Current Trends Report of the Recommendations of the 1985 DES Task Force of the U.S. Department of Health and Human Services

In 1978, the U.S. Department of Health, Education, and Welfare set up a DES (diethylstilbestrol (a synthetic estrogen)) Task Force to review all aspects of the DES question and to develop recommendations regarding health issues of DES and research gaps that exist. In 1985, a second DES Task Force of the U.S. Department of Health and Human Services (DHHS) was convened to review recent studies showing a possible increased risk of breast cancer among women given DES during pregnancy and a possible excess of precancerous abnormalities of the cervix and vagina among women exposed to DES in utero (1). BREAST CANCER

Since 1978, results of four investigations relevant to this issue have been published (2-5). Two of these studies were randomized clinical trials reporting the long-term follow-up results of the use of DES during pregnancy. In one, 80 diabetic women received hormonal treatment, and 76 diabetic women received placebos. After 29 years of follow-up, four cases of breast cancer had occurred among the exposed women, and none, among the unexposed women (2). In another study, 10 cases of breast cancer were found among 319 DES-exposed women, and nine, among 331 unexposed women, suggesting there was no excess risk. Exposure occurred in the early 1950s.

Two observational follow-up studies of women treated with DES during pregnancy have also been reported recently (4,5). In these studies, the overall relative risk of breast cancer among the exposed women ranged from 1.2 to 1.5. One study noted that there was no increased risk in the first 20 years of follow-up but that the relative risk rose to 1.6 during the 20-29 years after exposure and to 2.5 for those followed 30 years or more (5).

The 1985 Task Force concluded that:

1. These levels of excess risk are difficult to evaluate, since it is difficult to rule out various sources of bias that could be responsible for such excesses.

2. In the two observational studies, the interpretation involves assessing whether the excess risks are due to the drug itself or to the indications for the use of the drug. Data from two recent studies suggest that spontaneous abortion before a first birth is a risk factor for the development of breast cancer (6,7). In the observational studies, a primary indication of DES use was previous spontaneous abortion. The Task Force felt it would be useful to analyze the data on risk according to frequency of spontaneous abortion before a first live birth. Unless or until such analyses can be done and evaluated, it was felt that separating a drug effect from an effect related to the indication for drug use remains an open issue.

3. In all these studies, it is possibile that DES-exposed mothers are more likely to have had more intensive medical attention and, therefore, higher rates of breast cancer diagnosis. This could take the form of earlier diagnosis or an excess of cases or both.

4. The 1985 DES Task Force concluded that women who used DES during their pregnancies may subsequently experience an increased risk of breast cancer. However, a causal relationship is still unproven, and the observed level of excess risk is similar to that for a number of other breast cancer risk factors. (See Editorial Note below.)

SQUAMOUS CELL ABNORMALITIES OF THE UTERINE CERVIX IN DES-EXPOSED DAUGHTERS

In 1974, the National Cancer Institute began a multi-institutional cooperative research study, the National Cooperative Diethylstilbestrol Adenosis Project (DESAD Project). The DESAD Project was a large collaborative study involving four groups of DES-exposed persons and having a complex study design.

The 1978 DES Task Force concluded that, in the uterine cervix, the risks for squamous cell cancer were the same in unexposed and exposed daughters, i.e., there was no reliable scientific evidence to indicate that a risk of squamous cell cancer was associated with DES exposure in utero. This conclusion was based primarily on clinical evaluations and on the results from the initial screening examination of DES-exposed daughters in the DESAD Project.

A recent study that has reopened the issue of cervical abnormalities is a report from the DESAD Project summarizing the cytologic and pathologic abnormalities of the cervix and vagina noted during the first 7 years of follow-up of DES-exposed daughters (8). One subset of 744 women was identified from reviews of obstetrical records as exposed in utero to DES and was matched with another subset of 744 women who had not been exposed to DES. Over 7 years of screening, the incidence rate of mild, moderate, and severe dysplasia and of carcinoma in situ of the uterine cervix was substantially higher in the exposed women than in the unexposed (15.7, compared with 7.9 cases per 1,000 persons per year of follow-up) (8). The 1985 Task Force reviewed this report (8) and concluded that a relationship between DES exposure in utero and the risk of subsequently developing squamous cell cancer is not proven but needs further study.

The following considerations were thought to be important in interpreting the reported new finding of an increase in dysplasia among DES-exposed daughters (8):

1. While dysplasia is recognized as a potential risk for the development of squamous cell carcinoma, it does not always progress into carcinoma.

2. There was no difference between the matched cohorts of exposed and unexposed women in regard to a history of a prior diagnosis of dysplasia or in the prevalence of dysplasia at the initial examination. The nearly twofold difference in incidence rate for any degree of dysplasia, in the presence of essentially similar prevalence rates for the two groups (as noted in the 1978 DES Task Force Report), needs to be addressed.

3. There is an unexplained difference between the exposed and unexposed daughters in the frequency of a history of genital herpes: 11.8% of 703 DES-exposed and only 6.3% of 695 unexposed. This raises the possibility that the increased frequency of dysplasia in the DES-exposed daughters could be related to this higher frequency of a history of genital herpes infection in that group, rather than to the DES exposure. However, there is also the possibility that DES might be related to increased herpetic infection through long-term postnatal immunosuppression or through some other mechanism.

4. The possibility of an ascertainment bias also needs to be evaluated, since the likelihood that a woman would be biopsied is greater if the area of metaplasia (associated with DES exposure) is larger.

RECOMMENDATION

The Task Force recommended that physicians continue attempts to notify women for whom they had prescribed DES and that DHHS continue to support and encourage research on the possible adverse effects of DES. The Task Force outlined specific areas for further study.

In addition, the Task Force recommended continued dissemination of information to all physicians and DES-exposed mothers and offspring and continued implementation of recommendations for the surveillance of DES-exposed mothers, daughters, and sons. Recommendations for screening DES mothers for breast cancer are the same as those for other women. Details of screening DES-exposed daughters for cervical and vaginal lesions are given in the DES Task Force Report. Copies of the full report can be obtained by contacting: DES, Office of Cancer Communication, Building 31, National Cancer Institute, Bethesda, Maryland 20892; telephone (800) 4-CANCER. Reported by the 1985 DES Task Force, US Dept of Health and Human Svcs.

Editorial Note

Editorial Note: Previously reported risk factors for breast cancer include a family history of breast cancer, nulliparity, late age at first birth of a child, prior atypical proliferative disease of the breast, certain ethnic characteristics, high socioeconomic status, early menarche, late menopause, high-fat diet, pregnancies of less than 4-5 months' duration, irregular menstrual cycles, obesity, and lack of exercise (9-11).

Similarly, there are multiple risk factors for cervical cancers. Among those reported are early sexual activity (especially with multiple partners), infections with genital herpes and human papilloma virus, multiple sex partners of the male mate, multiparity, and high chronic alcohol intake (12).

References

1. U.S. Department of Health and Human Services. Report of the 1985 DES Task Force. Bethesda, Maryland: National Institutes of Health, 1985.

2. Beral V, Colwell L. Randomized trial of high doses of stilboestrol and ethisterone in pregnancy: long-term follow-up of mothers. Br Med J 1980;281:1098-101.

3. Vessey MP, Fairweather DVI, Norman-Smith B, Buckley J. A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers

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