Continuation of Follow-up of DES-Exposed Cohorts
Condition: Breast Cancer; Autoimmune Disease; Prostate Cancer; Ovarian Cancer; Endometrial Cancer
MeSH terms: Endometrial Neoplasms; Autoimmune Diseases
Study type: Observational

Summary: 
      Diethylstilbestrol (DES), a drug first synthesized in 1938, was administered to several
      million pregnant women in the U.S. and Europe for the prevention of spontaneous abortion and
      premature delivery. In 1971, Herbst reported a strong association between DES use in
      pregnancy and the occurrence of vaginal clear cell adenocarcinoma (CCA) in exposed female
      offspring. Animal models have demonstrated a range of DES effects on offspring exposed in
      utero, including reproductive dysfunction, immune system changes, behavioral and sexual
      abnormalities, and increases in various reproductive cancers in males and females. In the
      mid-1970's, several separate cohorts of DES-exposed daughters and unexposed comparison groups
      were followed for the occurrence of cancer, precursor lesions, and reproductive effects, but
      systematic follow-up of these cohorts had ceased by 1990. In 1992, Congress passed a bill
      (H;.R. 4178) mandating the continued follow-up of DES-exposed cohorts. The National Cancer
      Institute, in collaboration with five field centers, reassembled previously studied cohorts
      of DES-exposed and unexposed mothers, daughters and sons, and identified subjects with
      documented exposure status who had not been studied previously, through familial links within
      the cohorts. Standardized baseline questionnaires were mailed to cohort members to ascertain
      the risk of cancer and other disorders. Pathology reports were collected for reported cancers
      and preneoplastic conditions. Two separate rounds of follow up have been conducted and a
      third is almost complete. Patients from the Registry for Research on Hormonal Transplacental
      Carcinogenesis (the Registry) will be added to the follow-up effort in the third phase. The
      purpose of this study is to continue the follow-up, by means of mail questionnaires and
      medical record collection, which was begun during the first phase of the study. Concern has
      arisen that DES-exposed daughters may be at higher risk of breast cancer. Exposure to high
      levels of endogenous estrogen in utero has been hypothesized to increase the risk of breast
      cancer and DES is a potent estrogen. Cancer risk in the sons will also continue to be
      assessed, especially for increased risks of prostate cancer. Since the offspring who were
      exposed to DES in utero are currently reaching their late forties, when cancer rates begin to
      rise, it is important to continue the follow-up of these cohorts to determine if there are
      long-term increases in cancer risk.
    

Detailed description: 
      Diethylstilbestrol (DES), a drug first synthesized in 1938, was administered to several
      million pregnant women in the U.S. and Europe for the prevention of spontaneous abortion and
      premature delivery. In 1971, Herbst reported a strong association between DES use in
      pregnancy and the occurrence of vaginal clear cell adenocarcinoma (CCA) in exposed female
      offspring. Animal models have demonstrated a range of DES effects on offspring exposed in
      utero, including reproductive dysfunction, immune system changes, behavioral and sexual
      abnormalities, and increases in various reproductive cancers in males and females. In the
      mid-1970's, several separate cohorts of DES-exposed daughters and unexposed comparison groups
      were followed for the occurrence of cancer, precursor lesions, and reproductive effects, but
      systematic follow-up of these cohorts had ceased by 1990. In 1992, Congress passed a bill
      (H;.R. 4178) mandating the continued follow-up of DES-exposed cohorts of mothers, daughters,
      sons and grandchildren. The National Cancer Institute, in collaboration with five field
      centers, reassembled previously studied cohorts of DES-exposed and unexposed mothers,
      daughters and sons, and identified subjects with documented exposure status who had not been
      studied previously, through familial links within the cohorts. Standardized baseline
      questionnaires were mailed to cohort members to ascertain the risk of cancer and other
      disorders. Pathology reports were collected for reported cancers and preneoplastic
      conditions. Three separate phases of follow up have been conducted. Patients from the
      Registry for Research on Hormonal Transplacental Carcinogenesis at the University of Chicago
      will be added to the follow-up effort and mailed the questionaire used in the third phase of
      follow-up. A cohort of daughters of women exposed and not exposed to DES in utero have been
      added to the study to assess the effects of DES on third generation women.

      The purpose of this study as a whole is to continue the follow-up, by means of mailed
      questionnaires and medical record collection, which was begun during the first phase of the
      study. Concern has arisen that DES-exposed daughters may be at higher risk of breast cancer.
      Exposure to high levels of endogenous estrogen in utero has been hypothesized to increase the
      risk of breast cancer and DES is a potent estrogen. Cancer risk in the sons will also
      continue to be assessed, especially for increased risks of prostate cancer. Since the
      offspring who were exposed to DES in utero are currently reaching their late forties, when
      cancer rates begin to rise, it is important to continue the follow-up of these cohorts to
      determine if there are long-term increases in cancer risk.

      We are planning to add a biospecimen collection component to the study. We propose to conduct
      a pilot study, nested within our ongoing combined cohort of DES-daughters, at Boston
      University to determine the feasibility of recruiting women participating in our study for
      phlebotomy and to investigate potential differences in the hormone metabolites and
      methylation patterns of germline DNA in 60 of these samples representing three groups of
      women: those exposed to high doses of DES prenatally, those exposed to low-doses of DES
      prenatally, and unexposed. Hormone metabolites and DNA methylation will be assessed in
      relation to DES exposure. Hormone metabolites will be measured at NCI s Frederick laboratory.
      DNA methylation will be assessed by Dr. Shuk-Mei Ho, the Jacob G. Schmidlapp Chair of the
      Department of Environmental Health, Director of the Center for Environmental Genetics, and
      Co-Leader of the Hormonal Malignancies Program in the Joint Cancer Center, at the College of
      Medicine in the University of Cincinnati, OH, and at Stephen Chanock s laboratory at NCI. The
      findings of this pilot study may have profound implications for the mechanisms by which
      endocrine disruption in the fetus influences human health. IRB approval of the data
      collection protocol has been received from Boston University.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        DES-exposed and unexposed mothers, daughters and sons, and identified subjects
      
Keywords: Cancer; DES; Endocrine Disrupting Chemicals; In Utero