Drs. King and Schottenfeld have provided an interesting review
of the literature in their attempts to relate changes in breast
cancer incidence over time to secular changes in postulated risk
As discussed, numerous attempts have been made to assess the extent
to which screening might explain recent recorded increases in
breast cancer incidence. These studies generally conclude that
screening probably explains most of the observed increase, although
other factors might play a residual role. Difficulties in disentangling
screening effects from other predictors of disease occurrence
have led some investigators to focus exclusively on mortality
data. This provides less evidence for an "epidemic"
of disease; in fact, recent data show striking downward trends
over time, which are mirrored by the latest available incidence
The authors note a recent study showing that established risk
factors account for only 41% of breast cancer cases in the United
States. As indicated, this percentage might have been higher had
speculative risk factors also been taken into account. King and
Schottenfeld describe many of these speculative factors, including
physical activity, obesity, diet, alcohol consumption, exogenous
hormone use, and organochlorines. Relationships with these factors
have been difficult to reconcile, although several recent findings
may be useful in guiding our future research directions.
Physical Activity/Dietary Factors
The authors correctly indicate that future research regarding
the effects of physical activity requires validated approaches
for assessing energy expenditure, particularly in conjunction
with exposures relevant to caloric intake. The relationship of
dietary factors may benefit from a focus on nutritional factors
other than the traditionally investigated dietary fat, especially
given recent evidence of a possible etiologic role for vitamins
A and C [1,2], fiber , and olive oil . Studies assessing
combined effects of various nutritional factors (eg, diets high
in fat and low in micronutrients) may be particularly informative.
Although studies have conventionally focused on recent diet, evidence
that adolescence is a vulnerable period for breast cancer risk
supports the need for a consideration of effects of exposures
earlier in life . In fact, it has been proposed that even in
utero exposures may be important , including factors that determine
initial growth patterns. Of further note is the consistency with
which alcohol has emerged as a predictor of breast cancer risk,
although the biologic rationale for the association remains elusive.
Further studies are needed to clarify biologic mechanisms underlying
alcohol associations, including effects of different consumption
patterns on endogenous hormone levels .
In terms of defining anthropometric associations, studies showing
that breast cancer risk is most affected by recent weight are
important , especially given obvious preventive implications.
Further, this observation may explain the apparent contradictory
results regarding body size derived from case-control and prospective
studies. Studies that carefully consider effects of body size
over time are therefore needed. Also, studies which include an
assessment of predictors of height could provide important etiologic
information, especially given the consistency of this association
in recent studies and the lack of apparent explanation for the
association in well-nourished populations .
The Role of Hormones and Oral Contraceptives
As pointed out in the article, clarification of the role of exogenous
hormones has been complicated. The authors stress the need for
future studies to address the relationship of risk to combined
hormone replacement therapy, which is important given the large
numbers of women who are taking estrogens for prevention of other
Although oral contraceptives have not been consistently identified
as being responsible for increasing risk in any subgroup of women,
there is accumulating evidence that such usage may be a factor
in women with early-onset cancers . Whether this represents
a cohort effect associated with unique usage patterns or specific
tumor effects has yet to be determined. Of particular importance
will be future studies addressing effects of specific pill types
and relationships with tumor characteristics. Studies addressing
the relationship of exogenous hormones to hormone receptor status
may be especially helpful in clarifying trend patterns, since
the largest increase in breast cancers in recent times has been
in estrogen receptor-positive tumors .
Although the King/Schottenfeld article discusses many speculative
risk factors for breast cancer, a few additional factors merit
attention. No mention is made of the possible etiologic role of
environmental factors other than organochlorines. Electromagnetic
radiation has been the cause of much concern, because of its effects
on pineal melatonin production  and observations of increased
rates of male breast cancer among electrical line workers .
Investigators are also now studying occupational exposures in
women, especially as more women enter the workforce. This may
affect other lifestyle factors, including breastfeeding and childbearing
practices (including the incidence of induced abortions), factors
whose relationships to breast cancer remain controversial.
The authors speculate that future studies of the interactions
of speculative factors with genetic factors may provide important
etiologic clues, but they limit their discussion to genetic markers
such as BRCA1, BRCA2, and p53, which affect only a small proportion
of the general population. Given the recent identification of
a variety of more common genetic susceptibility markers, such
as the P450 mono-oxgenases, N-acetyltransferase, glutathione S-transferase,
and alcohol dehydrogenase, it may be more informative to explore
their interactions with various environmental factors-especially
since many of these markers could clarify mechanisms underlying
various postulated risk factors.
Further clarification of the etiologic role of suggested risk
factors for breast cancer may achieve a greater understanding
of the causes of breast cancer and provide more appropriate preventive
measures. Ultimately, however, disease prevention programs will
depend on our developing a better understanding of the biology
of the disease, which is still poorly defined. Although recent
trends indicate that breast cancer may no longer be an "epidemic"
in the classic sense, it remains all too common an occurrence.
Hopefully, future etiologic research efforts will lead to more
effective preventive approaches, especially since most of the
established risk factors are not readily amenable to change.
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