et al. open up the next saga in the continuing story of
diethylstilbestrol (DES): increased risk of breast cancer
in adult women following their exposure in the womb.
trends reported by Palmer et al. point to yet another
health burden to be bourne by victims of the a drug industry
eagerly pushing its products in the face of mounting evidence
that not only did DES not achieve its intended effects, it
caused harm. These findings also highlight the need for DES
daughters to be especially vigorous in monitoring for breast
more on DES, see Chapter
4 in Our Stolen Future, or visit DES
Stories, a book by Margaret Braun
women were exposed in the womb to DES during the 1950's and 1960's
because the drug was recommended for control of difficult pregnancies.
Other health effects have long since been established, most notably
cell carcinoma. That cancer is a disease normally seen in older
women, but rare even in that age group. Its appearance in teenage
girls gave the first indications of DES's impacts.
early-age association between breast cancer risk and DES exposure
comparable to the link between clear cell carcinoma and DES emerged
from studies of young adult DES daughters. With DES daughters now
reaching the age at which breast cancer incidence rises in women
in general, another question becomes possible: does DES
increase the risk of breast cancer as DES daughters enter into the
decades of life when breast cancer is most common?
did they do? Palmer et al. assembled data on breast
cancer incidence in a cohort of women exposed in utero
to DES and now participating in a long-term health study. Their
original enlistment in the study was unrelated to presence or absence
of breast cancer. The exposed women (a total of 4281) were matched
with unexposed women (a total of 2095) of the same age. Among them,
78 women developed breast cancer. One case was excluded because
the medical records could not confirm the diagnosis. For most cases,
data allowed classification of tumor type (estrogen receptor-positive
or -negative) as well as histology, tumor size and nodal status.
et al. based their calculation of risk on person-years,
or the number of years each woman was in the cohort through to one
of four possible ending dates: (1) breast cancer diagnosis, (2)
the last date of last-known check-up, (3) date of death (not from
breast cancer) or (4) date of response to a questionnaire distributed
their statistical analysis, Palmer et al. considered a
number of known factors affecting breast cancer risk, including
age at menarche, age at first birth and number of births. They also
examined the impact of several other potentially confounding variables,
including family history of breast cancer, menopausal stauts, and
use of hormone replacement therapy, but did not employ them in the
final statistical analysis because they did not affect the outcome.
did they find? Looking at all women in the study group
combined, irrespective of age, there is no significant elevation
in breast cancer risk associated with DES exposure. The risk ratio
is 1.4 but the 95% confidence interval extends far beneath 1.0 (table
the entire cohort by age, however, reveals a substantially different
picture. For exposed women over 40, breast cancer risk is
elevated compared to unexposed women, with a rate ratio of 2.5.
The number of cancer cases in women above the age of 40 still remains
small, and the trends hover at the edge of statistical significance.
women under the age of 40 do not appear to have increased risk of
breast cancer compared to unexposed women of the same age. Hence
the lack of significant risk elevation in all women combined appears
to result from a dilution of the real effect in women over 40-yrs
old by pooling them with younger women.
analysis of the cumulative incidence of breast cancer in relation
to age suggests what is happening: Beginning in their fifth
decade of life (ages 40+), the data suggest that breast cancer
risk rises faster in DES daughters than in unexposed women.
from Palmer et al. 2002
analysis of tumor characteristics revealed suggestive but inconclusive
patterns. For the entire cohort, risk was stronger for estrogen-positive
tumors compared to estrogen-negative tumors (risk ratio of 1.9 vs.
0.4). The data also suggested a greater elevation in risk for tumors
with no nodal involvement vs. metastatic disease (risk
ratio of 3.6 vs. 0.8).
about the importance of timing of exposure during pregnancy was
also inconclusive, but trends suggested that exposure during the
first 8 weeks did not elevate risk whereas exposure subsequently
does it mean? The overall implication of these results
is that in utero exposure to a potent synthetic estrogen,
diethystilbestrol, alters the developmental pathway of exposed women
in ways that increase their vulnerability to breast cancer decades
later in life. This adds to a body of emerging
evidence indicating that to understand breast cancer,
research must focus on exposures during critical windows of vulnerability
in development, including in the womb. Studies that only
ask about exposure levels at the time of diagnosis will provide
as for example, the 2002
Long Island Breast Cancer Study Project.
the current trends in these data holds as the study cohort ages
and moves further into the decades in life of higher breast cancer
risk, the DES effect should become clearer and the significance
level of the results should strengthen. This already appears to
be happening: Palmer et al. compare their results with
study of breast cancer risk in the same study cohort, published
in 1998, which found a rate ratio of 1.2 (compared to 1.4. in the
current study) based on roughly 50% fewer cases. They also note
that the median age of women at the end of the current study was
43, and hence the incidence of breast cancer is still quite low
within the study population.
the basis of these results, the authors make two recommendations
..."further follow-up of DES-exposed women is imperative
in order to establish whether there is a causal association
with breast cancer risk and to assess the hypothesis raised
by the present data; namely, that in-utero DES exposure
is related to increased risk of estrogen receptor-positive
disease. The cohort of US women exposed to DES in the 1950s
and 1960s has now reached the age at which breast cancer incidence
is appreciable. Receptor testing currently occurs more routinely,
and it should be possible to determine receptor status for
almost all new cases."
(2) "it behooves DES-exposed women to follow the advice
given all women aged 40 and older: undergo screening mammography
every 1–2 years, and perform breast self exam regularly"