Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.

BACKGROUND: Selenium and alpha-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of gamma-tocopherol, a major component of vitamin E in the U.S. diet and the second most common tocopherol in human serum. A nested case-control study was conducted to examine the associations of alpha-tocopherol, gamma-tocopherol, and selenium with incident prostate cancer. METHODS: In 1989, a total of 10,456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, alpha-tocopherol, and gamma-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: The risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol (odds ratio (highest versus lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32; P(trend) =.28). For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (P:(trend) =.002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (P(trend) =.27). Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high. CONCLUSIONS: The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium.

Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer.

BACKGROUND: Glutathione S-transferases (GSTs) are encoded by a superfamily of genes and play a role in the detoxification of potential carcinogens. In a nested case-control study, we investigated associations between genetic variability in specific GST genes (GSTM1, GSTT1, and GSTP1) and susceptibility to breast cancer. METHODS: In 1989, a total of 32 898 individuals donated blood samples to a research specimen bank established in Washington County, MD. Genotypes of blood specimen DNA were determined for 110 of 115 women with incident cases of breast cancer diagnosed during the period from 1990 through 1995 and up to 113 of 115 control subjects. Associations between specific genotypes and the development of breast cancer were examined by use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The GSTM1 homozygous null genotype was associated with an increased risk of developing breast cancer (OR = 2.10; 95% CI = 1.22-3.64), principally due to an association with postmenopausal breast cancer (OR = 2.50; 95% CI = 1.34-4.65). For GSTP1, the data were suggestive of a trend of increasing risk with higher numbers of codon 105 valine alleles (compared with isoleucine alleles); a 1.97-fold increased risk of breast cancer (95% CI = 0.77-5.02) was associated with valine/valine homozygosity. The risk of breast cancer associated with the GSTT1 homozygous null genotype was 1.50 (95 % CI = 0.76-2.95). The risk of breast cancer increased as the number of putative high-risk genotypes increased (P for trend <.001) (OR = 3.77; 95% CI = 1.10-12.88 for a combined genotype of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity). CONCLUSIONS: Our findings suggest that genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.

Prospective study of serum micronutrients and ovarian cancer.

BACKGROUND: Antioxidant micronutrients, such as alpha-tocopherol (vitamin E), the carotenoids, and selenium, may protect against the development of cancer by preventing free radical damage at the cellular level. PURPOSE: A nested case--control study was conducted among donors to a serum bank to examine the association between levels of serum micronutrients and/or cholesterol and the development of ovarian cancer. METHODS: In 1974, sera were collected from 20,305 residents of Washington County, MD, over a 4-month period and stored at -70 degrees C. Serum micronutrient concentrations of women who developed ovarian cancer (case subjects, n = 35) were compared with those of women who remained free of cancer and who were matched to case subjects on age and menopausal status (control subjects, n = 67). Serum levels of retinol (vitamin A), alpha- and beta-carotene (the major provitamin A), lycopene (a carotenoid), and alpha- and gamma-tocopherol were measured using high-performance liquid chromatography. Serum selenium was measured by neutron activation analysis. Cholesterol was measured by enzymatic assay. The data were categorized into thirds and conditional logistic regression analyses were performed to determine the association between prediagnostic serum cholesterol and micronutrient levels and the development of ovarian cancer; matched odds ratios (ORs) were determined from these regression analyses. P values for trend and for interaction were calculated with the use of two-sided likelihood ratio tests. RESULTS: Higher serum alpha-tocopherol levels were associated with an increased risk of ovarian cancer (P for trend = .04); however, this association diminished after adjustment for cholesterol. Women with higher serum cholesterol levels had an increased risk of ovarian cancer compared with women in the lowest third of cholesterol levels (OR = 3.2; 95% confidence interval = 0.9-11.3). The association between serum cholesterol levels and the risk of ovarian cancer was examined, stratifying by micronutrient level. The general pattern observed was an increased risk of ovarian cancer associated with cholesterol levels greater than 200 mg/dL, regardless of the micronutrient level. Serum selenium was associated with a decreased risk of ovarian cancer only among case participants diagnosed 4 or more years after blood collections (P for trend = .02). Concentrations of carotenoids and retinol were not associated with the development of ovarian cancer. CONCLUSIONS: Selenium may have a protective role against the development of ovarian cancer. Higher serum cholesterol levels were associated with an increased risk of developing ovarian cancer; an association that persisted regardless of serum micronutrient level. IMPLICATIONS: Given the small size of this study and the inconsistency of results among the few prospective studies of ovarian cancer conducted to test these associations, replications of these findings are highly desirable.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five U.S. studies.

BACKGROUND: Environmental exposure to organochlorines has been examined as a potential risk factor for breast cancer. In 1993, five large U.S. studies of women located mainly in the northeastern United States were funded to evaluate the association of levels of 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and polychlorinated biphenyls (PCBs) in blood plasma or serum with breast cancer risk. We present a combined analysis of these results to increase precision and to maximize statistical power to detect effect modification by other breast cancer risk factors. METHODS: We reanalyzed the data from these five studies, consisting of 1400 case patients with breast cancer and 1642 control subjects, by use of a standardized approach to control for confounding and assess effect modification. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) by use of the random-effects model. All statistical tests were two-sided. RESULTS: When we compared women in the fifth quintile of lipid-adjusted values with those in the first quintile, the multivariate pooled OR for breast cancer associated with PCBs was 0.94 (95% CI = 0.73 to 1.21), and that associated with DDE was 0.99 (95% CI = 0.77 to 1.27). Although in the original studies there were suggestions of elevated breast cancer risk associated with PCBs in certain groups of women stratified by parity and lactation, these observations were not evident in the pooled analysis. No statistically significant associations were observed in any other stratified analyses, except for an increased risk with higher levels of PCBs among women in the middle tertile of body mass index (25-29.9 kg/m(2)); however, the risk was statistically nonsignificantly decreased among heavier women. CONCLUSIONS: Combined evidence does not support an association of breast cancer risk with plasma/serum concentrations of PCBs or DDE. Exposure to these compounds, as measured in adult women, is unlikely to explain the high rates of breast cancer experienced in the northeastern United States.

Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer.

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.

Keratinocyte Carcinoma as a Marker of a High Cancer-Risk Phenotype.

Keratinocyte carcinoma (KC) (also referred to as nonmelanoma skin cancer) is by far the most common form of human cancer. A personal history of KC is well established to be associated with increased risk of recurrent KC and malignant melanoma, a less common yet more fatal form of skin cancer. More surprising is that a substantial body of epidemiologic evidence now indicates that a personal history of KC is significantly associated with an overall elevated risk of noncutaneous malignancies. This association is not limited to one or a few types of cancer but applies across many different types of malignancy. This association has been consistently observed in prospective studies across genders for both major histologic types of KC, basal cell carcinoma and squamous cell carcinoma. The risk of other cancers has been even stronger in those with younger compared with older age of onset of KC. A robust body of evidence lends support to the notion that KC may be a marker of a high cancer-risk phenotype. The underlying mechanisms for this association remain to be elucidated, but the cross-cutting nature of this association across numerous malignancies suggests that research to uncover these mechanisms is a promising line of inquiry that could potentially yield valuable insight into human carcinogenesis.

Household exposure to passive cigarette smoking and serum micronutrient concentrations.

BACKGROUND: The associations observed between passive smoking and adverse health outcomes have generated controversy. In part, this could be because the diets of passive smokers, like those of active smokers, differ from those of persons who are not exposed to cigarette smoke, especially with regard to antioxidants. OBJECTIVE: Our objective was to assess the relation between household exposure to passive smoking and serum concentrations of retinol, tocopherols, and carotenoids. DESIGN: A cross-sectional study was conducted in Washington County, MD, to compare exposure to passive smoking at home, recorded in a private census of county residents in 1975, with micronutrient concentrations assayed in serum collected in 1974. This comparison was possible for 1590 control subjects in nested case-control studies conducted between 1986 and 1998. RESULTS: Among persons who were not current smokers, those who lived with smokers tended to have lower serum total carotenoid, alpha-carotene, ss-carotene, and cryptoxanthin concentrations than did those who lived in households with no smokers. There was little evidence that exposure to passive smoking was associated with reduced serum concentrations of lutein and zeaxanthin, lycopene, retinol, alpha-tocopherol, or gamma-tocopherol. CONCLUSIONS: Among nonsmokers, exposure to passive smoking tended to be associated with lower serum concentrations of the carotenoids most strongly associated with active smoking (total carotenoids, alpha-carotene, ss-carotene, and cryptoxanthin). The associations were weaker for passive smoking than for active smoking. The consistency of the associations observed for active and passive smoking indicates that exposure to passive smoking may result in decreased circulating concentrations of selected micronutrients.

Antibodies to human papillomavirus 16 and subsequent in situ or invasive cancer of the cervix.

Our objective was to examine whether past infection with human papillomavirus (HPV)-16, as determined by an antibody assay, is a risk factor for subsequent cervical cancer. Incident cases of in situ or invasive cervical cancer occurring between 1975 and 1990 in a cohort of over 11,000 healthy women in Washington County, MD, were identified. The baseline sera of cases and of matched controls, collected in 1974, were examined for IgG antibodies reactive with virus-like particles of HPV-16, a cancer-associated HPV, and HPV-6, a low-risk HPV. Postdiagnosis sera of 11 cases were also assessed similarly. Fourteen cases of invasive and 28 cases of in situ cervical cancer and 83 matched controls were evaluated. The main outcome measure was the risk of cervical cancer in women who had HPV-16 or HPV-6 antibodies in prediagnostic sera. Antibodies to HPV-16 but not to HPV-6 were a marker for subsequent occurrence of cervical cancer. Case sera were reactive more often and more strongly with HPV-16 virus-like particles than were sera of matched controls. The presence of antibodies to HPV-16 was significantly associated with an increased risk of cervical cancer (odds ratio, 3.9; 95% confidence limits, 1.4, 10.7); high antibody levels to HPV-16 were associated with an even greater risk of cervical cancer (odds ratio = 7.5, 95% confidence limits 1.5, 36.3). The association with cervical cancer was strengthened after adjustment for smoking and years of education. In tests of 11 pairs of pre- and postdiagnostic sera, HPV-16 antibodies did not decline markedly over a 7-13-year time period, and seroconversion to HPV-16 appeared to have occurred in 2 cases. The serological data indicate that HPV-16 infection is associated with future risk of cervical cancer and strengthen the evidence for the etiological role of HPVs in cervical cancer.

Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and the subsequent risk of developing colon cancer.

This purpose of this study was to evaluate whether serum dehydroepiandrosterone (DHEA) and its sulfate conjugate, dehydroepiandrosterone sulfate (DHEAS), are associated with the likelihood of developing colon cancer. A nested case-control study was conducted using the serum bank and cancer registry in Washington County, Maryland. From a population of 20,305 county residents who donated blood in 1974, incident cases of colon cancer that occurred from 1975 to 1991 (n = 117) were matched to one cancer-free control by age, race, and sex. Serum specimens that were stored at -70 degrees C since 1974 were assayed for DHEA and DHEAS. Compared with the controls, the mean serum concentrations of cases were 3% lower for DHEA (P = 0.90) and 13% lower for DHEAS (P = 0.60). When DHEA levels were analyzed according to fourths, no noteworthy associations were observed. Compared with the lowest fourth, the highest fourth of serum DHEAS was nonsignificantly associated with a halving in the risk of colon cancer (odds ratio, 0.50; 95% confidence limits, 0.18, 1.37; Ptrend = 0.22), and further analyses showed the potential protective association was confined largely to males (highest-versus-lowest fourth odds ratio, 0.26; 95% confidence limits, 0.06, 1.16; Ptrend = 0.06). This prospective study does not provide strong evidence that circulating DHEA and DHEAS concentrations are associated with the risk of colon cancer. Among men, DHEAS was associated with a decreased risk of colon cancer, but the association was within the bounds of chance. Further studies are needed to either support or refute the potentially promising lead hinted at by the results for DHEAS.

Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the risk of developing gastric cancer.

Although the incidence of gastric cancer varies widely between countries it is nonetheless a leading cause of cancer deaths worldwide. Migration studies indicate that dietary choices are an important exogenous factor. The United States has a very low incidence of gastric cancer, suggesting that exogenous etiological agents are at a minimum and providing a favorable setting for detecting important endogenous etiological factors. Dehydroepiandrosterone and dehydroepiandrosterone sulfate are endogenous steroids produced in the adrenal gland. Epidemiological studies show that the risk of developing specific cancers is related to the serum or urinary levels of these steroids. In addition, dehydroepiandrosterone prevents a variety of spontaneous and chemically induced tumors when administered to laboratory animals. To examine the association between circulating levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate and the development of gastric cancer, we measured the serum levels of these steroids in 13 individuals who donated serum to the Washington County Maryland serum bank in 1974 and who subsequently developed gastric cancer and in 52 matched controls. Prediagnostic serum levels of dehydroepiandrosterone were 38% lower in cases as compared to controls (P = 0.09). The risk of developing gastric cancer increased with decreasing levels of both steroids. Adjustment for confounding factors such as smoking or the interval between blood donation and time to diagnosis did not alter the findings. These results suggest that there may be a role for this steroid in the prevention of gastric cancer.

Serological precursors of cancer: malignant melanoma, basal and squamous cell skin cancer, and prediagnostic levels of retinol, beta- carotene, lycopene, alpha-tocopherol, and selenium.

To determine the association between prediagnostic serum levels of retinol, beta-carotene, lycopene, alpha-tocopherol, and selenium and the subsequent risk of malignant melanoma, and basal and squamous cell skin cancer, a nested case-control study among residents of Washington County, MD, was performed. Cases with melanoma (n = 30), basal cell (n = 32), and squamous cell (n = 37) skin cancer who were admitted to hospital for treatment or biopsy of metastatic lesions were each matched by age, sex, and race with two controls. There were no significant associations between serum micronutrient levels and the risk of subsequent skin cancer.

Association between CYP17 polymorphisms and the development of breast cancer.

A nested case-control study was conducted to determine whether a genetic polymorphism in the CYP17 gene, which encodes for an enzyme that mediates steroid hormone metabolism, was associated with an increased risk of breast cancer. No association was found between the presence of an A2 allele and the subsequent development of breast cancer [A1/A2 odds ratio, 0.61 (95% confidence interval, 0.33-1.14); A2/A2 odds ratio, 0.89 (95% confidence interval, 0.41-1.95)]. No significant association was observed with risk factors presumed to be surrogates for endogenous estrogen exposure, nor was there an association observed with the stage of disease at diagnosis. Genotype frequencies in this Caucasian population were similar to those reported for African-American, Asian, and Latino women. Additional studies of larger size are needed to achieve a consensus regarding the relevance of CYP17 genotypes to the risk of developing breast cancer.

The risk of cervical cancer in relation to serum concentrations of folate, vitamin B12, and homocysteine.

Due to its role in the synthesis and repair of DNA, folate may protect against the development of cervical cancer. Prospective data on the possible association between folate and cervical cancer have been lacking. There is also a paucity of prospective evidence concerning the possible associations between cervical cancer and vitamin B12, which shares pathways with folate, and homocysteine, a marker of low B vitamin concentrations. A nested case-control study was conducted to prospectively evaluate the associations between cervical cancer and serum concentrations of folate, vitamin B12, and homocysteine. Among a community-based cohort of women who donated blood in 1974 for a serum bank in Washington County, Maryland, 39 cases of cervical cancer diagnosed between 1975 and mid-1990 were included in the study (13 cases of invasive cervical cancer and 26 cases of carcinoma in situ). Two controls were matched to each case by age, race, and sex. Stored serum from the cases and controls was assayed for folate, B12, and homocysteine concentrations. For folate, adjusted odds ratios were 1.0, 0.62, and 0.60 for the low to high thirds of the serum concentrations, respectively, a trend in the protective direction that was not statistically significant (P for trend = 0.42). Overall, the results for vitamin B12 tended to mimic those for folate, whereas the associations for homocysteine tended to be in the opposite direction. None of the results of this study were statistically significant, but patterns of the associations are in accord with hypothesized mechanistic pathways concerning B vitamins and cervical cancer.

The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity.

Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.

Serum concentrations of organochlorine compounds and the subsequent development of breast cancer.

A nested case-control study was conducted to examine the association between serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the primary metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and polychlorinated biphenyls (PCBs) and the development of breast cancer up to 20 years later. Cases (n = 346) and controls (n = 346) were selected from cohorts of women who donated blood in 1974, 1989, or both, and were matched on age, race, menopausal status, and month and year of blood donation. Analyses were stratified by cohort participation because median DDE and PCB concentrations among the controls were 59 and 147% higher in 1974 than 1989, respectively. Median concentrations of DDE were lower among cases than controls in both time periods [11.7% lower in 1974 (P = 0.06) and 8.6% lower in 1989 (P = 0.41)]. Median concentrations of PCBs were similar among cases and controls [P = 0.21 for 1974 and P = 0.37 for 1989 (Wilcoxon signed rank test)]. The risk of developing breast cancer among women with the highest concentrations of DDE was roughly half that among women with the lowest concentrations, whether based on concentrations in 1974 [odds ratio (OR), 0.50; 95% confidence interval (CI), 0.27-0.89; P(trend) = 0.02] or in 1989 (OR, 0.53; 95% CI, 0.24-1.17; P(trend) = 0.08). The associations between circulating concentrations of PCBs and breast cancer were less pronounced but still in the same direction (1974: OR, 0.68; 95% CI, 0.36-12.9; P(trend) = 0.2; and 1989: OR, 0.73; 95% CI, 0.37-1.46; P(trend) = 0.6). Adjustment for family history of breast cancer, body mass index, age at menarche or first birth, and months of lactation did not materially alter these associations. These associations remained consistent regardless of lactation history and length of the follow-up interval, with the strongest inverse association observed among women diagnosed 16-20 years after blood drawing. Results from this prospective, community-based nested case-control study are reassuring. Even after 20 years of follow-up, exposure to relatively high concentrations of DDE or PCBs showed no evidence of contributing to an increased risk of breast cancer.

Pulmonary embolism in the cardiac surgical patient.

Pulmonary embolism (PE) is thought to occur infrequently after cardiac operations, possibly because systemic heparinization during cardiopulmonary bypass prevents deep vein thrombosis. This retrospective study was undertaken to determine the actual incidence of PE after cardiac operations and to identify risk factors. Between January 1, 1985, and December 31, 1989, 5,694 adult patients (greater than 18 years old) had open heart operations at the Johns Hopkins Hospital. Thirty-two patients (20 men and 12 women) had PE within 60 days of operation, an overall PE incidence of 0.56%. The diagnosis of PE was established by ventilation/perfusion scan, pulmonary angiogram, or autopsy. Mortality among patients with PE was 34%. Using a case-control method, preoperative and postoperative risk factors for PE were identified by multivariate and multiple logistic regression analyses. Preoperative risk factors included bed rest (p less than 0.003), prolonged hospitalization before operation (p less than 0.004), and cardiac catheterization performed through the groin within 15 days before operation (p less than 0.01). Post-operative risk factors were congestive heart failure (p less than 0.008), prolonged bed rest (p less than 0.05), and deep vein thrombosis (p less than 0.03). This study demonstrates that PE is an unusual complication after cardiac operations, has a high mortality rate, and is often related to perioperative immobility and recent groin catheterization. These results also suggest that minimizing preoperative hospital stay may be important in PE prophylaxis.

Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and risk of melanoma or squamous cell carcinoma of the skin.

BACKGROUND: Dehydroepiandrosterone (DHEA) and its analogs have potent chemoprotective actions in mouse skin tumorigenesis models. To assess this association in humans, we investigated the relationship of prediagnostic serum concentrations of DHEA and dehydroepiandrosterone sulfate (DHEAS) to the subsequent risk of developing malignant melanoma and squamous cell carcinoma of the skin in residents of Washington County, Maryland, USA. PATIENTS AND METHODS: In a nested case-control study, serum that had been stored in 1974 was thawed and assayed for DHEA and DHEAS for 23 cases of malignant melanoma and 28 cases of squamous cell carcinoma and 1-2 matched controls per case. RESULTS: The mean serum concentrations of DHEA or DHEAS were similar in cases and controls. There were no statistically significant trends in the risk of developing malignant melanoma or squamous cell skin cancer by concentration of either steroid (all p-for-trends >0.30). CONCLUSION: The results of this study do not support the hypothesis that physiological concentrations of DHEA or DHEAS protect against skin cancer in humans.

Epidemiology of breast cancer in older women: implications for future healthcare.

Breast cancer in elderly women is already a significant public health problem. Elderly women have a 6-fold higher breast cancer incidence rate and 8-fold higher mortality rate compared with non-elderly women. Because of demographic trends, the number of elderly women diagnosed with breast cancer is likely to increase substantially in the coming decades. Specifically, if incidence rates remain constant, we project a 72% increase in the number of elderly women in the US diagnosed with breast cancer by 2025, an increase from approximately 89,500 in 1998 to almost 154,000 in 2025. If this projection holds true, the sheer magnitude of the increase in patients has profound implications for the delivery of medical care. Considerable planning is needed to ensure that the infrastructure is in place to effectively treat these patients. The burgeoning number of elderly patients with breast cancer accentuates the need for more definitive evidence concerning preventing and treating breast cancer in the elderly. Treatment patterns for elderly patients with breast cancer have been shown to differ from those for non-elderly patients, but the evidence base for differentiating treatment plans by age is deficient. For example, information is needed to tease apart the relative importance of age per se compared with important age-related factors, such as comorbidity. Patient care will benefit from an interdisciplinary team approach that includes oncologists, geriatricians, surgeons, radiation oncologists, nurses and social workers. The continued increase in life expectancy necessitates well-crafted strategies for the primary and secondary prevention of breast cancer. Carefully addressing the priorities for breast cancer prevention and control in the elderly during the first portion of the century may reap substantial dividends by the end of the century.