Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis.

Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986-2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (P (Trend) = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73-1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43-1.14). The trend did not extend to mixed ductal-lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.

Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES).

Prenatal exposure to diethylstilbestrol (DES) is associated with adverse health outcomes, including anatomic anomalies of the reproductive tract in women and of the genitourinary tract in men. The mouse model, which replicates many DES-related effects seen in humans, suggests that prenatal DES exposure causes alterations that may affect the next generation of offspring. We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers' reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34). Our data suggest a possible association between the mother's prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters' elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Exposure to breast milk in infancy and adult breast cancer risk.

BACKGROUND: There is considerable interest in the possibility of an infectious etiology for human breast cancer. Although studies have shown that certain strains of mice transmit mammary tumor virus via breast milk, few epidemiologic studies have addressed this topic in humans. METHODS: We evaluated the relationship between having been breast-fed as an infant and breast cancer risk among 8299 women who participated in a population-based, case-control study of breast cancer in women aged 50 years or more. Case women were identified through cancer registries in three states (Massachusetts, New Hampshire, and Wisconsin); control women were identified through statewide driver's license lists (age <65 years) or Medicare lists (ages 65-79 years). Information on epidemiologic risk factors was obtained through telephone interview. We used multiple logistic regression to assess having been breast-fed and maternal history of breast cancer in relation to breast cancer occurrence both in premenopausal women (205 case women; 220 control women) and in postmenopausal women (3803 case women; 4071 control women). RESULTS: We found no evidence that having been breast-fed increased breast cancer risk in either premenopausal women (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.41-1.04) or postmenopausal women (OR = 0.95; 95% CI = 0.85-1.07). In addition, breast cancer risk was not increased by having been breast-fed by a mother who later developed breast cancer. CONCLUSION: Our results do not support the hypothesis that a transmissible agent in breast milk increases breast cancer risk. Because premenopausal women were not well represented in our study population, our findings with regard to this group may not be generalizable and should be viewed with caution.

Cancer risk in men exposed in utero to diethylstilbestrol.

BACKGROUND: An association between prenatal diethylstilbestrol (DES) exposure and cancer in men, especially testicular cancer, has been suspected, but findings from case-control studies have been inconsistent. This study was conducted to investigate the association between prenatal DES exposure and cancer risk in men via prospective follow-up. METHODS: A total of 3613 men whose prenatal DES exposure status was known were followed from 1978 through 1994. The overall and site-specific cancer incidence rates among the DES-exposed men were compared with those of the unexposed men in the study and with population-based rates. The relative rate (RR) was used to assess the strength of the association between prenatal DES exposure and cancer development. All statistical tests were two-sided. RESULTS: Overall cancer rates among DES-exposed men were similar to those among unexposed men (RR = 1.07; 95% confidence interval [CI] = 0.58 to 1.96) and to national rates (RR = 0.99; 95% CI = 0.65 to 1.44). Testicular cancer may be elevated among DES-exposed men, since the RRs for testicular cancer were 3.05 (95% CI = 0.65 to 22.0) times those of unexposed men in the study and 2.04 (95% CI = 0.82 to 4.20) times those of males in the population-based rates. The higher rate of testicular cancer in the DES-exposed men is, however, also compatible with a chance observation. CONCLUSIONS: To date, men exposed to DES in utero do not appear to have an increased risk of most cancers. It remains uncertain, however, whether prenatal DES exposure is associated with testicular cancer.

Dysplastic nevi in association with multiple primary melanoma.

Risk factors for multiple primary cutaneous melanoma were evaluated in a case-control study. Eight cases of multiple primary melanoma were matched on sex, age, and education to 24 first primary melanoma controls. Risk factors examined in the analysis included pigmentary characteristics, history of sun exposure, and nevi. The importance of histologically dysplastic nevi (DN) and clinically atypical nevi was of particular interest. Single-factor conditional logistic regression analysis showed that first primary melanoma patients with histological DN are at increased risk for a second primary (odds ratio, 6.2; 95% confidence interval, 1.2-33.4). Patients with two or more clinically atypical nevi also have elevated risk for a second primary (odds ratio, 8.8; 95% confidence interval, 1.0-80.7). Two-factor logistic models were used to evaluate the effect of histological DN while controlling singly for all other variables as potential confounders. Odds ratios for the association of histological DN varied from 6.1 to 10.4 when adjusting singly for pigmentary and sun exposure variables. In the two-factor model that included histological and clinical DN, both variables retained marginally significant statistical association with multiple primary melanoma. These results suggest that DN is a marker of increased risk for multiple primary melanoma and suggest that melanoma patients with evidence of DN should be followed closely for the development of additional primaries.

Immunological effects of treatment with sequential administration of recombinant interferon gamma and alpha in patients with metastatic renal cell carcinoma during a phase I trial.

Many anticancer mechanisms of the interferons have been proposed but none have been associated with clinical response to date. The biological activities of the interferons in vivo have included effects upon the natural killer cell, T- and B-lymphocytes, and macrophages. This report details a prospective study of the immunological effects on peripheral blood mononuclear cells of sequentially administered recombinant (r) interferon (IFN) gamma and rIFN alpha in 28 patients with metastatic renal cell carcinoma. Natural killer cell activity, T-cell phenotype (CD4, CD8, CD56, CD16, CD4/HLA-DR, CD8/HLA-DR, CD56/HLA-DR) and 2',5'-oligoadenylate synthetase were measured prior to therapy, during therapy, and following completion of treatment. Statistical analysis of all parameters was performed for the entire group, by individual patient, by dosage, by time, and by clinical response. An overall significant depression in natural killer cell activity and in the percentage of circulating CD56, CD16, and CD8+ cells were noted. Significant increases in 2',5'-oligoadenylate synthetase and in the percentage of circulating CD4 cells were also noted. Although an association between the magnitude of change in percentage of CD16+ cells and 2',5'-oligoadenylate synthetase and dosage of rIFN gamma and rIFN alpha, respectively, was observed, optimal biological dose of this sequence of rIFNs could not be determined due to the limited number of patients. A decrease in the percentage of circulating CD8+ cells was observed among patients with objective clinical response (partial and complete). Sequentially administered rIFN gamma and rIFN alpha can modulate immunological parameters in vivo in patients with metastatic renal cell carcinoma. A fall in percentage of circulating CD8+ cell is associated with response and suggests that this sequence of rIFN alpha and rIFN gamma might influence T-cell mediated antitumor activity.

Dysplastic nevi in relation to superficial spreading melanoma.

The aim of the present study was to evaluate the frequency with which histologically confirmed dysplastic nevi are observed among patients with superficial spreading melanoma compared to patients with nodular melanoma. A pathology review of 117 new cases of first primary nonfamilial cutaneous melanoma identified 61 patients with superficial spreading melanoma and 19 with nodular melanoma. Study participants received a physician-conducted skin examination which included enumeration of clinically benign and atypical nevi and the surgical excision of the clinically most atypical nevus. Patients' dysplastic nevus status was established by histological review of the clinically most atypical nevus. A comparison based on the tumor subtypes showed that dysplastic nevi occur nearly four times more frequently among patients with a prior diagnosis of superficial spreading melanoma relative to nodular melanoma (odds ratio = 3.6; P = 0.03).

Psychotropic medication use and risk of epithelial ovarian cancer.

Long-term use of psychotropic medication may increase the risk for epithelial ovarian cancer through increased gonadotropin secretion or direct ovarian stimulation of adrenergic receptors, effects which may affect ovarian cancer pathogenesis. An earlier case-control study found that prior use of antidepressants or benzodiazepine tranquilizers was associated with a 2-fold increase in risk of epithelial ovarian cancer. However, that study lacked details on all types of psychotropic medications, length of use, and the categorization of the specific action of these medications on the hypothalamic-pituitary-ovarian axis. In a new case-control study conducted in eastern Massachusetts (MA) and all of New Hampshire (NH), we identified all women with newly diagnosed ovarian cancer between May 1992 and March 1997. We interviewed 563 women diagnosed with malignant or borderline epithelial ovarian tumors and 523 controls identified through random digit dialing and the use of Town Books (residential listings by name, age, and precinct). Participants were asked to provide the name of medications used for 6 months or longer, the age at first use, and total months or years of use. Psychotropic medications included amphetamines, sedatives, barbiturates/anticonvulsants, antidepressants, and antipsychotics. Self-reported use of psychotropic medication for 6 months or longer was associated with a statistically significant increase in risk of invasive ovarian cancer [odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.3]. Relative to nonusers, risk was greatest in those whose first use occurred premenopausally for more than 2 years (OR, 2.9; CI, 1.3-6.6). The association was largely confined to use of medications that operate through dopaminergic mechanisms (OR, 2.9; CI, 1.3-6.4) or gabaergic pathways (OR, 1.5; CI, 0.9-2.5) as opposed to serotoninergic pathways (OR, 1.0; CI, 0.4-2.1). These results are consistent with the hypothesis that psychotropic medications induce gonadotropin secretion, which in turn may increase ovarian cancer risk. However, until other studies confirm our findings and determine whether they apply to medications with specific neuroendocrine actions, it is premature to advise a change in clinical practice and conclude that these medications indeed play a role in the etiology of ovarian cancer.

A case-control study of galactose consumption and metabolism in relation to ovarian cancer.

Consumption or metabolism of dairy sugar and ovarian cancer have been linked based on evidence that galactose may be toxic to ovarian germ cells and that ovarian cancer is induced in animals by depletion of oocytes. We assessed consumption of dairy products and obtained blood for biochemical and molecular genetic assessment of galactose metabolism in 563 women with newly diagnosed epithelial ovarian cancer and 523 control women selected either by random digit dialing or through lists of residents in eastern Massachusetts and New Hampshire. We observed no significant differences between cases and controls in usual consumption of various types of dairy products or total daily lactose (the principal source of galactose in the diet); nor did we find that RBC activity of either galactose-1-phosphate uridyl transferase (GALT) or galactokinase differed. The mean (and SE) activity of uridine diphospho-galactose 4'-epimerase (in micromoles per hour per gram of hemoglobin) was, however, significantly lower (P < 0.005) in cases compared with controls, 20.32 (0.31) versus 21.64 (0.36). Ovarian cancer cases were also more likely to carry the N314D polymorphism of the GALT gene, generally predisposing to lower GALT activity. The difference was most evident for endometrioid and clear cell types of ovarian cancer, in which 3.9% of cases were found to be homozygous for N314D compared with 0.4% of controls, yielding an odds ratio and 95% confidence interval of 14.17 (2.62-76.60). We conclude that, whereas adult consumption of lactose carries no clear risk for the disease, certain genetic or biochemical features of galactose metabolism may influence disease risk for particular types of ovarian cancer.

Menstrual factors in relation to breast cancer risk.

We evaluated menstrual factors in relation to breast cancer risk in a large, population-based, case-control study. Case women were ascertained through state-wide registries covering Wisconsin, Western Massachusetts, Maine, and New Hampshire; control women were randomly selected from driver's license and Medicare lists in each state. Information regarding menstrual characteristics was obtained through a telephone interview. The study population comprised 6888 breast cancer cases and 9529 control women. Because exogenous hormones influence menstrual cycle patterns, we repeated our analyses in a subgroup of women who had never used oral contraceptives or hormone replacement therapy. Our results indicate decreased breast cancer risk with menarcheal age of 15 years or more, relative to menarche at age 13; the relation was stronger among premenopausal [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.57-0.91] as opposed to postmenopausal women (OR, 0.90; 95% CI, 0.80-1.03). Risk was slightly reduced among premenopausal women whose menstrual cycles did not become regular until at least 5 years after onset of menses, relative to those whose cycles became regular within 1 year (OR, 0.80; 95% CI, 0.63-1.02). There was no clear relation between breast cancer risk and irregular menstrual cycles, episodes of amenorrhea, or menstrual cycle length. Early menopause, whether natural or surgical, was associated with decreased breast cancer risk; surgical menopause before age 40 conferred the strongest protective effect (OR, 0.57; 95% CI, 0.47-0.71). We found no evidence of increased risk with late natural menopause (OR, 0.92; 95% CI, 0.80-1.06). Results in the subgroup of women who never used exogenous hormones were similar to those for the entire group.

Factors associated with atypical nevi: a population-based study.

We conducted a case-control study to identify factors associated with the presence of clinically atypical nevi. Potential participants were selected, using a two-staged sampling scheme, from a population-based cohort of 50,000 Swedish women who had responded to a previous health survey questionnaire. Of 500 women sampled for study recruitment, 400 (80%) agreed to participate. Study participants underwent a physician-conducted skin examination, which identified 130 women who had at least one clinically atypical nevus (cases) and 270 women without these lesions (controls). The physician-conducted skin examination also assessed women for benign nevus counts; other risk factor information was based upon responses to a health survey questionnaire. We found a strong and highly statistically significant relationship between number of benign nevi and the presence of at least one clinically atypical nevus (P < 0.0001). Women with 100 or more benign nevi had a 26-fold increased likelihood of having an atypical nevus. We noted statistically significant interactions between number of benign nevi and other factors of interest; thus, the results are reported separately for women with low (<50) or high (> or =50) counts of benign nevi. Among women with low counts of benign nevi, the likelihood of having an atypical nevus increased with degree of freckling; there was also a suggested role for early sun exposure. Among women with high counts of benign nevi, difficulty tanning and lack of peeling sunburns between ages 10 and 19 appeared to increase the likelihood of case status; our data also suggested an inverse relationship between parity and atypical nevi in this subgroup.

Collection of genomic DNA from adults in epidemiological studies by buccal cytobrush and mouthwash.

Blood samples are an excellent source of large amounts of genomic DNA. However, alternative sources are often needed in epidemiological studies because of difficulties in obtaining blood samples. This report evaluates the buccal cytobrush and alcohol-containing mouthwash protocols for collecting DNA by mail. Several DNA extraction techniques are also evaluated. The study was conducted in two phases. In phase 1, we compared cytobrush and mouthwash samples collected by mail in two different epidemiological studies: (a) cytobrush samples (n = 120) from a United States case-control study of breast cancer; and (b) mouthwash samples (n = 40) from a prospective cohort of male United States farmers. Findings from phase 1 were confirmed in phase 2, where we randomized cytobrush (n = 28) and mouthwash (n = 25) samples among participants in the breast cancer study to directly compare both collection methods. The median human DNA yield determined by hybridization with a human DNA probe from phenol-chloroform extracts was 1.0 and 1.6 microg/2 brushes for phases 1 and 2, respectively, and 27.5 and 16.6 microg/mouthwash sample for phases 1 and 2, respectively. Most (94-100%) mouthwash extracts contained high molecular weight DNA (>23 kb), in contrast to 55-61% of the brush extracts. PCR success rates for amplification of beta-globin gene fragments (268, 536, and 989 bp) were similar for cytobrush and mouthwash phenol-chloroform extracts (range, 94.4-100%). Also, we obtained high success rates in determining the number of CAG repeats in the androgen receptor gene, characterizing tetranucleotide microsatellites in six gene loci, and screening for mutations in the BRCA1/2 genes in a subset of phenol-chloroform DNA extracts. Relative to DNA extracted by phenol-chloroform from cytobrush samples, DNA extracted by NaOH had lower molecular weight, decreased PCR success rates for most assays performed, and unreliably high spectrophotometer readings for DNA yields. In conclusion, although DNA isolated from either mouthwash or cytobrush samples collected by mail from adults is adequate for a wide range of PCR-based assays, a single mouthwash sample provides substantially larger amounts and higher molecular weight DNA than two cytobrush samples.

A two-stage validation study for determining sensitivity and specificity.

A two-stage procedure for estimating sensitivity and specificity is described. The procedure is developed in the context of a validation study for self-reported atypical nevi, a potentially useful measure in the study of risk factors for malignant melanoma. The first stage consists of a sample of N individuals classified only by the test measure. The second stage is a subsample of size m, stratified according the information collected in the first stage, in which the presence of atypical nevi is determined by clinical examination. Using missing data methods for contingency tables, maximum likelihood estimators for the joint distribution of the test measure and the "gold standard" clinical evaluation are presented, along with efficient estimators for the sensitivity and specificity. Asymptotic coefficients of variation are computed to compare alternative sampling strategies for the second stage.

Quantitative DNA analysis of small renal cortical neoplasms.

DNA aneuploidy is common in large renal cortical neoplasms (RCNs), but the incidence in small RCNs is not known. This study was undertaken to investigate whether the traditional 3.0-cm size distinction between small (benign) and large (malignant) tumors might have an objective correlate in the form of abnormal DNA content. Quantitative DNA analysis was performed retrospectively, by image analysis, on 59 RCNs measuring 5.0 cm or less from 30 nephrectomy specimens with solitary tumors and 17 with multiple tumors. DNA indices and the proportion of cells with DNA content greater than that of the G0/G1 population were evaluated with respect to tumor size, stage, and histologic parameters. There was a relationship between the presence of detectable nondiploid stem lines (NDSLs) and tumor size, stage, nuclear grade, and proportion of non-G0/G1 cells, but not histologic pattern. The relationship of NDSLs to tumor size was more apparent in the solitary tumor group, while the relationship of a high proportion of non-G0/G1 cells to tumor size was stronger in the multiple tumor group. Our results show that the incidence of NDSLs increases with tumor size and nuclear grade, and suggest that as RCNs enlarge, the emergence of NDSLs heralds potential biologic aggressiveness. Further, solitary tumors and multiple synchronous tumors may be biologically different in terms of etiologic factors and growth potential.

An overview of the epidemiology of cutaneous melanoma.

Incidence of cutaneous melanoma has increased over the last several decades. Screening for melanocytic lesions is an effective approach to reducing incidence. This article presents information useful in melanoma screening, including histologic types of tumors, measurements, and anatomic sites. Causes of tumors, including ultraviolet radiation and the role of steroid hormones, are discussed. In addition, the presence of atypical and benign nevi is addressed.

Children with a TV in their bedroom at higher risk for being overweight.

OBJECTIVE: We examined having a TV in the bedroom as a risk factor for child overweight. DESIGN: Cross-sectional study. SETTING: School- and telephone-based surveys in New Hampshire and Vermont between 2002 and 2004. PARTICIPANTS: Two thousand three hundred and forty-three children enrolled in public schools, aged 9-12 years, and one of their parents. MAIN EXPOSURES: The child having a TV in the bedroom. MAIN OUTCOME MEASURES: Age- and gender-standardized child body mass index (zBMI). Overweight was defined as equal to or above the 95th percentile for zBMI. RESULTS: Overall, 22.3% (N=523) of the children were overweight, and almost half of all children (48.2%, N=1130) had a TV in their bedroom. Children with a TV in their bedroom had a higher zBMI and were significantly more likely to be overweight compared to those without a TV in their bedroom (27.3 versus 17.7%, respectively; P<0.05). After controlling for sociodemographics, physical activity, frequency of TV or movie watching and internet use, children with a TV in their bedroom who watched at least one session of TV or movies per day were more likely to be overweight compared to those without a TV in their bedroom (odds ratio=1.32, 95% confidence interval: 1.03, 1.70). CONCLUSIONS: Having a TV in the bedroom is a risk factor for child overweight, independent of reported physical activity, participation in team sports, TV or movie watching time and internet use at home. Further study is needed to fully understand the mechanism by which having a TV in the bedroom increases children's risk for overweight.

Whole genome amplification of buccal cytobrush DNA collected for molecular epidemiology studies.

When cytobrush buccal cell samples have been collected as a genomic DNA (gDNA) source for an epidemiological study, whole genome amplification (WGA) can be critical to maintain sufficient DNA for genotyping. We evaluated REPLI-g WGA using gDNA from two paired cytobrushes (cytobush 'A' kept in a cell lysis buffer, and 'B' dried and kept at room temperature for 3 days, and frozen until DNA extraction) in a pilot study (n=21), and from 144 samples collected by mail in a breast cancer study. WGA success was assessed as the per cent completion/concordance of STR/SNP genotypes. Locus amplification bias was assessed using quantitative PCR of 23 human loci. The pilot study showed > 98% completion but low genotype concordance between cytobrush wgaDNA and paired blood gDNA (82% and 84% for cytobrushes A and B, respectively). Substantial amplification bias was observed with significantly lower human gDNA amplification from cytobrush B than A. Using cytobrush gDNA samples from the breast cancer study (n =20), an independent laboratory demonstrated that increasing template gDNA to the REPLI-g reaction improved genotype performance for 49 SNPs; however, average completion and concordance remained below 90%. To reduce genotype misclassification when cytobrush wgaDNA is used, inclusion of paired gDNA/wgaDNA and/or duplicate wgaDNA samples is critical to monitor data quality.

Birth weight and breast cancer risk.

Exploring whether the positive association between birth weight and breast cancer risk differs by other breast cancer risk factors may help inform speculation about biological mechanism. In these data, high birth weight was associated with breast cancer risk in younger and in more educated women, but was not associated overall.

Mortality in women given diethylstilbestrol during pregnancy.

We used Cox regression analyses to assess mortality outcomes in a combined cohort of 7675 women who received diethylstilbestrol (DES) through clinical trial participation or prenatal care. In the combined cohort, the RR for DES in relation to all-cause mortality was 1.06 (95% CI = 0.98-1.16), and 1.11 (95% CI = 1.02-1.21) after adjusting for covariates and omitting breast cancer deaths. The RR was 1.07 (95% CI = 0.94-1.23) for overall cancer mortality, and remained similar after adjusting for covariates and omitting breast cancer deaths. The RR was 1.27 (95% CI = 0.96-1.69) for DES and breast cancer, and 1.38 (95% CI=1.03-1.85) after covariate adjustment. The RR was 1.82 in trial participants and 1.12 in the prenatal care cohort, but the DES-cohort interaction was not significant (P = 0.15). Diethylstilbestrol did not increase mortality from gynaecologic cancers. In summary, diethylstilbestrol was associated with a slight but significant increase in all-cause mortality, but was not significantly associated with overall cancer or gynaecological cancer mortality. The association with breast cancer mortality was more evident in trial participants, who received high DES doses.