810 Breast Cancer
Concise Review for Clinicians
Advances in Screening, Diagnosis, and Treatment of Breast Cancer
BETTY A. MINCEY, MD, AND EDITH A. PEREZ, MD
Breast cancer is the most common cancer in women in the
United States; this year, approximately 215,900 new cases
will be diagnosed. Mammography remains the corner-
stone of screening, with technologies such as ultrasonog-
raphy and magnetic resonance imaging having an in-
creasingly defined role. Improved risk assessment and
prevention strategies have been implemented, and current
research in these areas includes better identification of
patients at risk, the use of aromatase inhibitors and other
agents to reduce risk, and the use of surrogate markers.
Breast cancer staging has been optimized recently; also,
local management of breast cancer, adjuvant systemic
therapies, and treatment of patients with advanced disease
B reast cancer is the most common cancer in women in
the United States, with incidence increasing about
0.5% per year. In the year 2004, an estimated 215,900 new
cases of invasive breast cancer (stages I-IV) will be diag-
nosed, and about 40,100 women and 470 men will die of the
disease.1 New strategies to decrease the risk of breast cancer
are being studied and implemented. Although breast cancer
is a leading cause of death in women (second only to lung
cancer), mortality rates have declined recently. This reduc-
tion in mortality, despite the increase in incidence, is attrib-
uted to improvements in screening, diagnosis, and treatment.
SCREENING
Despite controversy surrounding recent reports, mammog-
raphy remains the cornerstone of breast cancer screening.
Mammographic screening for early detection of breast can-
cer reduces mortality and is widely recommended as an
integral part of annual preventive health care for all women
beginning at age 50 years and continuing for as long as a
woman’s life expectancy is at least 10 years. For women
older than 40 years, most major health organizations rec-
ommend annual or semiannual screening mammography.2,3
From the Division of General Internal Medicine (B.A.M.), Multidis-
ciplinary Breast Clinic (B.A.M., E.A.P.), and Division of Hematology
and Oncology (E.A.P.), Mayo Clinic College of Medicine, Jackson-
ville, Fla.
A question-and-answer section appears at the end of this article.
Individual reprints of this article are not available. Address corre-
spondence to Edith A. Perez, MD, Division of Hematology and On-
cology, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jack-
sonville, FL 32224 (e-mail: perez.edith@mayo.edu).
Mayo Clin Proc. 2004;79:810-816
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, June 2004, Vol 79
have been evolving. Advances in screening, diagnosis, and
treatment of breast cancer continue to influence our ap-
proach to patients with this disease. Many improvements
have been made as well in supportive care, including in-
creased tolerability of therapy and notable amelioration of
disease symptoms.
Mayo Clin Proc. 2004;79:810-816
AI = aromatase inhibitor; CI = confidence interval; DCIS =
ductal carcinoma in situ; ER = estrogen receptor; LCIS =
lobular carcinoma in situ; NSABP = National Surgical Adju-
vant Breast and Bowel Project; PR = progesterone receptor;
STAR = Study of Tamoxifen and Raloxifene
The sensitivity of first mammography ranged from 71% to
96% in studies of a 1-year screening interval.2,3 The posi-
tive predictive value of abnormal mammographic results
requiring biopsy ranged from 12% to 78% in these studies
and increased with age.2,3
Young women at increased risk of breast cancer devel-
opment should be advised to undergo mammography be-
fore age 40 years. Current guidelines suggest that women
with BRCA1 or BRCA2 mutations should begin screening
mammography at age 25 years or 10 years earlier than the
youngest age at which breast cancer has been diagnosed in
their family.4 Although it is intuitive to recommend this
approach to women with a strong family history of breast
cancer and unknown genetic makeup, data are not currently
available to quantify benefit for this group. Unfortunately,
mammography in these groups of young women has a sensi-
tivity of only about 33% in most studies. Ultrasonography
does not improve this sensitivity and is not recommended for
screening; magnetic resonance imaging of the breast has a
sensitivity of between 90% and 100% but is expensive and
has not been endorsed for screening purposes.2,3 Ongoing
trials are further exploring these technologies.
The clinical breast examination is an important part of
breast cancer screening and surveillance because up to 10%
of breast cancers may be clinically evident while mam-
mographically occult.2,3 The role of breast self-examination
has not been well-defined.
RISK ASSESSMENT
For some women, the risk of developing breast cancer is
high enough to warrant consideration of prevention strate-
810 © 2004 Mayo Foundation for Medical Education and Research
Mayo Clin Proc, June 2004, Vol 79
gies in addition to screening and surveillance. Current
methods for defining risk include use of the modified
Gail model, use of the Claus model, and determination of
BRCA mutation carrier status.4 The modified Gail model
combines relative risks associated with age, race, age at
menarche, number of previous breast biopsies, history of
atypical ductal hyperplasia, and family history of breast
cancer in first-degree relatives for estimation of 5-year and
lifetime risks of breast cancer development in an individual
woman.
The online risk-assessment tool, located at www
.breastcancerprevention.com, provides comprehensive in-
formation approved by the National Cancer Institute and
includes a system of scoring an individual’s risk of devel-
oping breast cancer in the next 5 years and by age 80 years.
A score of 1.66% or higher for the next 5 years indicates
high risk. This model is reasonable for estimating risk in
most women but may seriously underestimate risk in
women with strong family histories of breast cancer. For
such women, the Claus model, which considers only family
history, can be used to estimate risk. In appropriate cases,
genetic counseling and testing for mutations in BRCA1 or
BRCA2 genes may be considered.
None of the risk models consider a history of lobular
carcinoma in situ (LCIS), which is primarily regarded as a
risk factor rather than a precursor lesion and is associated
with an annual risk of approximately 1% for breast cancer
development in either breast.
An additional risk factor is mammographic density.
Breasts with larger amounts of connective and epithelial
tissue appear denser than do breasts with more fat. Mam-
mographically dense breast tissue is one of the strongest
established risk factors for breast cancer, conferring a 4-
to 6-fold increased risk for women with the most dense
breast tissue compared with those with the least dense.5
Mammographic density also decreases the sensitivity of
mammography. The relative importance of mammographic
density as a risk factor and the underlying mechanisms
responsible for the increased risk in women with dense
breast tissue are topics of ongoing research.
PREVENTION
Women with a substantially increased risk of breast cancer
should be counseled regarding options for breast cancer
prevention. Defining the level of risk that warrants inter-
vention may be difficult and should be done on an indi-
vidual basis, taking into account a woman’s age, comor-
bidities, and her own thoughts about her risk and how it
affects her quality of life. Decisions regarding interven-
tions such as chemoprevention or surgical prophylaxis
must be highly individualized and will vary greatly among
women with similar risk levels.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Breast Cancer 811
Tamoxifen, a selective estrogen receptor (ER) modula-
tor that has been used for years to treat breast cancer, is
the only agent currently approved by the US Food and
Drug Administration to decrease the risk of breast cancer.
Its approval by this agency for prevention of breast cancer
was based on the results of the National Surgical Adjuvant
Breast and Bowel Project (NSABP) P-1 study, in which a
relative risk reduction of approximately 50% was observed
for women with a 5-year risk of 1.66% or higher, as calcu-
lated by the modified Gail model (despite notable adverse
effects among 13,388 women, including 3 women in the
tamoxifen group who died of pulmonary emboli vs none in
the placebo arm). A meta-analysis of 5 worldwide trials
that evaluated tamoxifen vs placebo in women at increased
risk of breast cancer revealed a 38% (95% confidence
interval [CI], 28%-46%; P<.001) relative reduction in risk
of breast cancer development at 5 years of follow-up.6 In
terms of absolute numbers, patients in the placebo group
had an approximate 13% risk of developing a ductal carci-
noma in situ (DCIS) or invasive breast cancer during the
study periods vs 7% of those in the tamoxifen arm. There
was no effect on ER-negative breast cancer but a 48%
relative decrease in ER-positive disease. However, the risk
of endometrial cancer was increased (odds ratio, 2.4; 95%
CI, 1.5-4.0), as was the risk of venous thromboembolism
(odds ratio, 1.9; 95% CI, 1.4-2.7). Survival differences
between tamoxifen and placebo have not been shown to
date. Ongoing trials are evaluating other prevention strate-
gies. The Study of Tamoxifen and Raloxifene (STAR),
NSABP P-2 trial is comparing 5 years of tamoxifen use vs
raloxifene use, another selective ER modulator, with eligi-
bility determined as for the NSABP P-1 study by an esti-
mated baseline risk of breast cancer higher than 1.66% at 5
years, based on the modified Gail model. The accrual goal
for STAR is 19,000 women, which should be achieved this
year. A large prevention study (MAP.3) about to begin at
multiple medical centers in the United States and Canada
will compare the effectiveness of the aromatase inhibitor
(AI) exemestane, either alone or in combination with
celecoxib, with placebo for reducing the risk of breast
cancer in high-risk women.
For women with a substantially elevated risk of breast
cancer development, particularly those proved to carry mu-
tations in BRCA1 or BRCA2, surgical options for preven-
tion should be discussed.4 Available data regarding risk
reduction with surgical prophylaxis indicate that bilateral
mastectomy reduces the risk of breast cancer development
by approximately 90% and that oophorectomy reduces the
risk of breast cancer by approximately 50% if performed
before menopause.4 These risk reductions are based on
retrospective, observational studies and on more recent
prospective observational studies of women at high risk.
812 Breast Cancer
Three important areas of research in the prevention
setting include better identification and definition of pa-
tients at increased risk of breast cancer development, the
use of AIs, and the use of agents that may decrease the risk
of hormone receptor–negative disease. Surrogate markers
for breast cancer risk are being sought so that pilot trials of
new agents can be completed with fewer participants in less
time than is needed to show actual changes in cancer inci-
dence. An example of a potential surrogate marker is mam-
mographic density. Because it is not only measurable but
also may be altered potentially by interventions such as
selective ER modulators or AIs, mammographic density
may prove to be a useful surrogate marker for both risk and
risk reduction. A small, ongoing 1-year study (MAP.2) will
determine the effectiveness of exemestane in reducing
mammographic density.
BREAST CANCER STAGING
Most patients presenting with breast cancer have disease
localized to the breast or to the breast and axillary lymph
nodes; however, 40% to 50% eventually may develop
metastatic disease. A new staging system became standard
in 2003: the 6th American College of Physicians Staging,7
which assigns a stage from 0 to IV on the basis of the
anatomical extent of the tumor, including invasiveness, size,
and lymph node or distal involvement. Stage 0 (Tis) breast
cancers are DCIS (or intraductal) carcinomas. Lobular carci-
noma in situ increasingly is considered a risk factor for
subsequent breast cancer, but it is still included as a malig-
nancy in the most recent staging system and is classified as
“Tis (LCIS).”7 Stages I through IV are invasive tumors, most
commonly of the infiltrating ductal type. The histological
subtype of breast cancer is not part of the staging system but
is important for its potential influence on patient outcome.
LOCAL MANAGEMENT OF PRIMARY
BREAST CANCER
The management of primary breast cancer, whether inva-
sive or in situ, begins with local treatment. The only exclu-
sion is LCIS, which is managed as a determinant of in-
creased risk; in other words, management after a biopsy
specimen shows LCIS does not require full excision, lump-
ectomy, or mastectomy. As a determinant of increased risk
of subsequent breast cancer, LCIS is managed by observa-
tion (follow-up) and chemoprevention. Most women with
newly diagnosed breast cancer have a choice between
breast conservation therapy with lumpectomy and radiation
or mastectomy. Although the chance of recurrence is
higher with breast conservation therapy, the effect of both
therapies on overall survival is the same. Women with
large tumors or those with multifocal breast cancer often
are not candidates for breast conservation.
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Mayo Clin Proc, June 2004, Vol 79
Sentinel lymph node evaluation has essentially become
a standard of care as part of the staging of invasive breast
cancer. Outside of clinical trials, if the sentinel lymph node
is negative for tumor by hematoxylin and eosin pathologi-
cal evaluation, then axillary node dissection is not per-
formed. However, a full axillary node dissection is per-
formed if the sentinel lymph node is positive for tumor.
Ongoing clinical trials are evaluating the feasibility of ob-
viating full dissection in patients whose sentinel lymph
node is positive for malignancy. Routine evaluation of the
sentinel lymph node in the setting of DCIS has not been
established, although it is included sometimes in patients
with multifocal or high-grade DCIS.
External beam radiotherapy is a standard component of
local treatment of patients with invasive breast cancer
when breast conservation is undertaken.8 For women who
have undergone mastectomy, this therapy is not routinely
recommended unless the tumor is large (>5.0 cm), there is
chest wall involvement, or more than 3 axillary lymph
nodes are involved. The use of postmastectomy radiation
therapy for patients with 1 to 3 lymph nodes positive for
malignancy is controversial.
Generally, radiation therapy after breast conserving sur-
gery consists of whole breast external beam radiotherapy
administered over 5 to 6 weeks, but new techniques are
evaluating partial breast irradiation. Partial breast irradia-
tion is administered generally to the portion of the breast
that includes the tumor bed and an area of surrounding
margin. One advantage of this technique is that it might
allow the use of higher doses of radiation, shortening treat-
ment duration from 5 to 6 weeks to only a few days.2,3
The necessity of radiation therapy is uncertain in
women with small, low- to intermediate-grade DCIS un-
dergoing lumpectomy of a tumor with negative margins.
Several ongoing clinical trials are addressing this issue. For
now, radiation therapy is a standard component of breast
conservation in most women with DCIS.
ADJUVANT SYSTEMIC THERAPY
The goals of adjuvant systemic therapy include preventing
the recurrence of primary breast cancer and decreasing the
risk of death from the disease while ameliorating the risks
of toxicity.9,10 Improvements in this area will depend on
scientifically rigorous and well-designed clinical trials.
Major areas of research include predictors of outcome and
response using gene profiling, optimization of existing
agents, and incorporation of biologically based treatments.
Systemic therapy may consist of antiestrogen hormonal
therapy, adjuvant chemotherapy, or both.
Premenopausal or postmenopausal women with DCIS
that expresses ER who are treated with lumpectomy with or
without radiation have an approximate 50% relative benefit
Mayo Clin Proc, June 2004, Vol 79 Breast Cancer 813

Table 1. Aromatase Inhibitors (AIs) as Adjuvant Therapy for Postmenopausal Women

With Hormonally Responsive Breast Cancer
Randomization Reduction in
Prior Median Relative reduction
recurrence
No. of adjuvant Duration follow-up in contralateral
Study* patients hormones of intervention Treatment (mo) Relative† Absolute‡ breast cancer (%)
ATAC12 9366 None 5y Tamoxifen 47 14%‡ 2.4% at 4 y 38
Anastrozole (P=.03)
Tamoxifen +
anastrozole†
MA.1713 5187 5 y of 5y Placebo 30 43% 6% at 4 y 46
tamoxifen Letrozole (P<.001)
IES14 4742 2 or 3 y of 3 or 2 y§ Tamoxifen 30.6 32% 4.7% at 3 y 56
tamoxifen Exemestane (P<.001)
*ATAC = Arimidex, Tamoxifen Alone or in Combination; IES = International Exemestane Study; MA.17 = Letrozole vs Placebo After 5 Years of
Tamoxifen.
†In favor of AI.
‡Results of the combined arm similar to those of tamoxifen alone.
§3 years after 2 years of tamoxifen, or 2 years after 3 years of tamoxifen.

in decreasing disease recurrence (but only a small absolute
benefit, about 1%-2%) from the 5-year use of adjuvant
tamoxifen; AIs currently are being evaluated in clinical
trials for postmenopausal women. However, no evidence at
this time suggests that these hormonal agents affect sur-
vival of patients with DCIS. Chemotherapy is not recom-
mended as adjuvant therapy in the setting of DCIS.
The selection of hormonal adjuvant therapy for women
with invasive breast cancer depends on the menopausal sta-
tus of the patient because the status determines the source of
estrogen production (the ovaries in premenopausal women,
peripheral tissues in postmenopausal women). Patients with
resected invasive breast cancer whose tumors express ER
and/or progesterone receptor (PR) typically receive 5 years
of antiestrogen treatment in the form of tamoxifen; an even
better approach appears to be the use of an AI (such as
anastrozole) if the patient is postmenopausal.11,12 Clinical
trials have shown that continuing to use tamoxifen after 5
years is not helpful (and may be detrimental in terms of
increased tumor relapse). A recent study showed that the AI
letrozole improves disease-free survival if used for 5 years in
postmenopausal women who have completed 5 years of
tamoxifen use and who are free of disease.13 Another recent
study showed that for postmenopausal women with hormon-
ally responsive tumors, it is better to switch to the AI
exemestane after 2 to 3 years of tamoxifen use because
exemestane significantly improves disease-free survival
compared with 5 years of tamoxifen use.14 New clinical trials
are comparing the efficacies of the following: 5 years of
tamoxifen use followed by 5 years of AI use, 5 or even 10
years of AI use, or 2 to 3 years of tamoxifen use followed by
AI use for the rest of the 5-year period of hormonal therapy.
Three AIs are available for use in the United States:
anastrozole, letrozole, and exemestane; only anastrozole has
been approved for the adjuvant setting, but approval of letro-
zole and perhaps exemestane for this indication is expected
this year. Adjuvant AIs for postmenopausal women with
hormonally responsive tumors are summarized in Table 1.12-14
For premenopausal women, one of the central issues
related to hormonal therapy is the role of ovarian ablation
as a substitute for, or in combination with, systemic chemo-
therapy. Several ongoing trials are addressing this issue,
including the Suppression of Ovarian Function Trial
(SOFT), IBCSG 24-02; the Tamoxifen and Exemestane
Trial (TEXT), IBCSG 25-02; and the Premenopausal En-
docrine Responsive Chemotherapy (PERCHE) trial,
IBCSG 26-02; information is available at the Cancer Trials
Support Unit (CTSU) Web site (www.ctsu.org).
Combination chemotherapy is recommended for many
premenopausal or postmenopausal women with invasive
breast cancer who are eligible to receive adjuvant therapy.
Adjuvant chemotherapy should be discussed with patients
diagnosed as having invasive tumors larger than 1.0 cm.9,10
Many types of chemotherapy approaches are available, and
recent data have provided a better understanding of opti-
mal regimens. Anthracycline (doxorubicin or epirubicin)-
containing regimens are better than cyclophosphamide,
methotrexate, 5-fluorouracil type of chemotherapy; thus,
this latter regimen is used less frequently than it was 5 to
10 years ago. Taxanes (paclitaxel or docetaxel) improve
disease-free and overall survival for patients with node-
positive breast cancer (data are pending regarding their
therapeutic ratio in patients with node-negative breast can-
cer). Taxanes may be used either sequentially or concur-
rently with the anthracyclines, depending on the agent
used. The typical duration of adjuvant systemic chemo-
therapy ranges from 2 to 6 months; the duration of older
regimens was 6 months to 2 years. Variations in drug ad-

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
814 Breast Cancer
ministration appear to alter the efficacy of chemotherapy,
and newer trials are exploring this strategy.
Treatment of patients with node-negative disease is
evolving, and many ongoing trials are attempting to iden-
tify predictors of response and to select patients most likely
to benefit from different therapies. In general, the same
principles as those outlined for node-positive disease also
apply to patients with node-negative breast cancer; how-
ever, although the relative improvements with chemo-
therapy are the same irrespective of whether the nodes are
involved, the absolute improvements are expected to be
lower for patients with node-negative disease because of
their lower risk of breast cancer recurrence.
If both chemotherapy and hormonal therapy are recom-
mended, the chemotherapy is given first to minimize toxic-
ity and improve efficacy.
LONG-TERM FOLLOW-UP
The role of routine diagnostic tests in patients who have
undergone primary treatment of resected breast cancer has not
been established. However, mammography performed every
6 months is generally recommended after lumpectomy and
radiation until stabilization of the resection scar, and yearly
thereafter. Yearly mammography is generally recommended
for the contralateral breast because of the risk of new primary
breast cancer in the other breast of approximately 0.5% per
year. Blood tests (including so-called serum tumor markers,
complete blood cell count, chemistry panel) and radiological
studies (such as chest radiography, magnetic resonance imag-
ing, computed tomography, bone scanning, or positron emis-
sion tomography) are not recommended routinely. History
and physical examination by medical personnel is recom-
mended about every 6 months for the first 5 years after
diagnosis for most patients with resected invasive breast can-
cer, and specific diagnostic studies are guided by the clinical
information elicited during those visits or if intervening prob-
lems are identified by the patient.
In patients who will experience a recurrence of breast
cancer, approximately 17% of recurrences will be diagnosed
within 5 years of the initial diagnosis. Patients with breast
cancer continue to be at risk for metastatic disease for 20 or
more years after diagnosis; therefore, clinical vigilance and
prompt diagnostic evaluation of suspicious symptoms and
signs are recommended. The most common sites of meta-
static disease are bone, liver, lungs, skin, and brain, but other
sites such as the peritoneum and retina may be affected by
breast cancer.
MANAGEMENT OF LOCALLY
ADVANCED/METASTATIC DISEASE
As alluded to previously, about 40% to 50% of patients
diagnosed as having stage I through III breast cancer may
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Mayo Clin Proc, June 2004, Vol 79
ultimately develop metastatic disease (although this num-
ber is expected to decrease with the institution of better
adjuvant therapies). The goals of systemic chemotherapy in
this setting are to ameliorate symptoms of breast cancer,
optimize quality of life, delay disease progression, and
prolong survival.
The decision regarding therapy choice(s) for patients
with metastatic breast cancer depends on several factors,
including prior therapies that were administered in the
adjuvant setting, biological characteristics of the tumor,
sites of involvement, and the patient’s overall clinical con-
dition (comorbid conditions, performance status). In gen-
eral, hormonal approaches are considered appropriate for
patients with hormonally responsive tumors (essentially
defined as ER-positive and/or PR-positive) that involve
bone or soft tissues or even asymptomatic visceral disease.
Otherwise, chemotherapy is the first choice. Two critically
important biological factors that must be remembered in
making treatment decisions are ER and HER2 status, and
all patients diagnosed as having metastatic breast cancer
should have their tumor tested for both of these markers
(preferably based on a new biopsy, but data from the origi-
nal tumor are sometimes used) to determine whether the
patient may benefit from targeted therapies against these
proteins.
Hormonal Therapy
Although tamoxifen is recommended for premeno-
pausal women with advanced disease, the luteinizing hor-
mone–releasing hormone agonists offer another viable op-
tion. For postmenopausal women, the AIs have provided a
therapeutic ratio superior to that of tamoxifen and have
become the first agents of choice. Clinical trials are ongo-
ing to determine whether there are meaningful differences
in efficacy and tolerability among the 3 available AIs. An
additional option for treating patients with hormonally re-
sponsive tumors is fulvestrant, a “pure” antiestrogen that
appears to be slightly better or similar in efficacy to the AI
anastrozole. Currently, use of fulvestrant is either as a
substitute for AIs or, perhaps more commonly, after dis-
ease progression while the patient is taking antiaromatase
agents. These hormonal agents may be used in sequence
but not in combination. If tumors become refractory to
hormonal therapy, if significant visceral disease is present,
or if a tumor has no hormonal receptors, then chemo-
therapy is the treatment of choice.
Treatment of Patients With HER2-Negative Disease
The selection of systemic chemotherapy for patients
with HER2-negative breast cancer continues to be a chal-
lenge because many options are available. Although the
existing approaches do not lead to ultimate cure of the
Mayo Clin Proc, June 2004, Vol 79
disease, management goals include amelioration of symp-
toms from the malignancy and improvements in the
quality and duration of life. Some patients receive single-
agent treatment, whereas others may benefit from combi-
nation therapies. In general, combination therapies lead to
better response rates and time to progression, but not
always to better survival, than do sequential single-agent
approaches.
No single chemotherapy regimen is best for all pa-
tients; however, many options are available because of
clinical investigations that revealed the antitumor activ-
ity of anthracyclines (doxorubicin, epirubicin), antime-
tabolites (capecitabine, gemcitabine), and antitubulin
agents such as the taxanes (paclitaxel, docetaxel) and
vinorelbine. Overall, individualization of care is critically
important. All patients with metastatic breast cancer
should seek information regarding available clinical trials,
which would be discussed in more detail by the medical
oncologist.
More than 50 new agents are being evaluated currently
in clinical trials, especially agents targeting proteins and
genes believed to be involved in the pathogenesis of breast
cancer: antiangiogenesis agents (bevacizumab, SU-11248),
antimetabolites (gemcitabine, pemetrexed), topoisomerase
inhibitors (irinotecan), farnesyl transferase inhibitors
(tipifarnib), epidermal growth factor receptor inhibitors
(gefitinib, erlotinib, cetuximab, lapatinib), novel taxanes
(ABI-007) and other tubulin-stabilizing agents (ixabepi-
lone), raf-1 kinase inhibitors (BAY 43.9600), and others.
Physicians and patients should seek available information
from clinical trials to help improve the outcome of patients
with advanced breast cancer.
Treatment of Patients With HER2-Positive Disease
Patients with HER2-positive disease (defined as either
positive for HER2 gene amplification by fluorescence in
situ hybridization or HER2 3+ positive protein overex-
pression by immunohistochemistry) are treated differently
than are those with HER2-negative breast cancer, at least in
terms of first-line chemotherapy for metastatic disease. If
the tumor is ER-positive and/or PR-positive and HER2-
positive, hormonal therapy alone (without trastuzumab)
may be appropriate if the patient has only soft tissue
or bone disease and no evidence of rapidly progressive
metastases.
Patients with visceral disease or symptomatic progres-
sive tumors that are no longer responding to hormones or
are ER-negative and/or PR-negative should be treated with
the anti-HER2 monoclonal antibody trastuzumab added to
chemotherapy. This recommendation is based on the sur-
vival advantage of this approach compared with chemo-
therapy alone. It is recommended that trastuzumab not be
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Breast Cancer 815
used concurrently with anthracyclines because of an in-
creased risk of cardiac toxicity. Trastuzumab therapy is
associated with a small risk of congestive heart failure,
which is managed with otherwise standard therapies for
congestive heart failure (angiotensin-converting enzyme
inhibitors, diuretics, β-blockers, digoxin). This cardiac tox-
icity appears to be different from that related to anthra-
cyclines because it is not dose dependent, appears not to be
associated with identifiable structural cardiac abnormali-
ties, and tends to improve promptly with therapy in most
patients.14 Ongoing clinical trials are evaluating the poten-
tial role of trastuzumab as part of adjuvant therapy for
HER2-positive resected invasive breast cancer.
SUPPORTIVE CARE ISSUES
Many improvements have been made in supportive care,
which translate into better tolerability of therapy and
marked amelioration of disease symptoms. These advances
include newer antiemetics, use of prophylactic growth fac-
tor support (to maintain neutrophils and hemoglobin), and
bisphosphonates. The 2 bisphosphonates currently avail-
able, pamidronate and zoledronic acid (others are being
investigated), are used in the setting of lytic bone me-
tastases to ameliorate pain and decrease the risk of skeletal-
related events such as fractures.
CONCLUSIONS
Breast cancer management is a rapidly evolving field. New
technologies are being incorporated to better understand
the biology of this disease and to help identify the genes
involved in prognosis and responsiveness to therapy. These
findings, added to improved risk assessment and preven-
tion strategies, as well as screening, diagnosis, treatment,
and supportive care, hold great promise for the future.
Education and translational clinical trials will be the key to
success.
REFERENCES
1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA
Cancer J Clin. 2004;54:8-29.
2. Humphrey LL, Helfand M, Chan BKS, Woolf SH. Breast cancer
screening: a summary of the evidence for the U.S. Preventive
Services Task Force. Ann Intern Med. 2002;137(5, pt 1):347-360.
3. Smith RA, Saslow D, Andrews Sawyer K, et al, High-Risk Work
Group, Screening Older Women Work Group, Mammography
Work Group, Physical Examination Work Group, New Technolo-
gies Work Group, Breast Cancer Advisory Group. American Can-
cer Society guidelines for breast cancer screening: update 2003. CA
Cancer J Clin. 2003;53:141-169.
4. Mincey BA. Genetics and the management of women at high risk
for breast cancer. Oncologist. 2003;8:466-473.
5. Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ.
Mammographic densities as a marker of human breast cancer risk
and their use in chemoprevention. Curr Oncol Rep. 2001;3:314-
321.
816 Breast Cancer Mayo Clin Proc, June 2004, Vol 79

6. Cuzick J, Powles T, Veronesi U, et al. Overview of the main 2. Which one of the following is the only agent currently
outcomes in breast-cancer prevention trials. Lancet. 2003;361:296- approved by the US Food and Drug Administration
300. to decrease the risk of primary breast cancer
7. Green FL, Page DL, Fleming ID, et al, American Joint Committee
on Cancer, eds. AJCC Cancer Staging Handbook: From the AJCC development?
Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; a. Raloxifene
2002. b. Tamoxifen
8. Recht A. Integration of systemic therapy and radiation therapy for
c. Idoxifene
patients with early-stage breast cancer treated with conservative
surgery. Clin Breast Cancer. 2003;4:104-113. d. Alendronate
9. National Institutes of Health Consensus Development Panel. Na- e. Risedronate
tional Institutes of Health Consensus Development Conference
Statement: adjuvant therapy for breast cancer, November 1-3,
3. In which one of the following situations is external
2000. J Natl Cancer Inst. 2001;93:979-989. beam radiotherapy not routinely recommended?
10. Mincey BA, Palmieri FM, Perez EA. Adjuvant therapy for breast a. After lumpectomy for invasive breast cancer
cancer: recommendations for management based on consensus re-
view and recent clinical trials. Oncologist. 2002;7:246-250.
b. After mastectomy in patients with 1 to 3 involved
11. Pritchard KI. The best use of adjuvant endocrine treatments. axillary lymph nodes
Breast. 2003;12:497-508. c. After mastectomy for patients with >3 involved
12. ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ axillary lymph nodes
Group. Anastrozole alone or in combination with tamoxifen versus d. After mastectomy for a primary tumor >5 cm
tamoxifen alone for adjuvant treatment of postmenopausal women e. After lumpectomy for large DCIS (>2.5 cm)
with early-stage breast cancer: results of the ATAC (Arimidex,
Tamoxifen Alone or in Combination) trial efficacy and safety 4. Which one of the following is the current
update analyses. Cancer. 2003;98:1802-1810. recommended duration of adjuvant tamoxifen
13. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole treatment for patients with resected hormonally
in postmenopausal women after five years of tamoxifen therapy for
early-stage breast cancer. N Engl J Med. 2003;349:1793-1802.
responsive breast cancer?
14. Coombes RC, Hall E, Gibson LJ, et al, Intergroup Exemestane a. 6 months
Study. A randomized trial of exemestane after two to three years of b. 1 year
tamoxifen therapy in postmenopausal women with primary breast c. 5 years
cancer. N Engl J Med. 2004;350:1081-1092.
d. 10 years
e. For life
Questions About Breast Cancer 5. Which one of the following proteins is targeted by the
monoclonal antibody trastuzumab?
1. Which one of the following is not included in the Gail a. Raf-1 kinase
model for prediction of breast cancer risk? b. HER1
a. Presence of the BRCA1 gene mutation c. HER2
b. Family history of breast cancer in first-degree d. HER3
relatives e. HER4
c. History of atypical ductal hyperplasia
d. Number of prior breast biopsies Correct answers:
e. Age at menarche 1. a, 2. b, 3. b, 4. c, 5. c

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