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The morbidity and mortality from breast cancer remains high despite
significant advances in our understanding and management over the
last several decades. Therefore, prevention and early detection have
become important challenges for the medical community. In addition to
an enormous health benefit, several billion dollars would be saved
annually if breast cancer were prevented and/or the disease were
detected at an earlier stage. The widespread use of screening
mammography, the increasing recognition that breast density is a major
risk factor, the identification of high-risk individuals based on family
history, the detection of deleterious mutations, and the proof of
principle that tamoxifen and raloxifene can reduce the risk for breast
cancer all anticipate more effective early management of this disease.
Etiology
Heredity
Hormonal Factors
Women with a long lifetime exposure to estrogen are also more likely to
develop breast cancer. The risk for breast cancer increases by 20% if
menarche occurs before the age of 12. Furthermore, women who
experience a late menopause, are nulliparous, or deliver their first child
after 30 are also at increased risk. An induced abortion does not result in
an increased risk of breast cancer ( Box 26-1 ).
Box 26-1
INDICATIONS FOR GENETIC TESTING IN BREAST CANCER[*]
A first-degree relative with breast cancer before age 40
Two or more relatives with breast or ovarian cancer at any age
Three or more relatives with breast, ovarian, or colon cancer at
any age
* The indications for genetic testing in breast cancer and in other cancers are in rapid
evolution as the true risks become better defi ned and as prevention (e.g., tamoxifen)
and early detection (e.g., mammography, MRI) strategies mature.
The subject of HRT and its role in the etiology and progression of breast
cancer has been among the most intensely studied in medicine. Studies
evaluating the role of hormone replacement in postmenopausal women
have reported contradictory resultsnot surprising given that many of
the studies evaluated different doses, preparations, follow-up times, and
different age cohorts. Results from the WHI study (i.e., the largest
prospective randomized clinical trial to address the issue of HRT on
breast cancer development), however, conclusively demonstrated an
increased risk of invasive breast cancer (relative risk = 1.26) among
those women taking estrogen plus progestin compared with placebo
control subjects. Additionally, the supplementation of postmenopausal
women with estrogen plus progestin in the WHI trial led to increased
mammographic density and breast cancer, These findings have sparked
an intense debate, with proponents of HRT advocating no change in
prescribing habits and opponents vociferously advocating the opposite.
Diet
Women of tall stature or who have high body fat and mass have higher
rates of breast cancer than other women. An increase in estrone and
estradiol as BMI increases has also been documented. The recognition
that a hormone (leptin) produced by fat cells vigorously stimulates the
growth of normal and malignant breast cells may provide an important
biologic link to the phenomenologic observation, Some animal studies,
however, have shown that caloric restriction in general, rather than a
low-fat diet per se, decreases risk of breast cancer. This effect of caloric
restriction could underlie the observation that women who exercise have
a lower risk of breast cancer. Another consideration is that women who
exercise ovulate less frequently and therefore are not exposed to the
higher levels of estrogen that normally occur in women who ovulate
regularly.
New areas that are currently being evaluated for the enhancement of
primary and secondary prevention strategies include digital
mammography, DCE-MRI, DCE-CT with ultrasound, PET, optical
scanning, ductal lavage for cytologies and molecular testing, nipple
aspirates, and blood and urine assays for growth factors and
autoantibodies to oncoproteins and to tumor DNA. Validated biologic
markers of breast cancer risk and/or more sophisticated screening
modalities might well increase our ability to detect lesions earlier in high-
risk populations.
Chemoprevention
Successful therapeutic prevention for breast cancer has progressed
faster than for any other malignancy. Two compounds, tamoxifen and
raloxifene, which are estrogen receptor antagonists, have been shown
to reduce the incidence of primary breast cancer in women at high risk.
In a head-to-head randomized trial of tamoxifen and raloxifene, efficacy
was comparable with a 50% reduction of breast cancers; the toxicity of
raloxifene was considerably less than that of tamoxifen, Based on the
positive activity of anastrozole (an inhibitor of estrogen synthesis) in the
adjuvant setting and its minimal toxicity, a randomized trial of this
compound versus raloxifene in women at high risk for breast cancer is
now underway. Preclinical studies at our institution using a transgenic
mouse model suggest that antiprogestational agents may be of
particular benefit in BCRA1-positive breast cancers. The pros and cons
of chemoprevention for breast cancer were recently reviewed, and the
overall conclusion was that it cannot yet be recommended for general
usage but should be useful for reduction of risk among high-risk
individuals.
There are several other options for a woman who is at very high risk for
breast cancer, including bilateral mastectomy or oophorectomy and
lifestyle modification. Prophylactic bilateral mastectomies have been
performed on some mutation carriers, but cases of breast cancer
developing in the remaining breast tissue after subcutaneous and total
mastectomies have been reported. In addition, such surgeries are
dramatic procedures for a woman who has only a probability of
developing breast cancer, and a decision analysis paradigm for these
interventions is available.No long-term data exist on the effect of these
surgeries in increasing the life expectancy of mutation carriers, yet one
meta-analysis reveals considerable global variation in the utility of
prophylactic surgery among unaffected BRCA1 and BRCA2 mutation
carriers. Bilateral oophorectomy has been proposed as another option
for premenopausal women who have completed their childbearing.
Although castration has been shown to decrease the risk of breast
cancer in young, nulliparous women, especially when it is performed
before the age of 35, this remains a very controversial area in the
management of breast disease. Secondary prevention can be
accomplished by instructing these high-risk women about the
importance of clinical breast examinations by a physician and screening
mammograms, which should begin at a younger age, preferably at least
5 years earlier than the age at which the relative developed breast
cancer. Observational studies and initial clinical trials suggest that
moderate physical exercise and control of obesity may decrease the risk
for breast cancer, as has been suggested for colorectal cancer. Recently,
several randomized interventional trials have been initiated to definitively
address these issues.