CORRESPONDENCE

RESPONSE: Re: Zinc Supplement Use and Risk of Prostate Cancer

Michael F. Leitzmann, Edward Giovannucci

Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (MFL); Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA (EG).

Correspondence to: Michael F. Leitzmann, MD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS-MSC 7232, Bethesda, MD 20892 (e-mail: leitzmann{at}.mail.nih.gov)

We respond briefly to the points raised by Costello et al. concerning our paper on zinc supplement use and the risk of prostate cancer (1). First, Costello et al. suggest that we should have provided P values for the pair-wise statistical comparisons of each zinc-user group with the nonuser group and used the Bonferroni correction for multiple comparisons. However, the standard method of providing estimates of disease risk according to distinct levels of an exposure in epidemiologic studies is the relative risk with its corresponding 95% confidence interval, and not the P value (2). We recognize that there is a difference of opinion regarding the adjustment for multiple comparisons: We do not believe that a uniform adjustment of the critical level of statistical significance for the P value is the best approach in this circumstance (2) because our study does not represent a multiple-inference situation.

Second, Costello et al. express concern about our small sample size at the highest level of zinc intake. We acknowledge that our risk estimate for men who consumed more than 100 mg/day of supplemental zinc (relative risk = 2.29) is somewhat imprecise as indicated by its wide confidence interval (95% confidence interval = 1.06 to 4.95). However, Costello et al. do not dispute the highly statistically significant positive tests for trend for level of supplemental zinc intake (Ptrend = .003) and duration of supplemental zinc use (Ptrend<.001) that remained statistically significant even after we excluded nonusers of zinc supplements from the analysis. The test for trend used in our study is a robust overall test for statistical significance that takes into account the entire range of supplemental zinc intake. Moreover, the Cox proportional hazards regression model used in our analysis (3) is not characterized by large sample-approximation requirements, as is the contingency table approach proposed by Costello et al.

Third, Costello et al. state that we failed to refer to published studies that conflict with our findings. On the contrary, we referred to six studies that reported results on zinc and prostate cancer that were not in agreement with our results (49), including two important studies by Costello's group (4,5) showing that high cellular zinc levels inhibit prostate cancer cell growth. In fact, our initial motivation to examine the zinc–prostate cancer hypothesis was based on study results suggesting that zinc protects against prostate carcinogenesis (49). Somewhat to our surprise, we observed an increased risk of advanced prostate cancer associated with high-dose and long-term use of zinc supplementation. The apparent 25% decrease in risk of advanced prostate cancer among men reporting 1–24 mg/day of supplemental zinc intake was not statistically significant after adjusting for potentially confounding variables. Unfortunately, we could not discuss the epidemiologic literature on zinc and prostate cancer in detail within the context of a brief communication, but we did acknowledge potential alternative explanations for our findings (e.g., confounding).

Fourth, Costello et al. argue that any analysis and interpretation of the potential effects of dietary zinc on prostate cancer should include a consideration of circulating or cellular levels of zinc. We acknowledge the importance of the simultaneous exploration of the various mechanistic pathways through which zinc may modify prostate carcinogenesis. Thus, we agree with Costello et al. that readers should not conclude that our study is the definitive study on zinc and prostate cancer. Quite the contrary: It is the first study that provides prospective data on the relationship between long-term intake of high doses of zinc and the risk of prostate cancer. We hope our findings stimulate future progress toward understanding the complex interactions between zinc levels (dietary, serum, and tissue) and prostate carcinogenesis.

REFERENCES

1 Leitzmann MF, Stampfer MJ, Wu K, Colditz GA, Willett WC, Giovannucci EL. Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 2003;95:1004–7.[Abstract/Free Full Text]

2 Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Boston (MA): Little, Brown and Company; 1998. p. 201–29.

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6 Iguchi K, Hamatake M, Ishida R, Usami Y, Adachi T, Yamamoto H, et al. Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction. Eur J Biochem 1998;253:766–70.[Abstract]

7 Ishii K, Usui S, Sugimura Y, Yoshida S, Hioki T, Tatematsu M, et al. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion. Int J Cancer 2001;92:49–54.[CrossRef][ISI][Medline]

8 Ishii K, Usui S, Sugimura Y, Yamamoto H, Yoshikawa K, Hirano K. Inhibition of aminopeptidase N (AP-N) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells. Biol Pharm Bull 2001;24:226–30.[CrossRef][ISI][Medline]

9 Zaichick VY, Sviridova TV, Zaichick SV. Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int Urol Nephrol 1997;29:565–74.[Medline]



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