the information has practical application now. Some shows the beginning of research projects with exploration or new understanding as the main purpose, and hopefully, practical applications will follow.

Surely, though, this research will define how prostate cancer is diagnosed, treated and hopefully prevented in generations to come.

The following are summaries of the research proposals written with QUEST readers in mind.

Possible Genetic Predispositions to Prostate Cancer
What's a SNP? What's a HapMap?

We designed a study to identify genetic differences that might predispose men to prostate cancer.

These genetic differences we examine are called SNPs.

The DNA sequence of any two people is 99.9% identical. The variations, however, may greatly affect an individual's risk for a particular disease. Places in the DNA where individuals differ at a single DNA base are SNPs (single nucleotide polymorphisms).

Sets of nearby SNPs on the same chromosome are inherited in blocks. This pattern of SNPs on a block is called a haplotype.

Blocks may contain a large number of SNPs, but a few SNPs are enough to uniquely identify the haplotypes in a block.

The HapMap is a map of these haplotype blocks.

HapMap might be a new word for QUEST readers, but it is a key research tool for scientists looking for genetic differences that predispose people to certain diseases.

In our study, one of the largest genotyping projects of prostate cancer SNP, to date, we looked for candidate SNPs that showed a connection to prostate cancer as well as genes that showed different activity in normal tissue and in prostate cancer tumor tissue.

Our Conclusion: We identified seven novel SNPs associated with prostate cancer.

Although these SNPs will be totally unfamiliar to most readers, we list them to give an idea of how complicated and interconnected the genetic searches can be:

ID3 appears to control cell differentiation; EZH2 has been associated with metastatic disease; Hepsin is associated with aggressive prostate cancer; BCAS1 is a protein of unknown function that is over-expressed in breast cancer; CAV2 has not been studied but is a candidate for further study, along with CAV1 which appears o contribute to metastasis in androgen-insensitive prostate cancer; EMP3 may be involved in regulating cell production; MLH1 is a DNA repair enzyme previously associated with colon cancer and now seems to contain a SNP which suggests that patients who inherit it might not be able to repair the DNA in the prostate.

Much research work needs to be done to further explore SNPs and their functions in prostate cancer.

Once we know more about these SNPs and these regions, we should be able to develop tests to predict which drugs or vaccines would be most effective in altering their behavior for the good of patients.

James Burmester, Brian Suarez, Jennifer Lin, Carol Jin, Raymond Miller, Sherry Salzman, Kai QiZahnz, Douglas Redding, William Catalona

Challenge of Prostate Cancer Diagnosis
"We have to balance these four statements:

Not all men with prostate cancer need to be diagnosed.

Not all men with prostate cancer need to be treated.

Not all men with prostate cancer die of their disease.

Prostate cancer is the second most common cause of male cancer deaths."

Richard Babaian, MD, Professor of Urology and Director of the Prostate Cancer Detection Clinic, The University of Texas, Anderson Cancer Center, Houston

PSA Tests and Their Connection to Non-Recurrence Survival Rates
We wanted to look at the effect of lowering the PSA threshold, from 4 to 2.6, for biopsy on the non-recurrence cancer rate of men who had been operated on for prostate cancer which appeared to be self-contained in the prostate gland.

Between 1989 and 2001, 36,000 participated in Dr. Catalona's PSA Study.

From those participants, 2,242, underwent a RRP for clinically localized cancer.

We separated our study population into two groups, according to their year of surgery: Era 1 was from 1989-1995, when the PSA threshold for biopsy was 4.

Era 2 was from 1996 to 2001, when Dr. Catalona recommended PSA threshold for biopsy be lowered to 2.6.

We looked at these patients over a 12-year period, and the difference in patient outcomes was significant.

The percentage of men with clinical stage T1c disease, the least advanced form of prostate cancer, increased dramatically between Eras 1 and 2.

Also, a significant increase was noted in the percentage of men with organ-confined disease (69% in Era 1 and 75% in Era 2.

And perhaps, most important, the recurrence-free survival rate at 5 and 8 years after the RRP showed significant improvement in those men who were advised to have a biopsy after a PSA 2.6 test result. After five years, the non-recurrence rate was 71% for Era 1 and 77% for Era 2. After eight years, the non-recurrence rate was 79% for Era 1 and 82% for Era 2.

Our Conclusion: Lowering the PSA threshold for biopsy has resulted in finding cancers in an earlier stage and has resulted in improved non-recurrence survival rates.

Thomas L. Jang, Misop Han, William J. Catalona

Digital Rectal Exams (DRE) and Low PSA
Recommending a biopsy for men with a suspicious DRE but a low PSA is controversial.

Limited data exists regarding the treatment outcomes of men with CaP diagnosed by suspicious DRE and low PSA results.

We took a look at men who were treated with suspicious DRE and low PSA.

Of the 3,481 men diagnosed with CaP as part of Dr. Catalona's PSA Study, 235 men underwent RRP for CaP diagnosed for a suspicious DRE with a PSA less than 2.6.

In these men, we found two distinct types of prostate cancer detected with DRE at PSA levels below 2.6. Approximately 2/3 of the men had a low grade and low stage tumor with a low risk for recurrence following the RRP. But 1/3 of the men had high grade or high stage tumor with a high risk for cancer recurrence following the RRP.

Our Conclusion: PSA results alone are not sufficient to recommend biopsy or to raise suspicion. Digital Rectal Exams (DRE) as well as PSA level should be incorporated in CaP screening programs.

Misop Han, Sheila Hawkins, William J. Catalona

Salvage Radiation Therapy for Recurrence of Cancer After RRP
For men who show evidence (through a rising PSA) of cancer recurrence after a RRP, treatment options are limited but under most circumstances, necessary.

One treatment of choice is Salvage Radiation Therapy (sRT).

In our group of 3,478 who underwent RRP by Dr. Catalona between 1983 and 2003, 307 men received sRT, the need for further treatment indicated by a rising PSA.

We looked at which men responded to the treatment (responders) and achieved undetectable PSA and which men did not respond (non-responders) to sRT treatment.

What we found was that Gleason score 8-10 was more common in those who didn't respond to treatment than those who did. Also more non-responders (67%) had a preoperative PSA greater than 20 than responders (47%).

Also, the median PSA of non-responders at the start of sRT was 1.3 and in responders, 0.7.

The only predictor for early recurrence following sRT was seminal vesicle invasion.

In follow-up on this group of men who did have a rising PSA after surgery and did have sRT, 55% had an undetectable PSA after 5 years and 35% of that group had an undetectable PSA after 10 years.

Thus 25% of men with a rising PSA after RRP had a complete and lasting response to the sRT.

Our Conclusion: The initial response to sRT is more likely to be effective, meaning the PSA will become undetectable, in men with lower preoperative PSA and then lower pre-radiation PSA after RRP. (These results do not affect treatment, but they can assist the doctors and patients in follow-up schedules and routines.)

Misop Han, Sheila Hawkins, William J. Catalona

Effect of Adjuvant Radiation Therapy (aRT) on Potency and Continence After RRP
Increasing evidence suggests that aRT is beneficial in selected patients with adverse pathologic findings following RRP.

However, not all patients with adverse findings have tumor recurrence if they don't have radiotherapy. In addition, some will have disease that spread beyond the radiation fields. And men are concerned about the potential adverse effects of radiotherapy on recovery of erections and urinary continence.

Limited data is available regarding the effects of aRT potency and continence. Over a three-year follow-up, we evaluated postoperative potency and continence in patients treated with aRT and compared them to similar patients not receiving postoperative radiotherapy.

Both groups were similar in that they were preoperatively potent, had bilateral nerve-sparing procedure, did not receive hormonal therapy, and had tumor stageT3 disease.

Patients receiving aRT did not have a higher probability of being incontinent. They were only slightly more likely to be impotent, but the difference was not significant.

Our Conclusion: aRT following a nerve-sparing radical prostatectomy does not adversely affect postoperative urinary continence and has a slight adverse effect on potency.

Age is the most significant factor affecting continence and potency.

Jo Ann V Antenor, Kimberly A. Roehl, Hui Zhu, Keegan L. Maxwell, William J. Catalona

Identifying Prostate Cancer Aggressiveness
The severity of prostate cancer varies widely. Some cancers progress quickly to invasive, life-threatening disease while other remain inactive for many years and have no impact on life span.

Genetic factors may help drive this variability. Previous studies have detected linkage between a gene on chromosome 7q32 and Gleason score (a measure of tumor aggressiveness).

We look at genetic studies of brothers and see if they have a proportion of marker genes that correlate with their Gleason scores. Then we look at other finely spaced markers in this group and in other brothers previously studied. We found a possible candidate for tumor aggressiveness near 7q32, a gene called PODXL. So we start looking for missing pieces in the codes of PODXL. If we find them, and we did, we study the connection between those missing links and prostate cancer aggressiveness in the pairs of brothers with prostate cancer and in a control group of brothers with no cancer.

When looking at aggressive prostate cancer, we found that carrying one deletion increased risk by 60 percent, and carrying two deletions more than doubled risk, in comparison with carrying no deletions.

Our Conclusion: These observations suggest that PODXL may be the tumor aggressiveness gene linked to chromosome 7q32. Using information about such genes to distinguish which men have an increased risk of developing more aggressive disease will provide valuable information about the most appropriate course of treatment among men diagnosed with prostate cancer.

John S. Witte, Brian K. Suarez, William J. Catalona, Graham Casey

Does PSA Screening Detect Harmless Cancers?
Autopsy studies have revealed that a good percentage of men aged 30 years and older have microscopic evidence of prostate cancer. Clinical studies suggest that only one in six (17%) men are diagnosed with prostate cancer during their lifetime. Some people say that if detection methods become more sensitive, then harmless cancers will be found and therefore unnecessary treatments could result.

Dr. Catalona's PSA screening study of 35,000 men from 1989 to 2001 shows such a fear of over detection is unfounded. Even after lowering the PSA cutoff for biopsy from 4 to 2.6, and increasing the number of biopsy cores; 10% of men in the study were subsequently diagnosed with prostate cancer.

After RRP, we found that virtually all the cancers detected were clinically localized; approximately 70-80% were confined to the prostate gland; and less than 7% (that is 7% of the 10% diagnosed, a very low number) were possibly "insignificant" tumors. These results are representative of cancer diagnosis characteristics in US screening populations.

Our Conclusion: Early detection of CaP catches cancer while it is still organ-confined. This early detection finds relevant cancer (and harmless ones in only rare cases). Treatment of CaP when organ-confined allows for substantial non-recurrence rate after a RRP.

Christopher M. Gonzalez, Kimberly A. Roehl, Jo Ann V. Antenor, Ronald Yap, William J. Catalona

Familial Prostate Cancer and Sporadic Cases
Reports conflict over whether hereditary prostate cancer has different clinical and pathology features than sporadic cases (those cases seemingly without hereditary influence).

We compared clinical outcomes, pathology reports and 7-year PSA recurrence-free rates in these sets of patients.

Our Conclusion: In our population, the sporadic cases are similar to the hereditary cases.

Jo Ann V Antenor, Kimberly A Roehl, Jonathan Rubenstein, William J Catalona

Lowering PSA for Biopsy in Older Men
A Report from Dr. Catalona’s PSA Studies

The traditional PSA screening cutoff of 4.0 for prostate biopsies detects cancers but about 30% of the cancers detected with this PSA cutoff have extended beyond the prostate.

Lower PSA cutoffs are being investigated to achieve earlier cancer detection, especially in younger men, and lower PSA cutoffs are being more widely used in younger men in routine clinical practice. (see articles on lower PSA threshold for biopsy in this issue of QUEST and in Fall QUEST 2003)

Physicians and patients are asking whether lower cutoffs should be used in men of all ages, since the prevalence of CaP is low in young men and the prevalence of both benign hyperplasia and CaP are higher in older men.

The likelihood of finding CaP in screening studies is a function of patient age; however, limited age-related data exists for men with a PSA level of 2.6-4 and DRE results that are not suspicious for CaP.

We evaluated the cancer detection rate, Gleason score and clinical and pathological tumor stage as a function of age in Dr. Catalona's PSA Study.

We found a trend for increased cancer detection to follow increasing age.

We also found the risk for prostate cancer in men with a PSA of 2.6-4 and non-suspicious DRE increases with age. In this narrow, low PSA range, tumor stage and grade were similar in all age groups.

Our Conclusion: Lower PSA cutoffs should also be considered in older men.

Robert B. Nadler, Kimberly A Roehl, Jo Ann V Antenor, Scott Eggener, William J Catalona