You are on page 1of 9

BREAST CANCER

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

Primary prevention depends on our ability to identify individuals who are


at increased risk for the development of breast cancer. Although many
risk factors cannot be changed, knowledge of their presence can be
used to identify high-risk individuals. Age, socioeconomic class,
geographic location, race, and ages of menopause, menarche, and first
birth are examples of risk factors that are difficult to change but
important to recognize. The incidence of breast cancer, like that of most
cancers, increases with age. The majority of cases are diagnosed in
women older than 40 years of age, with only 10% to 15% occurring in
women younger than 40 years old and fewer than 5% occurring among
women younger than 35 years of age. Affluent women and individuals
born in colder climates or in the Western hemisphere also tend to have a
higher incidence of breast cancer. White women have more breast
cancers than black, Asian, Hispanic, or Native American women. It is of
considerable interest that Hispanic and Native American women have
many of the same demographic variables (obesity, high fat, and low
vegetable diet) that are associated with a high incidence of breast
cancer in whites, yet their incidence of breast cancer is less than half
that of whites. Determining whether this difference is genetically based
or if it reflects some other protective dietary or environmental factor is an
important issue to address. By identifying who is at higher risk for breast
cancer, health professionals can then counsel this subgroup of women
and their families about the risks for breast disease and various ways to
modify these risks, and they can encourage enrollment into clinical trials
aimed at studying novel approaches for breast cancer risk reduction.
The most important step in trying to discern who is at risk is to take a
detailed personal and family history extending back at least three
generations. Nearly 25% of women diagnosed with breast cancer have a
family history of the disease. Recent advances in our understanding of
the molecular biology of breast cancer have led to the identification of
specific mutations that might help identify women with a hereditary
predisposition to developing breast cancer and might help predict who
will respond to adjuvant therapy. Medical records, including pathology
reports, should be obtained whenever possible to help complete an
accurate pedigree. Recall bias is a significant problem when
constructing pedigrees and can profoundly influence how we counsel
patients; therefore, it is important to collect documentation whenever
possible. Family histories must be gathered from the maternal and
paternal sides of the family. This latter step is often neglected and
makes it impossible to counsel anyone in a meaningful way.

Although most cases of breast cancer are sporadic and a product of


many genetic insults, approximately 5% are due to specific inherited
germline mutations in the BRCA1 and BRCA2 tumor suppressor genes.
The estimated lifetime risk for breast cancer in BRCA1 and BRCA2
mutation carriers ranges from 55% to 85%, in comparison with the 13%
lifetime risk for the general population. Women with these mutations are
also at increased risk for the development of a second breast cancer;
BRCA1 mutation carriers carry up to a 65% lifetime risk, and BRCA2
carriers might share a similar risk. Therefore, carriers of mutations in the
BRCA genes and women with a personal or family history might benefit
from prevention strategies and genetic counseling.

Genetic testing should be offered to individuals with a strong family


history (breast or ovarian cancer in two or more generations), a history
of multiple primaries (ovarian or breast, colon, endometrial), early age of
onset of breast cancer (<35 years), or individuals of Ashkenazi Jewish
descent, who carry a frequency of mutations in the BRCA genes
estimated to be 2.2%. Approximately one out of every 300 to 800
American women carries a BRCA1 mutation; however, not every one of
these women will develop breast cancer. This variable penetrance seen
in BRCA mutation carriers highlights one of the dilemmas of genetic
testing for BRCA gene abnormalities. Furthermore, a negative test might
offer false reassurance, because it could represent a false negative. In
addition, although a number of mutations in the BRCA genes have been
sequenced, there are probably many more that we have not identified
and for which we therefore cannot test. Practitioners should be aware of
the uncertainty inherent in genetic testing for BRCA mutations and be
prepared to counsel their patients accordingly.

Family history without a clearly defined genetic syndrome is also


important in counseling women about their risks for developing breast
cancer. A woman with a first-degree relative with premenopausal breast
cancer carries anywhere between a 1.8- and an 8.8-fold increased risk
of developing a breast cancer in the future and is at high risk for
harboring a deleterious mutation. This risk decreases to 1.2- to 4.0-fold
in a woman who has a first-degree relative who developed breast cancer
after menopause. Having a second-degree relative with breast cancer
increases a woman's risk by approximately 1.5-fold.

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.

Compelling data in support of the aforementioned WHI results have


emerged from recent epidemiologic reports indicating a sharp decrease
in breast cancer incidence in 2003, particularly in estrogen receptor
(ER)positive tumors. This time period represents the first year after
results of the WHI trial were released, with a resultant immediate 50%
decrease in HRT use. The rapidity of this observed decreased breast
cancer incidence supports an effect of hormone therapy on progression
of subclinical lesions. These reports from the California Cancer Registry
and in the national U.S. Surveillance, Epidemiology, and End Results
(SEER) registry have sparked a renewed debate about the role of HRT
in early breast cancer development, because it represents the first
significant decrease in breast cancer incidence in the United States in
more than half a century.

In contrast, the preponderance of evidence suggests that the risk for


breast cancer from oral contraceptive use is very low or nonexistent. An
overview of 54 epidemiologic studies evaluating the role of oral
contraceptives and breast cancer found the RR of current users to be
1.24 vs. no risk for women who had not taken them for 10 or more
years. Thomas summarized the results of five cohort studies and found
that the overall risk for ever-users to be 1.06. On the other hand, in a
large, matched case-control study of BRCA mutation carriers use of oral
contraceptives was associated with increased risk of breast cancer in
BRCA1 (overall risk = 1.20) but not in BRCA2.

Oral contraceptives are used by more than 150 million women


worldwide and offer a number of health benefits, including reduction in
dysmenorrhea, fibrocystic breast changes, iron deficiency anemia, pelvic
pain secondary to endometriosis, ectopic pregnancy, pelvic inflammatory
disease, functional ovarian cyst formation, and the incidence of
endometrial and ovarian cancers. Women should be counseled that
there could be a slightly increased risk of developing breast cancer,
although some believe that the apparent increase is due to surveillance
bias, because physicians examine women taking oral contraceptive pills
more frequently. Supporting this viewpoint is the observation that women
with breast cancer who have taken oral contraceptives in the past do not
experience lower survival rates when compared with women who have
not taken them. Based on these data, current prescribing practices for
oral contraceptives should not be changed, although the special case of
BCRA mutation carriers must be assessed carefully on an individual
basis.

Other risk factors associated with breast cancer, such as proliferative


fibrocystic changes in the breast, sedentary lifestyle, and diet, may be
used to design preventive strategies for the high-risk woman. Overall,
typical or atypical proliferative fibrocystic changes of the breast are
associated with a two- to fourfold increased risk for the development of
breast cancer. Because the clinical significance varies depending upon
the degree of hyperplasia and atypia present, the Cancer Committee of
the College of American Pathologists has replaced the term fibrocystic
disease with fibrocystic changes. Possible treatment options for relieving
symptoms related to fibrocystic changes include decreasing the
consumption of foods rich in methylxanthines (e.g., chocolate, coffee,
tea, and cola) or taking a supplement such as vitamin E, or medications
such as danocrine, bromocriptine, or tamoxifen. Although consumption
of these drugs has been shown to decrease fibrocystic changes in the
breast, studies have not been done to evaluate whether these changes
actually decrease the increased risk of breast cancer.

Diet

Numerous observational studies have reported on the role of diet in


breast cancer development with disparate findings, whereas
experimental studies are more definitive. Many public health agencies
advocate a low-fat, high-fiber diet to prevent breast cancer. Data linking
diet to breast cancer come largely from international and migration
studies. First-generation Japanese-American women and women who
have recently migrated from Japan have risks for the development of
breast cancer that approach those of Native American women.
Differences are seen among women from various countries as well; for
example, women in Great Britain have age-standardized mortality rates
of approximately 28 per 100,000 versus those of Japanese women of 6
per 100,000.

The WHI study is the only randomized prospective study performed to


address the role of diet in the development of breast cancer, in which
women were randomized to low-fat diets or no dietary intervention.In this
randomized trial of a low-fat dietary intervention among postmenopausal
women aged 50 through 79 years, the low-fat diet resulted in a
nonsignificant 8% reduction in breast cancer incidence over an 8-year
study period. However, secondary analysis revealed a benefit from the
dietary intervention among women with baseline high-fat diets, and
women who were strictly adherent to the intervention. Therefore, we
consider these results to be promising, if not definitive data related to
dietary modification of breast cancer risk. Initial data from the WHI study
related to calciumvitamin D supplementation compared to placebo
among postmenopausal women revealed no reduction in breast cancer
risk, although the incident breast cancers in the intervention group were
smaller in size.

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.

Numerous epidemiologic studies suggest that alcohol has an effect on


the development of invasive breast cancer. An extensive and detailed
meta-analysis of the six largest prospective cohort studies addressing
this issue showed that alcohol consumption was associated with a linear
increase in breast cancer incidence for intakes less than 60 g/day (about
two to five drinks). The association was not modified by other factors,
and higher alcoholic intakes (>60 g/day) were not associated with
additional increased risk. Low dietary levels of selenium and
antioxidants such as vitamins C and E, and -carotene have been
associated with breast cancer development and differences in survival.
-carotene is the major provitamin A carotenoid and has differentiating
and antiproliferative effects on a variety of cells, including mammary
carcinomas. Levels of -carotene have been analyzed in numerous
studies and are lower in women with higher staged breast cancer and
breast cancer in general. A case-control study from Europe, however,
observed no differences in vitamin A or -carotene levels between cases
and control subjects. Studies of soy intake in Singapore Chinese women
are of great interest. Soy intake was significantly associated with
lowered plasma estrone and with more favorable mammographic
patterns. Recently, there has been a great interest in gene-environment
interactions and studies of micronutrients in relationship to metabolic
pathways, and genetic polymorphisms are likely to be informative.
Among women at high risk for breast cancer for other reasons (e.g.,
heredity), reducing alcohol consumption should be a straightforward way
to reduce breast cancer risk.

Screening and Early Detection


Secondary prevention is aimed at detecting preinvasive lesions such as
ductal carcinoma in situ, lobular carcinoma in situ, or early-staged breast
cancers that have the potential to be cured with limited treatment.
Screening tests include the breast self-examination, the clinical breast
examination administered by health care professionals, and
mammography. Successful implementation of wide-scale screening
programs that incorporate these techniques, followed by treatment of
detected lesions, is probably responsible for most of the decline in the
overall death rate from breast cancer that occurred among American
women from 1989 through 1993. This decline continues and probably
represents both the increased use of mammography and the
effectiveness of systemic adjuvant therapy. Currently, 5-year survival
rates for localized breast cancers have increased to more than 98%.

Although we encourage women to perform monthly breast examinations,


a randomized trial indicated that this practice does not decrease overall
mortality rates. The most effective combination for decreasing the
incidence of invasive disease is the clinical breast examination and
mammography. The Breast Cancer Detection Demonstration Project
showed that the sensitivity of the clinical breast examination and
mammogram together was 70% to 80%, with sensitivity increased for
older patients. Although it is standard practice for a clinical breast
examination to be performed annually, there has been a great deal of
controversy surrounding the appropriate time to begin routine screening
with mammograms. Randomized controlled trials of a large number of
women on trials from several countries have unequivocally
demonstrated a 40% decrease in mortality from breast cancer in women
who have annual mammograms beginning at the age of 50. Throughout
the years, controversies have erupted regarding the magnitude of
benefit from screening mammography. We continue to recommend the
practice to women beginning at the age of 50 but encourage discussion
of the risks and benefits associated with this procedure.

The opinion on routine screening in women between the ages of 40 and


49, however, is mixed. Eight randomized controlled trials performed
between 1963 and 1982 do not demonstrate a statistically significant
difference in breast cancer mortality within 7 years after screening was
initiated in women randomized to receive or not receive screening
mammograms. A majority in a recent consensus panel used this
information to state that there currently was not sufficient evidence to
advocate routine screening mammography in women ages 40 to 49.
Five of these trials, however, demonstrated a 16% decrease in mortality
if follow-up continued for 10 years, prompting release of a minority report
advocating routine screening in the 40 to 49 age group. As the minority
report highlighted, the goal of mammography is to detect preinvasive
lesions, and 15% to 20% of breast cancers are now diagnosed as ductal
carcinoma in situ or lobular carcinoma in situ in younger women. The
minority report correctly pointed out that the risk from radiation during
mammography screening was overemphasized. The U.S. Preventive
Task Force has considered the issues carefully and recommends a
screening mammography every 1 or 2 years for women aged 40 and
older, a position we favor. An important recent observation is that
mammographic density is strongly associated with risk and is heritable.
This information should further target the premenopausal woman at
higher risk for breast cancer; determination of the underlying genetic
basis for breast density has now become of great interest, particularly in
that the use of a postmenopausal hormone therapy was strongly
associated with an increase in mammographic density in the
Postmenopausal Estrogen/Progestin Interventions and WHI trials.

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.

You might also like