The most recent statistics from the American Cancer Society estimate that 29,000 men will die of prostate cancer (PCa) in 2014 (the most of any urologic cancer), and an astounding 233,000 men will be diagnosed with PCa. This 10-fold difference between incidence and mortality in PCa is due to the fact that many men do not die from but rather die with indolent, non-aggressive disease. Yet PCa certainly has lethal potential, as evidenced by 29,000 cancer-related deaths per year. This implies that the most important question in this disease is to identify which patients with PCa have lethal disease, thus allowing physicians and patients to determine which PCa cases may be safely monitored, whereas others require aggressive curative treatments such as radical prostatectomy or radiation therapy.
In this context, PCa is also unique in that there are tremendous racial disparities in prostate cancer. Specifically, black American men are twice as likely to be diagnosed with, and die from, PCa as white American men. It has been suggested that black men may be prone to develop intrinsically more aggressive types of PCa. If this is true, then it is possible that understanding the biologic basis of aggressive PCa in black men may lend cancer researchers important insights into distinguishing lethal PCa in general.
ENVIRONMENT OR BIOLOGY?Some investigators have reported that black men with PCa have worse outcomes and lower survival due to environmental factors—namely, systematic differences in socioeconomic status (income, education, zip code, marital status, etc). Is it environment or biology? One study looking at men in the Chicago area found that demographic variables seemed to explain higher PCa-specific mortality rates in black men, while multiple others show that black men with PCa have worse survival even after controlling for socioeconomic factors.[3–5] Overall, the literature suggests that associations between socio-demographics and racial disparities in PCa outcomes are minimal at best.
At the same time, there is a compelling body of evidence to suggest that there are important biological differences that may cause PCa to demonstrate increased lethal potential in black men. In a study of black and white patients who otherwise were very similar and had equal rates of PCa screening and healthcare access, Moul et al. found that black men had much higher prostate specific antigen (PSA) values; and that the reason for this is that, while gram for gram black men's cancers made the same amount of PSA as white men, black men simply had much larger tumors. Researchers who looked at Detroit area epidemiologic data in a careful fashion concluded that, while young black men and young white men seem to have equal rates of PCa, black men have a two- to four-fold higher risk of developing high grade and metastatic PCa over their lifetimes.
RESEARCH FROM JOHNS HOPKINSTo go back to the original dilemma in PCa, the big question is to differentiate men who have aggressive PCa and require radical treatments such as surgery from men who are likely to have indolent PCa and may be safely monitored. To this end, leading clinicians have devised a management option, called active surveillance (AS), to monitor men with PCa who have favorable (low) risk characteristics. AS involves periodic physical exams, PSA tests, and prostate biopsies to ensure that men with low-risk PCa are safe to be monitored conservatively. At the same time, this strategy re-directs patients to curative surgery or radiation therapy if aggressive PCa features are detected on the monitoring protocol (such as high grade cancer on biopsy). This strategy is overall very successful – for men who are monitored in this manner, cancer specific mortality rates among the world's largest AS programs are very low-- <1%.8 There is a problem with this data, however: black men are underrepresented in the largest studies of AS (only 5-7% of these cohorts). Knowing what we know about PCa disparities in black men, what can we say about the safety of AS for black men with low risk PCa?
We were able to study very large cohorts of men with PCa who have either undergone radical prostatectomy (RP) or active surveillance (AS) at Johns Hopkins to obtain important insights into this question. First, we studied men with very low risk PCa who would have qualified for any AS program (AS eligibility criteria vary slightly among different programs) but instead underwent immediate RP. Very low risk PCa is characterized by meeting all of the following criteria: PSA <10 ng/ml, Gleason sum <7, clinical stage <T2a, number of positive cores <3, percent cancer per core ≤50, and PSA density ≤0.15 ng/ml/cc.9 Even among men who met all very low risk characteristics, black men were found to have significantly worse pathologic findings at RP as compared to whites (Figure 1); and most notable among these findings was pathologic upgrading. In findings published in Journal of Clinical Oncology, black men with Gleason sum 6 on biopsy were found to have Gleason sum 7 or more on final pathology at a rate of 27%, while upgrading only occurred in 14% of white men.
In a separate study in Urology, of men who were very low risk and were monitored on AS, black men were at significantly higher risk of being reclassified with high grade prostate cancer (biopsy Gleason sum 7 or more) on biopsy, when compared to white men (Figure 2).
Furthermore, in findings published in Urology, when we studied black and white men in all risk categories who underwent RP, we discovered that after adjusting for clinical and pathologic factors, black race was an independent risk factor for experiencing biochemical recurrence after treatment among men in the very low-, low-, and intermediate-risk categories. Our findings are consistent with results of a national study of black and white men with low-risk PCa that found that black men were significantly more likely to die from PCa despite 'curative' treatment. (This study and ours all adjusted for socioeconomic variables.)
This evidence is disconcerting, as it points to the fact that PCa demonstrates a distinctly higher level of clinical aggressiveness in black men. Why is this the case? First we did a study of very low risk black and white men who underwent RP, and completed a detailed microscopic exam of their surgical specimens to precisely map out their tumor nodules. Many men with PCa are found to have multiple islands of cancer within their prostate glands. Each of these nodules has a characteristic size and grade (cellular aggressiveness). The dominant nodule is defined as the largest cancer nodule with the highest Gleason grade—which would be expected to be the most important contributor to oncologic outcomes in these patients. In finding published in Journal of Urology, we found that black men had higher tumor volumes and were more likely to have multiple islands of cancer within their prostate glands. The most striking finding was tumor location (Figure 3).
The dominant nodule was much more likely to be located in the anterior aspect of the prostate gland (a distinct anatomic nodule that is difficult to sample with conventional biopsy techniques), whereas the dominant nodule was more likely to be located peripherally in the posterior aspect of the prostate in white men. When considering only high grade dominant nodules, these race-specific anatomic differences were more even more pronounced. Thus it appears that PCa in black men is biologically distinct, as evidenced by its predisposition to be located in the anterior aspect of the prostate gland (findings consistent with an earlier study of men with low risk PCa as well).
Presently we are performing advanced genome-wide RNA and oncogene expression studies using tumor specimens from matched multi-institutional cohorts of black and white men, across a wide spectrum of risk characteristics. What investigators at Johns Hopkins, including Dr. Edward Schaeffer and Dr. Ashley Ross, are beginning to uncover are distinct molecular subtypes that characterize cancers that tend to occur in black men. Some of these molecular subtypes are also associated with specific zones of the prostate gland and are associated with aggressive or lethal PCa outcomes. In findings to be published and presented in Spring 2015 at the annual meeting of the American Urological Association, these findings will reveal important insights into the biologic basis of PCa racial disparities and simultaneously signify important clues into the underpinnings of lethal PCa overall.
- Differences in outcome for black men in the United States cannot be explained by socioeconomic factors alone, the biology of prostate cancer is different in black men than white men.
- Given similar "low-risk" features,
- Black men have worse cancer at the time of radical surgery.
- Black men have higher rates of progression to worse disease while on active surveillance.
- Black men are more likely to have large tumors in the anterior of the prostate – an area that is notoriously difficult to biopsy, possibly explaining why they are found to have worse cancer later.
- Future studies will address the genetic differences in prostate cancers of black men.
This blog was written by Debasish Sundi, MD. Dr. Sundi is a Chief Resident at the Brady Urological Institute and looking forward to a career in urologic oncology.
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