Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.

In utero exposure of women to DES is associated with a high lifetime risk of a broad spectrum of adverse health outcomes. (Funded by the National Cancer Institute.).

It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages z40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages z50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1509 -14)

Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age-and calendaryear specific standardized incidence rate ratios (SIR), and ageadjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure. ' 2007 Wiley-Liss, Inc.Key words: diethylstilbestrol; estrogen; cancer Diethylstilbestrol (DES), a potent synthetic estrogen, was first synthesized in 1938 and shortly thereafter promoted to prevent spontaneous abortion and premature delivery. 1 Over the next three decades, DES was administered to several million pregnant women in the United States and Europe. In 1971, a strong association was reported between DES and clear cell adenocarcinoma (CCA) of the vagina and cervix in young women. 2 Animal studies suggest the teratogenic and carcinogenic effects of prenatally administered DES may be due to changes in the expression of genes involved in the development of the reproductive tract 3 and raise concerns of elevated risk of other female reproductive tract cancers besides CCA.In the early 1990s, the National Cancer Institute (NCI) assembled new and previously established cohorts of DESexposed and unexposed individuals for combined follow-up. Baseline findings limited to analysis of the previously established cohorts showed DES was associated with an excess CCA risk and possibly with elevated breast cancer risk in older women, but did not indicate greater risk of endometrial or ovarian cancer. 4 More recent follow-up of the cohort for breast cancer incidence has shown a small but progressively increasing risk for DES exposure with age after 40. 5,6 To date, the follow-up experience of the combined cohort with regard to ove...

Context.-The association between in utero exposure to diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the vagina and cervix is well known, yet there has been no systematic study of DES-exposed daughters to determine whether they have an increased risk of other cancers. As many as 3 million women in the United States may have been exposed to DES in utero.Objective.-To determine whether women exposed to DES in utero have a higher risk of cancer after an average of 16 years of follow-up.Design.-A cohort study with mailed questionnaires and medical record review of reported cancer outcomes.Participants.-A cohort of 4536 DES-exposed daughters (of whom 81% responded) and 1544 unexposed daughters (of whom 79% responded) who were first identified in the mid-1970s.Main Outcome Measures.-Cancer incidence in DES-exposed daughters compared with population-based rates and compared with cancer incidence in unexposed daughters.Results.-To date, DES-exposed daughters have not experienced an increased risk for all cancers (rate ratio, 0.96; 95% confidence interval [CI], 0.58-1.56) or for individual cancer sites, except for CCA. Three cases of vaginal CCA occurred among the exposed daughters, resulting in a standardized incidence ratio of 40.7 (95% CI, 13.1-126.2) in comparison with population-based incidence rates. The rate ratio for breast cancer was 1.18 (95% CI, 0.56-2.49); adjustment for known risk factors did not alter this result.Conclusions.-Thus far, DES-exposed daughters show no increased cancer risk, except for CCA. Nevertheless, because exposed daughters included in our study were, on average, only 38 years old at last follow-up, continued surveillance is warranted to determine whether any increases in cancer risk occur during the menopausal years.