Created: February 2008
Based on evidence as at December 2006
This document provides a summary of findings from a search of the English language literature to examine the putative association between diethylstilbestrol (DES) exposure in utero and invasive breast cancer.
Selection of primary articles
English-language studies estimating the comparative risk of breast cancer in women exposed to diethylstilbestrol in utero were identified using a two-stage evaluation strategy to select studies of primary interest. No date restrictions were imposed.
Of the 323 citations identified, 271 (84%) failed to meet the eligibility criteria and were discarded. The remaining citations (52 [16%]) were those whose titles or abstracts agreed with entry criteria or those requiring full assessment either due to a lack of information (eg. citations without abstracts) or ambiguity of subject matter.
The second stage of evaluation required retrieval and assessment of the full text of the remaining citations against the eligibility criteria, as well as retrieval and assessment of potentially relevant studies from reviewed reference lists. This process resulted in the elimination of 49 articles. The remaining three articles form the basis of this review.
Descriptive characteristics of included studies
The three articles meeting the eligibility criteria described the experience of a total of 7,836 women in the United States.1-3
Two articles presented the results of the National Cancer Institute (NCI) DES Follow-up Study, a prospective cohort study of daughters of DES-exposed mothers with follow-up to 2003.1,2 The NCI Study assembled information from all extant US cohorts that had appropriate comparison groups and medical record documentation of exposure to DES. A total of 6,890 participants were identified. The exposed group (n=4,817 or 69.9%) was followed for a median of 24 years while the unexposed group (n=2,073) was followed for a median of 22 years. The primary end-point of interest was incident cases of self-reported breast cancer confirmed through review of medical records, pathology reports and death certificates.
The third article described the assembled results of two case-control studies of breast cancer among women under the age of 45 years from three Washington counties.3 Breast cancer cases were ascertained using information from population-based cancer registry while controls were selected using random digit dialling. Mothers of participants were contacted between 1994 and 1996 and asked to complete a questionnaire on pre-conceptional, prenatal (including DES use) and postnatal factors. Information from the mothers of 510 women with breast cancer and 436 controls was available for analysis.
Findings
Overall risk of breast cancer
The NCI DES Follow-up Study reported an overall rate of breast cancer of 77 per 100,000 person-years in those with documented DES exposure in utero versus a breast cancer rate of 74 per 100,000 person years in the unexposed group. After adjustment for a number of relevant variables including age, years of education, parity, age at first birth, age at menarche, use of hormone supplements or oral contraceptives, family history of breast cancer and birth weight, the breast cancer rate ratio was 1.40 (95% CI 0.86, 2.29) in exposed versus unexposed women.
The Washington Counties study reported a crude odds ratio of 2.26 (95% CI 0.80, 6.38) for the likelihood of breast cancer in women whose mothers reported DES use compared to those whose mothers did not report exposure to DES. (Adjusted estimates were not presented by the investigators because of the similarity of point estimates compared to crude results.)
Age-specific risks of breast cancer
Results derived from the entire cohort are expected to attenuate the relationship between breast cancer and DES exposure due to the lack of sufficient follow-up in age groups in which breast cancer risk is high. In the NCI DES Follow-up Study, women below the age of 40 contributed almost 70% of the total cumulative follow-up time, but only 24% of all breast cancers. Moreover, the upper age limit for enrolment into the Washington Counties study was 45 years. In this context, the lack of statistical significance in overall results is not surprising.
In spite of this limitation, the data suggested that prenatal exposure to DES may increase the risk of breast cancer. In women at least 40 years of age in the NCI DES Follow-up Study, the adjusted relative rate for breast cancer in those exposed to DES in utero was 2.05 (95% CI 1.12, 3.76) compared to unexposed women (Table 1). The relative rate of breast cancer in those aged 50 years was estimated as 3.85, although this was not statistically significantly different from the relative rate of those aged between 40 and 49 years.
Table 1. Age-specific risks of invasive breast cancer in women exposed to diethylstilbestrol in utero.
| Age (years) | Relative rate (95% CI)* | Reference | |
| <40 | 0.57 (0.24, 1.34) | NCI DES Follow-up Study | |
| ³40 | 2.05 (1.12, 3.76) | NCI DES Follow-up Study | |
| ³50 | 3.85 (1.06, 14.0) | NCI DES Follow-up Study | |
| <45 | 2.26 (0.80, 6.38)† | Washington Counties study | |
| 40 to 49 | 1.62 (0.83, 3.18) |
|
† Crude odds ratio and attendant 95% confidence interval
Dose-specific risks of breast cancer
Participants aged 40 years or older and who were exposed to increasing cumulative doses of DES in utero in the NCI DES Follow-up Study showed increasing rates of breast cancer compared to those who were unexposed to DES. The rate ratio for “low dose” cumulative exposure cohorts (where median cumulative doses were between 1,520 and 3,175 mg) was 1.63 (95% CI 0.86, 3.11) compared to 2.17 (95% CI 1.18, 3.97) for “high dose” cumulative exposure cohorts (where median cumulative doses were between 7,550 and 12,442 mg).
Relationship with other important factors
Prenatal DES exposure was associated with increased relative rates of breast cancer in women aged 40 years or older across a range of risk factors (Table 2). While a number of these comparisons fail to attain statistical significance likely due to the limitations outlined above, there is consistency in the direction and magnitude of the effect estimates.
Table 2. Age-adjusted relative rates of invasive breast cancer in women exposed to diethylstilbestrol in utero, according to breast cancer risk factors.
| Risk factor | Relative rate (95% CI) |
| Parous | 1.98 (1.06, 3.71) |
| Nulliparous | 1.72 (0.50, 5.86) |
| Family history | 2.26 (0.74, 6.91) |
| No family history | 1.83 (0.96, 3.51) |
| Ever use of hormone supplements | 1.69 (0.70, 4.08) |
| Never use of hormone supplements | 1.96 (0.96, 4.10) |
| Ever use of oral contraceptives | 1.63 (0.91, 2.94) |
| Premenopausal | 2.20 (1.02, 4.72) |
| Postmenopausal | 1.87 (0.72, 4.83 |
Conclusions
Evidence from studies enrolling close to 8,000 women suggests that exposure to DES in utero may increase the risk of breast cancer. While the precise estimation of the magnitude of this risk is limited by the lack of adequate follow-up, the direction of the effect, its relationship to age and its consistency of association with other breast cancer risk factors all support the potential for this link to be present. The magnitude of the relative risk is likely to be at least 1.5 compared to unexposed women. However, longer term follow-up may indicate the risk to be higher than this. The National Breast Cancer Centre’s** Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health professionals, places women with a risk between 1.5 and 3 times the population average in the moderately increased category.
There have been no studies on the effectiveness of screening strategies to detect breast cancer in DES daughters. Consideration of a need for a differential screening protocol should be considered as part of the review of BreastScreen policy for screening high risk women and the associated definition of high risk.
References
1. Palmer JR, Hatch EE, Rosenberg CL, et al. Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control. 2002;13(8):753-8.
2. Palmer JR, Wise LA, Hatch EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15(8):1509-14.
3. Sanderson M, Williams MA, Daling JR, et al. Maternal factors and breast cancer risk among young women. Paediatr Perinat Epidemiol. 1998;12(4):397-407.
4. National Breast Cancer Centre**. Advice about Familial Aspects of Breast Cancer and Epithelial Ovarian Cancer: A Guide for Health Professionals. Camperdown: NBCC, 2006.
Created: February 2008
** In February 2008, National Breast Cancer Centre (NBCC), incorporating the Ovarian Cancer Program, changed its name to National Breast and Ovarian Cancer Centre (NBOCC). In July 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia, to provide leadership in cancer control and improve outcomes for Australians affected by cancer.