A Prostate Cancer Research Program Overarching Challenge is to conduct research that improves a doctor's ability to distinguish between aggressive and indolent prostate cancer. Now that most American men are screened for prostate cancer using the prostate specific antigen (PSA) blood test, prostate cancer is diagnosed when it is small and more treatable by removing the prostate. However, 25% of these men will have their cancer recur despite having had their prostate removed. A third of these men will ultimately suffer from metastases, of which 40% will die of their disease. At this point, doctors still cannot be certain about which men with early prostate cancer are more likely to suffer and die of their prostate cancer. Our proposed research will directly address this problem.

We propose to study whether inflammation and a focal atrophy, a prostate lesion that is often inflamed, can help predict which men will have more aggressive prostate cancer; that is, prostate cancer that is already high-grade when it is diagnosed or that has a greater potential to recur after being treated. The reasons we will study inflammation are: (1) it is known to cause other cancers; (2) pathologists have long known that inflammation is present in the prostates of some men; and (3) we previously found that men who have more inflammation in their diagnostic prostate biopsies were much more likely to have high-grade prostate cancer. While our findings help support that inflammation influences risk of aggressive prostate cancer, we cannot know this for certain because we measured inflammation in the same biopsies that were used to determine if the men had cancer. In other words, we could not tell if the inflammation that we saw caused the high-grade cancer or was a reaction to the cancer. To fill in this critical knowledge gap, we propose to perform two population-based studies that will help us to learn whether prostate inflammation and inflamed focal atrophy predicts which men will be diagnosed with high-grade prostate cancer in the future and predicts which men with early prostate cancer will experience a recurrence in the months to years after they had prostatectomy.

In the first study, we will test whether prostate inflammation and focal atrophy influence the risk of being diagnosed with high-grade prostate cancer. We will create a unique study population by linking two completed trials: the Prostate Cancer Prevention Trial (PCPT) and the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Men in the PCPT who had a normal PSA test and digital rectal exam had prostate biopsies performed at the end of the trial. If cancer was not found, they were eligible to enroll in SELECT. Men in SELECT were followed for years for the diagnosis of prostate cancer. After linking the trials, we will measure the amount of inflammation and focal atrophy in the biopsies and assess whether the amount tell us who is more likely to be diagnosed with high-grade prostate cancer later. We have permission to use the tissue and data.

In the second study, we will test whether inflammation and focal atrophy in the prostates of men with early disease influence the risk of recurrence after they have surgery. We will use a study population that we previously developed with funds from the Department of Defense. The men in this population all had clinically localized prostate cancer, they were treated by having their prostates removed, and we followed them for recurrence. We will measure the amount of inflammation and focal atrophy in their benign and cancer tissue removed during surgery and whether the amount can tell us who is more likely to have their prostate cancer recur.

We are excited about our proposed research because it holds the promise of directly affecting the care of men in general and men diagnosed with prostate cancer. The findings from our study on high-grade prostate cancer may lead to a new way to prevent aggressive prostate cancer: by treating prostate inflammation. In the near term, effective and safe treatments for prostate inflammation would need to be identified. In the longer term, clinical trials could be done to determine whether treating inflammation in men's prostates would reduce the chance that they are diagnosed with aggressive prostate cancer in the future. Also, if we learn that men with focal atrophy are more likely to be diagnosed with aggressive prostate cancer, then in the near term our work would lead to studies on the causes and prevention of these lesions, with prevention trials to follow in the long term. The findings from our proposed study on recurrence may support inflammation and focal atrophy as additional factors that improve prognostication, which is needed for clinical decision-making for treatment and surveillance for men diagnosed with early prostate cancer. In the near term, additional studies would need to be done to confirm the findings. If confirmed, then inflammation and focal atrophy could be easily added to the list of prognostic factors that pathologists record and provide to patients and their doctors to make decisions about their care.