BREAST CANCER SOME DETAILS
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   Mutagenic factors

   There is a well-established relationship between exposure to ionizing
   radiation and the risk of developing breast cancer. Excess breast
   cancer risk is consistently observed in association with a variety of
   exposures such as fluoroscopy for tuberculosis and radiation
   treatments for acne, tinea, thymic enlargement, postpartum mastitis,
   or Hodgkin's disease. Although risk is inversely associated with age
   at radiation exposure, the manifestation of breast cancer risk occurs
   according to the usual age-related pattern. An estimate of the risk of
   breast cancer associated with medical radiology puts the figure at
   less than 1% of the total; however, it has been theorized that
   certain populations, such as AT (ataxia telangiectasia) heterozygotes,
   are at increased risk from the usual sources of radiation exposure.

   Recently published data provide more detailed information about
   treatment- related risks with Hodgkin's disease. Women treated for
   Hodgkin's disease by age 16 may have a subsequent risk of developing
   breast cancer as high as 35% by age 40.

   Evidence examining the effect of occupational, environmental, or
   chemical exposures on breast cancer risk is limited. There is some
   evidence to suggest that organochlorine residues in the environment
   such as those from insecticides might be associated with an increase
   in breast cancer risk, but the significance of this evidence has
   been debated.

   Mitogenic factors

   Of the many proliferative factors that may contribute to breast
   carcinogenesis, by far the most discussed and studied is estrogen,
   whether endogenous or exogenous. Estrogen stimulates the growth of
   breast tumor cells with an increase in the levels of growth
   stimulatory factors like transforming growth factor (TGF)-alpha. As a
   so-called antiestrogen, tamoxifen increases breast cell growth
   inhibitory factors like TGF-beta and concomitantly reduces
   stimulatory factors (TGF-alpha and inhibitory growth factor-1).

   Data from adjuvant breast cancer trials using tamoxifen have shown
   that tamoxifen not only suppresses recurrence of breast cancer but
   also prevents the occurrence of second primary breast cancers in the
   contralateral breast.

   In addition to tamoxifen, other hormonal manipulations have been
   proposed that may modulate the production of breast cell growth
   factors by suppressing ovarian function  or changing the
   endogenous hormonal environment. However, the evidence supporting
   these approaches is much less developed than that for tamoxifen
   intervention, and these approaches may be characterized as
   theoretical.

   The role of a low-fat diet in breast cancer prevention remains to be
   defined.

   Individual analytic (case-control and cohort) epidemiologic studies in
   adults may be hampered by small numbers of cases, relatively limited
   spectrum of fat intake, and dietary assessments that lack validation.
   A pooled analysis that incorporated results from seven cohort studies
   has addressed these issues and concluded that there is no evidence for
   an association between total dietary fat intake and breast cancer
   risk.

   A low-fat diet might influence breast cancer risk through hormonal
   mechanisms. For example, it has been reported that dietary fat and
   postmenopausal estrogen levels are directly related.
   Although active exercise may reduce breast cancer
   risk particularly in young parous women, there is little evidence
   to suggest a net effect of smoking on breast cancer risk.
   Case-control studies suggested that alcohol consumption is associated
   with a modestly increased risk of breast cancer. Several  but
   not all  prospective studies demonstrated such an effect.

   The list of chemoprevention agents that may be used in breast cancer
   prevention is long. Aside from tamoxifen, the other agent that has
   undergone the most development is fenretinide.
   Retinoids have been shown to have breast cell growth inhibitory effects
   through the upregulation of TGF-beta as well as differentiation effects.
   Other micronutrients that are considered to have potential for protection
   against breast cancer are vitamin E and selenium.
   As with other potential chemopreventive agents, the theoretical
   mechanisms of action for both are multiple and span the categories used
   to classify these agents.

Other Facts:

Statement 1:

Exposure of the breast to ionizing radiation is associated with an increased
risk of developing breast cancer, especially when the exposure occurs at a
young age.  This finding supports the avoidance of unnecessary breast
irradiation.  Exposure to organochlorines or a diet high in fat may also be
associated with increased breast cancer risk, but evidence from epidemiologic
studies is conflicting.  Other studies suggest that active exercise at
certain ages is a lifestyle factor that has the potential to reduce breast
cancer risk.

Statement 2:

Along with additional evidence, the data that tamoxifen prevents second
primary breast cancers in breast cancer patients suggest that tamoxifen may
be able to prevent breast cancer in women who have never had this disease.
There is limited evidence to suggest that fenretinide [N-(4-hydroxyphenyl)
retinamide, 4-HPR] may also be able to prevent breast cancer. Due to the
potential for side effects encountered with the regular use of any
pharmacologic agent, unproven preventive interventions with agents like
tamoxifen and/or fenretinide can be recommended at present only in the
context of a clinical trial.

Definition

By definition, primary prevention of breast cancer involves a reduction in
the incidence of invasive breast cancer, which should lead in turn to a
decrease in breast cancer mortality.

Theoretically, three levels of prevention are available for reducing breast
cancer incidence:  1) the avoidance of an exposure that could increase
breast cancer risk, 2) the use of a protective agent that neutralizes the
effects of an exposure, and 3) the use of an agent that compensates for the
effect of carcinogenic damage, thereby inhibiting progression of a
premalignant lesion to frankly invasive cancer.
In this framework, breast cancer preventive interventions would be
exemplified by
1) changes in diet or lifestyle or reduction of breast tissue exposure to
ionizing radiation at critical ages,
2) use of a radioprotective agent to counteract radiation exposure before
breast tissue is damaged,
3) use of an antiproliferative agent like tamoxifen to prevent the expansion
of premalignant breast cell clones.

Etiology and Pathogenesis of Breast Cancer

Genetic, epidemiologic, and laboratory studies support a stochastic model of
breast cancer development in which a series of genetic changes contribute to
the dynamic process known as carcinogenesis.  An accumulation of genetic
changes is thought to correspond to the phenotypic changes associated with
the evolution of malignancy.  The carcinogenesis sequence is viewed as
starting with tissue of normal appearance, followed by changes that lead to
hyperplasia and dysplasia, of which the most severe forms are difficult to
distinguish from carcinoma in situ.

The forces driving the carcinogenic process have been characterized as
mutagenesis and mitogenesis. Efforts at preventing breast cancer are directed
at these two processes.

The concept that breast cancer may be preventable is supported by the wide
international variation in breast cancer rates, which is an indicator that
there are potentially modifiable environmental and lifestyle determinants of
breast cancer.  Migration studies reinforce this premise; e.g., it has been
observed that Japanese immigrants to the United States acquire much of the
breast cancer risk of the host country within two generations.
Epidemiologic analysis indicates that four factors, including weight, may be
strongly associated with the international variation in breast cancer
incidence.

Dramatic evidence for a role of ovarian hormones in the development of breast
cancer is provided by studies of artificial menopause.  Subsequent to ovarian
ablation, breast cancer may be reduced up to 75%, depending on parity, weight,
and age at the time of artificial menopause, with the greatest reduction for
young, thin, nulliparous women.  It has been observed that removal of
one ovary also reduces the risk of breast cancer, but to a lesser degree than
the removal of both.  Other events associated with hormonal changes have
similarly been found to influence breast cancer risk.  After a transient
increase in breast cancer risk after childbirth, there is a long-term reduction
in breast cancer risk.  The degree of risk reduction appears to be
related to age.

An association between premature, intentional termination of pregnancy
(induced abortion) and subsequent risk of developing breast cancer has also
been observed in some epidemiological studies.

It is important to recognize that the hormonal factors correlated with breast
cancer risk may be related to other breast cancer risk factors such as a
high-fat diet or sedentary lifestyle.
Similarly, adolescent girls have been observed to experience a decreased
frequency of ovulation with moderate levels of exercise.  These studies,
based on epidemiologic observation, provide evidence of a significant
opportunity to prevent breast cancer in certain women by changing their
endogenous hormonal profile.

The underlying susceptibility of an individual also influences the degree to
which mutagens and growth factors accelerate the carcinogenic process.
However, known genetic syndromes, in which a high lifetime probability of
developing breast cancer is attributed to a specific aberrant allele,
contribute to the minority of breast cancers, estimated to be 5%.  Work that
identifies high-risk genes is important because of the insight into breast
cancer etiology that will come from the study of these genes, and also the
potential for identifying high-risk populations who are at increased need for a
preventive intervention.  Among the growing list of such genes are BRCA1
(breast cancer 1) and BRCA2, in each of which abnormalities are
estimated to account for roughly 2% of all breast cancer cases; AT (ataxia
telangiectasia), a recessive condition in which carrying one abnormal gene
may confer breast cancer risk to about 2% of the population; and p53, in
which abnormalities conferring cancer risk are much rarer.

The prevalence of high-risk BRCA1 mutations, estimated to be 1/800 in the
general population, is highest among women with younger-onset breast cancer
(8% for women diagnosed younger than age 35), and among women of
Ashkenazi Jewish ancestry (1% among all women; 21% among women diagnosed
with breast cancer age 40 or younger).  Note that the estimates for young
women are based on small sample sizes.  The prevalence of high-risk BRCA2
mutations is also higher among women of Ashkenazi Jewish ancestry.
Although the goal is to use this genetic information to target women who may
benefit from usual or enhanced prevention and early detection strategies,
there is little scientific evidence to support or quantify this potential
beneficial effect.