NSAIDs for the Prevention and Control of Lethal Prostate Cancer

Background: Modifiable risk factors for prostate cancer, and specifically lethal prostate cancer, are needed. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against prostate cancer development and progression, but the current evidence base is limited. To elucidate the potential role of NSAIDs in the primary and tertiary prevention of lethal prostate cancer, this dissertation investigated associations between NSAID use and (1) prostate cancer incidence, including incidence of lethal disease, and mortality, (2) prostate cancer outcomes among men diagnosed with prostate cancer, and (3) inflammation and markers of specific immune cells in benign prostate tissue. Methods: Associations between NSAID use and prostate cancer incidence and mortality were estimated for men in the Atherosclerosis Risk in Communities (ARIC) study, which enrolled participants from four communities in1987-1989. Associations between NSAID use and case-fatality were studied among men diagnosed with prostate cancer during ARIC follow-up (1987-2012), and associations between NSAID use and prostate cancer recurrence were studied among men treated surgically for localized prostate cancer at the Johns Hopkins Hospital (JHH) between 1993-2006. Associations between aspirin use and the presence and extent of inflammation, as well as markers of specific immune cells, were examined in benign prostate tissue collected without indication from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial (PCPT), who were enrolled in 1993-1997. Results: In the ARIC study, aspirin but not non-aspirin NSAID use was inversely associated with lethal and fatal prostate cancer. Aspirin use prior to diagnosis was also associated with prostate cancer case-fatality. In the JHH study, neither aspirin nor non-aspirin NSAID use pre- or post-surgery were inversely associated with prostate cancer recurrence. For aspirin, there was suggestive evidence of a positive association. In the PCPT study, aspirin use at trial entry was inversely associated with the extent of inflammation and the abundance of FoxP3, a marker of T regulatory cells, in benign prostate tissue collected seven years later. Conclusions: This dissertation provides support for the role of aspirin in the primary prevention of lethal prostate cancer, and suggests that aspirin may act by reducing the extent of inflammation within the prostate