Research Article Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study Daniel M. Moreira 1 , J. Curtis Nickel 2 , Leah Gerber 3,4 , Roberto L. Muller 3,4 , Gerald L. Andriole 5 , Ramiro Castro-Santamaria 6 , and Stephen J. Freedland 3,4,7 Abstract Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflamma- tion. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The asso- ciation of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and mul- tivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were signif- icantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independent- ly associated with acute and possibly chronic prostate inflam- mations. Cancer Prev Res; 8(4); 312–7. Ó2015 AACR. Introduction Cigarette smoking has been associated with higher prostate cancer mortality in all comers and more disease recurrence, metastasis, and cancer-specific mortality after surgery and radio- therapy for prostate cancer (1–5). Although, the pathways by which smoking affects prostate carcinogenesis and prostate cancer progression are largely unknown, several potential mechanisms have been proposed, including genetic and epigenetic changes, enhanced angiogenesis, life style factors, and inflammation. Indeed, the effects of cigarette smoking on the immune system are far-reaching and may affect the prostate. For example, there is evidence suggesting cigarette smoking promotes an overall sys- temic inflammatory state by increasing levels of proinflammatory markers (6). Moreover, inflammatory changes in distant organs, such as eyes, arteries, and pancreas, have been described among active smokers (7–9). Conversely, active smoking has been linked to a decreased risk of ulcerative colitis, an inflammatory bowel disease (10), and rosacea, an inflammatory skin disorder (11). Thus, the direct inflammatory effects of cigarette smoking on several organs, including the prostate, remain to be determined. Acute and chronic inflammatory infiltrates are frequently found in the prostate. Previous studies indicate that between 35% and 100% of prostate biopsies done for suspected prostate cancer had some histologic evidence of inflammation (12–15). However, factors associated with inflammatory changes in the prostate of men undergoing biopsy are largely unknown. To date, no studies have evaluated the association of cigarette smoking with histologic prostatic inflammation. Therefore, we sought to evaluate the association of smoking status and histologic inflam- mation in the prostates of men undergoing prostate biopsy in the REduction by DUtasteride of Prostate Cancer Events (REDUCE) trial. The REDUCE trial was a 4-year, placebo-controlled study evaluating daily dutasteride to reduce the risk of biopsy detectable prostate cancer among patients with negative baseline prostate biopsy (16). Repeat prostate biopsies were performed at 2 and 4 years. Thus, REDUCE uniquely allows the examination of the relationship between baseline cigarette smoking and inflamma- tory changes on baseline-negative biopsies and subsequent repeat prostate biopsies. We hypothesize that smoking is associated with greater risk of inflammation in the prostate. 1 Department of Urology, Mayo Clinic, Rochester, Minnesota. 2 Depart- ment of Urology, Queen's University, Kingston, Ontario,Canada. 3 Divi- sion of Urologic Surgery, Department of Surgery, Duke University School of Medicine, Durham, North Carolina. 4 Urology Section,Veter- ans Affairs Medical Center, Durham, North Carolina. 5 Division of Uro- logic Surgery, Department of Surgery,Washington University School of Medicine, St. Louis, Missouri. 6 GlaxoSmithKline Inc., Metabolic Path- ways and Cardiovascular R&D Unit, King of Prussia, Pennsylvania. 7 Department of Pathology, Duke University School of Medicine, Dur- ham, North Carolina. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). Corresponding Author: Daniel M. Moreira, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 516-234-5159; Fax: 516-234-5159; E-mail: Moreira.Daniel@mayo.edu doi: 10.1158/1940-6207.CAPR-14-0260 Ó2015 American Association for Cancer Research. Cancer Prevention Research Cancer Prev Res; 8(4) April 2015 312 Downloaded from http://aacrjournals.org/cancerpreventionresearch/article-pdf/8/4/312/2254718/312.pdf by guest on 12 June 2022