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Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.

Strategies for the prevention of cancer include those aimed at reducing the incidence of cancer (primary prevention) and cancer mortality through early detection of tumors (secondary prevention). The efficacy of prevention interventions is evaluated by clinical trials. The conduct of clinical trials is aided by the use of serological indicators of the carcinogenic process measured using plasma or red or white blood cells. The accessibility and acceptability of obtaining blood samples for the measurement of serological markers of carcinogenesis permit widespread applications in the conduct of clinical trials. Serological markers must be shown to be valid and reliable before their use. Serological markers identify a variety of stages in the process of carcinogenesis such as inherited or acquired susceptibility to cancer, environmental exposures to carcinogens, biological effects of exposures, and the presence of preinvasive or invasive cancer. Serological markers may be used in clinical trials to select high risk but disease-free individuals for participation in clinical trials based on susceptibility factors or carcinogenic exposures. Other uses of serological markers include monitoring adherence to interventions and establishing trial outcomes of intermediate cancer end points or incident invasive disease. Examples of these applications are discussed. Serological markers of carcinogenesis have widespread applications in clinical research and potentially for clinical practice. Currently, the only limitation to their widespread use is the availability of validated serological markers. Because of the ease and acceptability of their use, research into the development of serological markers should continue. Methods for quickly validating serological markers should be developed in order to aid the transition to clinical applications.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are steroids which may be associated with the development of breast cancer. To examine the association between serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing premenopausal breast cancer, we measured hormone levels in 15 women who donated blood to a community-based serum bank in 1974 and who subsequently developed premenopausal breast cancer and in 29 matched controls from the same group of volunteers. The mean serum level of dehydroepiandrosterone among cases was 10% lower than among controls. The risk of developing breast cancer for women in the highest tertile compared with the lowest tertile of serum dehydroepiandrosterone was 0.40 with a suggestion of a dose-response trend with increasing levels. No consistent association between dehydroepiandrosterone sulfate and the risk of premenopausal breast cancer was evident. In contrast to postmenopausal breast cancer, a protective effect of dehydroepiandrosterone against premenopausal breast cancer is suggested, but because of the small sample size, the results of this study need to be replicated by others.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids largely produced in the adrenal cortex and excreted in the urine. Many studies have demonstrated that administration of dehydroepiandrosterone to animals protects against a variety of chemical carcinogens. Epidemiological studies suggest that the circulating levels of these steroids in humans are related to the risk of developing some cancers and of dying from atherosclerotic cardiovascular disease. We measured serum levels of both of these steroids in 35 individuals who donated serum to a community-based serum bank in 1974 and who subsequently developed bladder cancer and in 69 matched controls from the same cohort of volunteers. Prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly lower among cases compared with controls. The risk of developing bladder cancer increased monotonically with decreasing serum levels of both steroids. The observed associations were not affected by adjustment for smoking or the time interval between serum collection and diagnosis. These results support a role for dehydroepiandrosterone and/or dehydroepiandrosterone sulfate in the prevention of bladder cancer.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids that are produced in the adrenal cortex. A number of studies have suggested that circulating levels of these hormones are related in some way to the risk of developing breast cancer. We measured serum levels of these steroids in 30 postmenopausal women who donated blood in 1974 for a community-based serum bank and who subsequently, at least 9 years later, developed breast cancer and in 59 matched controls from the same group of volunteers. Significantly elevated serum levels of dehydroepiandrosterone were found among cases prior to diagnosis compared to controls; serum levels of dehydroepiandrosterone sulfate were slightly increased among cases. In controls, current cigarette use was associated with increased serum levels of these steroids, and levels of both steroids decreased with age.

To examine the association between serum nutrients and the development of bladder cancer we measured selenium, alpha-tocopherol, lycopene, beta-carotene, retinol, and retinol-binding protein in serum collected from 25,802 persons in Washington County, MD, in 1974. Serum samples were kept frozen at -70 degrees C. In the subsequent 12-year period, 35 cases of bladder cancer developed among participants. Comparisons of serum levels in 1974 among cases and two matched controls for each case showed that selenium was significantly lower among cases than controls (P = 0.03), lycopene was lower among cases at a borderline level of significance (P = 0.07), and alpha-tocopherol was nonsignificantly lower (P = 0.13). For selenium there was a nearly linear increase in risk with decreasing serum levels (P = 0.03). When examined by tertiles, the odds ratio associated with the lowest tertile of selenium compared to the highest tertile was 2.06. Serum levels of retinol, retinol-binding protein, and beta-carotene were similar among cases and controls. These results support a role for selenium in the prevention of bladder cancer.