Cigarette Smoking and Risk of Prostate Cancer in Middle-Aged Men 1

Cigarette smoking may increase the risk of prostate cancer by affecting circulating hormone levels or through exposure to carcinogens. Although there are plausible mechanisms that could explain an association between smoking and prostate cancer, previous studies are inconsistent. The goal of this population-based casecontrol study was to assess this association in middle-aged men. Cases (n 753) were men ages 40–64 years diagnosed with prostate cancer from 1993 to 1996 identified using the Seattle-Puget Sound Cancer Registry. Age-matched controls without prostate cancer from the same region (n 703) were identified using random digit dialing. Participants completed detailed in-person interviews. Logistic regression was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to assess the prostate cancer-cigarette smoking relationship. Current smokers had an increased risk (OR 1.4, 95% CI 1.0–2.0) relative to nonsmokers. A dose-response relationship was noted between number of pack-years smoked and prostate cancer risk (trend P 0.03). The OR 1.6 (95% CI 1.1–2.2) for men with >40 pack-years of smoking, with a stronger association observed in men with more aggressive disease (OR 2.0, 95% CI 1.3–3.1). Smoking cessation resulted in a decline in risk (trend P 0.02). Smoking is associated with a moderately increased relative risk of prostate cancer. Furthermore, a dose-response relationship exists between number of pack-years smoked and cancer risk. Given that smoking cessation seems to reduce these risks, results from this study have public health ramifications and suggest that prostate cancer should be added to the list of tumors for which cigarette smoking is a risk factor. Introduction Prostate cancer is the most frequent solid tumor diagnosed and the second leading cause of cancer death among American men (1). Certain risk factors for prostate cancer, such as advanced age, African-American race, and first-degree family history of the disease, have been identified, yet few causative environmental exposures for prostate cancer are known (2). It is likely that environmental influences play a role in the development of prostate cancer because migration studies of Japanese immigrants to the United States have found that the risk of prostate cancer increased 5-fold with the change of environment (3). It would be valuable to identify modifiable environmental risk factors for prostate cancer that can serve as targets for public health interventions that might lower the incidence of this common malignancy. One such potential modifiable risk factor is cigarette smoking. There are several hypothetical mechanisms through which cigarette smoking may enhance prostate cancer risk. For example, cigarette smoking may alter circulating levels of steroid hormones. In particular, cigarette smoking has been associated with higher levels of bioavailable testosterone and lower levels of bioavailable estradiol in men (4). Studies found significant (Ps 0.01) positive correlations between cigarettes smoked/day and serum total androstenedione as well as total and free testosterone in men (5). This is significant because testosterone and its more potent metabolite DHT are necessary not only for normal prostate development and growth but also appear to enhance cell proliferation in the prostate, which potentially could be associated with malignant transformation. Conversely, estrogens act on the hypothalamus and pituitary to suppress secretion of gonadotropins, which may reduce testicular androgen production (6). Effectively, cigarette smoking may establish a hormonal milieu that is favorable for the development or progression of prostate cancer. In addition, cigarettes contain significant levels of cadmium, which has been linked to prostate carcinogenesis (7–9). Either or both of these mechanisms could support an association between cigarette smoking and prostate cancer. Despite reasonable theoretical underpinnings for a relationship between smoking and prostate cancer, conclusive epidemiological evidence of this association is lacking. Hickey et al. (10) recently completed a structured review of the existing literature on cigarette smoking and prostate cancer. They found 23 prospective cohort studies, 5 nested case-control studies, 1 retrospective cohort study, and 36 case-control studies addressing this issue. Although most of the prospective cohort studies and all of the nested case-control studies found no relationship, 33% of the 15 population-based case-control studies showed a significant association between cigarette smoking and prostate cancer risk. Hickey et al. (10) concluded that these conflicting Received 8/1/02; revised 3/21/03; accepted 3/31/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by Grant CA56678 and Contract N01-CN-05230 from the National Cancer Institute, NIH, Department of Health and Human Services. L. A. P. was supported, in part, by Training Grant T32 DK007721 from the National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Department of Health and Human Services. 2 To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MW-814, Seattle, WA 981091024. Phone: (206) 667-2715; Fax: (206) 667-2717; E-mail: jstanfor@fhcrc.org. 3 The abbreviations used are: DHT, dihydrotestosterone: OR, odds ratio; CI, confidence interval; PSA, prostate-specific antigen; BPH, benign prostatic hyperplasia; SHBG, sex hormone-binding globulin. 604 Vol. 12, 604–609, July 2003 Cancer Epidemiology, Biomarkers & Prevention on May 30, 2017. © 2003 American Association for Cancer Research. cebp.aacrjournals. org Downloaded from findings may be because many of the previous studies suffered from methodological shortcomings such as differential measurement error in outcomes, attribution bias, surveillance bias, and inadequate adjustment for confounders. They suggest that future studies avoid these pitfalls by collecting a more comprehensive smoking history, with particular information on cessation, and by obtaining information on potential confounding factors such as dietary fat intake and history of prostate cancer screening. The goal of the current study was to assess the association between cigarette smoking and prostate cancer while avoiding some of the methodological problems of prior research. Using a population-based case-control design, a detailed smoking history was obtained with particular attention to duration, amount of smoking, and smoking cessation. In addition, information was collected on stage and grade of cancer at diagnosis, which allowed examination of smoking associations according to clinical characteristics of the disease. Finally, we focused on men age 65 years who are at relatively low baseline risk for prostate cancer in an effort to discover modest associations that might otherwise be undetectable in an older population at greater absolute risk for this complex disease. Materials and Methods Study Subjects. We conducted a population-based casecontrol study of risk factors for prostate cancer in middle-aged men, including lifetime history of cigarette smoking. Case patients included Caucasian and African-American male residents of King County in northwestern Washington, 40–64 years old, who were diagnosed with biopsy-proven prostate cancer between January 1, 1993, and December 31, 1996. Eligible cases were identified from the Seattle-Puget Sound SEER cancer registry and included 100% ages 60 years and a random 75% sample of those who were ages 60–64 years at diagnosis. A comparison group (n 703) without a history of prostate cancer was identified through random digit dialing using a clustering factor of five residences/sampling unit (11). These individuals were male residents of King County, Washington, 40–64 years of age. Controls were frequency matched to case patient by age (same 5-year group) and recruited evenly throughout the ascertainment period of cases. All study participants signed informed consent for participation. The Fred Hutchinson Cancer Research Center’s Institutional Review Board approved study forms and procedures. Study subjects completed a structured in-person interview administered by a trained male interviewer. The questionnaire addressed the following areas: social and demographic factors; physical development, height, weight, and physical activity; reproductive history; detailed medical history, including history of BPH and prostate cancer screening; family structure and cancer history; dietary habits, including total dietary fat intake and servings of cruciferous vegetables consumed/week; lifetime smoking and alcohol consumption; lifetime sexual history; and occupational history. Clinical patient data were available from the cancer registry, including tumor grade and stage of disease at diagnosis. A detailed smoking history before reference date (date of diagnosis for cases and a similar assigned date for controls) was collected, including ages at onset and cessation, duration, and dose of cigarette smoking. Statistical Methods. ORs were calculated to estimate the association between prostate cancer and the following smoking variables (continuous and categorized): smoking status (nonsmoker, current, former); duration of smoking (1–9, 10–19, 20–29, 30–39, 40 years); number of cigarettes smoked/day (1–10, 11–20, 21–30, 31–40, 41); total pack-years of smoking ( 0–10, 11–20, 21–30, 31–40, 40); years since cessation in former smokers ( 0–9, 10–19, 20–29, 30 years); and age first smoked ( 15, 16–17, 18–19, 20 years). Multivariate logistic regression (12) analysis was used to compute ORs and estimate 95% CIs adjusted for potential confounders such as age, race, family history of prostate cancer, body m