Evidence Report/Technology Assessment: Number 33
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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of the Full Report
Authors: Levine C, Armstrong K, Chopra S, Estok R, Zhang S, Ross S.
Each year, more than 170,000 women are
diagnosed with breast cancer in the United
States alone, and it is the most common form
of cancer found in women worldwide. The
average lifetime risk of breast cancer in a
female infant born in the United States in the
year 2000 is 12 percent, or one in eight. The
most common cause of malpractice litigation
is the missed or delayed diagnosis of breast
cancer. Clearly, breast disease is a major
concern for women, and it has a substantial
effect on both individual and societal health
When a woman presents to her health care
provider with a breast symptom, the initial
management will nearly always include, at a
minimum, a clinical breast exam (CBE) and
mammogram or ultrasound, depending on
the age of the patient. Controversies abound
concerning the appropriate steps after the
initial imaging study. It is unclear whether
further management should be influenced by
patients' risk factors for breast cancer. Other
areas of controversy include management of
abnormal mammograms, management of
certain pathological diagnoses, and whether
all women with breast cancer require a full
axillary lymph node dissection (ALND).
These are but a few of the numerous
unresolved issues regarding the diagnosis and
management of breast disease. In an effort to
answer some of these questions, the Agency
for Healthcare Research and Quality
(AHRQ) directed MetaWorks, Inc., Boston,
MA, to undertake a systematic review of the
English-language literature since 1994
pertinent to women with breast disease. This
topic was nominated for review by Kaiser
This review focuses on women with breast
signs, symptoms, or mammographic
abnormalities for whom specific risk factors
for breast cancer are reported. Additional
areas of interest include specific biopsy
findings and initial management after breast
The MetaWorks investigators have
assembled an evidence base that should be
useful to health care providers in developing
evidence-based strategies to guide breast
disease management. It also will be useful to
investigators planning new clinical trials and
others making regulatory decisions. This
synthesis of the best available and most recent
evidence is intended to serve as an
information resource for local decisionmakers
and developers of practice guidelines and
recommendations. It focuses attention on
gaps in the literature and areas that warrant
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Reporting the Evidence
This report presents the results of a
systematic review of published studies of
adult patients who were evaluated for breast
symptoms. The following key questions
guided this review:
- What are the recommendations for
evaluation of breast symptoms,
mammographic findings and other
suspicious findings based on menstrual
status, use of hormone replacement
therapy (HRT), pregnancy, age, and family
- How are lobular carcinoma in situ (LCIS)
and atypical hyperplasia (AH) managed?
- How are nonpalpable lesions and
- What are the indications for sentinel node biopsy?
- What costs are associated with diagnosis and management
of breast disease as outlined above?
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MetaWorks investigators applied methods derived from
the evolving science of review research. The review followed
a work plan that had been developed and shared with
AHRQ, Kaiser Permanente, and a technical expert panel
(TEP) that included gynecologists, family practitioners,
internists, medical and surgical oncologists, radiologists, and
a consumer representative who is a breast cancer survivor.
The work plan outlined the methods to be used for the
literature search, study eligibility criteria, data elements for
extraction, and methodological strategies employed both to
minimize bias and maximize precision during the process of
data collection and synthesis.
The published English-language literature was searched
from January 1, 1994, to September 15, 1999, and the
retrieval cutoff date was March 15, 2000. Different Medline
search strategies were employed for each question.
- Question 1 (management of symptomatic breast disease
and suspicious findings): "breast neoplasms" AND
- Question 2 (management of LCIS and AH): "breast
neoplasms" AND ("diagnosis" OR "pathology") AND
("carcinoma in situ" OR "carcinoma, infiltrating duct"
OR "carcinoma, intraductal, noninfiltrating" OR
"carcinoma, lobular" OR "hyperplasia").
- Question 3 (management of nonpalpable lesions and
calcifications): "breast neoplasm" AND ("diagnosis" OR
"pathology" OR "radiology" AND "mammography" OR
"nonpalpable" OR "calcifications" OR
- Question 4 (indications for sentinel node biopsy): "breast
neoplasm" AND "lymph nodes" AND "pathology."
- Question 5 (costs): "breast neoplasms" AND ("costs" OR
"cost analysis" OR "economic").
The Current Contents CD-ROM database was searched
(breast cancer and diagnosis) to the same cutoff date. These
electronic searches were supplemented by a manual search of
the reference lists of all accepted articles, review articles from
1999, and relevant Internet sites.
Abstracts were screened using predefined exclusion
criteria, then full papers were reviewed and assessed for fit
with inclusion criteria. Only English-language studies
involving a minimum of 10 patients were eligible for
inclusion. Only randomized controlled trials (RCTs),
nonrandomized controlled trials (nRCTs), uncontrolled case
series (UCSs), and observational studies were accepted.
After initial screening of abstracts, it became clear that the
inclusion criteria needed to be refined in order to develop
evidence that addressed the specific questions that had been
posed. Questions 1 and 3 are actually facets of the same
question; namely, what is the management of patients with
risk factors for breast cancer who present with abnormal
clinical or mammographic findings? Thus, the refined
inclusion criteria for questions 1 and 3 included:
- Reporting of risk factors (age, menstrual status, pregnancy
history, HRT use, or family history).
- Description of suspicious findings (palpable lesion, nipple
discharge, or mammographic findings).
- Diagnosis of cancer at time of presentation and/or
- The inclusion criteria for question 2 included:
Diagnosis of LCIS and/or AH.
- Management options (observation, excisional biopsy,
magnetic resonance imaging [MRI], selective estrogen
receptor modulator [SERM] therapy, bilateral
- Diagnosis of cancer at time of presentation and/or
Initially, the review of AH was limited to atypical lobular
hyperplasia (ALH). All studies that involved only atypical
ductal hyperplasia (ADH) were rejected. Because of the
scant literature available regarding ALH, the focus of this
review was expanded to include both ALH and ADH.
Inclusion criteria for question 4 included:
- Indication for sentinel node biopsy (tumor size, tumor
location, absence of palpable axillary nodes, no history of
- Method of sentinel node identification (vital blue dye,
radiocolloid mapping, or both).
- Results of biopsy and comparison with gold standard
(axillary node dissection).
The only criteria for acceptance for question 5 were:
- Acceptance of study for one of the other questions.
- Discussion of costs, in U.S. dollars.
Studies that involved only screening populations were
rejected because the questions for this review were focused
on patients with clinical or mammographic abnormalities in
addition to risk factors. Populations of interest would not be
represented in screening studies, which by definition consist
of asymptomatic patients.
For questions 1 and 3, studies that involved only cancer
patients were rejected because the questions for this review
aimed to determine the incidence of cancer in patients with
specific findings, not to determine the prevalence of specific
findings in cancer patients.
For question 2, studies of patients who had cancer
concurrently with LCIS or AH were rejected, as it would be
impossible to determine whether these patients' outcomes
were related to their cancer or their LCIS/AH.
Rejection of studies with cancer populations obviously
did not apply to question 4, as sentinel node biopsy would
be done only in patients with a diagnosis of cancer.
Relevant data from all accepted studies were entered onto
data extraction forms (DEFs) designed specifically for this
project. Results that required extrapolation from graphs or
derivations from figures were not captured due to concerns
about accuracy. All data elements were extracted by one
investigator and reviewed by a second investigator; 100
hundred percent agreement between the two reviewers was
required prior to entry of data elements into the database. At
least one physician reviewed all data elements extracted from
All accepted studies were evaluated for quality by using
the previously published methods of Level of Evidence and
the Jadad Quality Score Assessment.
The elements extracted from each study varied,
depending on the question. In general, the information
captured included date of publication, location and type of
study, primary objective of study, number of patients with
various risk factors and clinical or mammographic findings,
management of the abnormal findings, number of patients
diagnosed with cancer, and any statistical measures reported.
No quantitative analyses were performed beyond descriptive
statistics to summarize findings.
A group of 11 peer reviewers, drawn from consumer
groups and professional organizations, was assembled to
review and provide suggestions for the draft final report of
this project. Their comments, in addition to those of the
TEP, were incorporated into the final report.
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- 109 studies (k) plus 11 kinship studies.
- 39,560 patients (n).
- Study designs: interventional 69 (UCS [k=66], nRCT
[k=2], RCT [k=1]); observational 40 (retrospective
[k=33], prospective [k=6], cross-sectional [k=1]).
- Study location: North America (k=69), Europe (k=33),
Questions 1 and 3 (risk factors, abnormal clinical or
- Risk factors were commonly reported, but age was the
only risk factor consistently reported in association with
symptoms and cancer diagnosis.
- There was no evidence to support modifying the workup
based on risk factors other than age.
- The only age-related modification reported was
ultrasound for younger women (specific age not reported)
and mammogram for older women.
Question 2 (LCIS and AH):
- Within 5 years after LCIS diagnosis, 4.2-9.3 percent of
patients were diagnosed with breast cancer (k=5, n=1,014
[of which 53 were diagnosed with cancer], overall
incidence = 5.2 percent). In studies that followed patients
for greater than 5 years, the incidence of cancer was 7.7-
26.3 percent (k=3, n=421 [of which 77 were diagnosed
with cancer], overall incidence = 22.3 percent).
- Within 5 years after AH diagnosis, 3.7-19.3 percent of
patients were reported to have developed breast cancer
(k=3, n=752 [of which 48 were diagnosed with cancer],
overall incidence = 6.4 percent). In studies that followed
patients for greater than 5 years, the incidence of cancer
was 13.6-33.6 percent (k=3, n=425 [of which 83 were
diagnosed with cancer], overall incidence = 19.5 percent).
- When the diagnosis of ADH was made by stereotactic
core biopsy (SCBX), it generally was followed by open
surgical biopsy to confirm the diagnosis and rule out
concurrent carcinoma, LCIS, or ductal carcinoma in situ
(DCIS). Forty-two percent of the ADH diagnoses were
changed as a result of excisional biopsy. Most changes
were to DCIS or invasive cancer, although approximately
20 percent changed to more benign diagnoses. Only one
study reported the incidence of diagnosis change after
ALH (in one of four patients, the diagnosis of ALH was
changed to LCIS).
- Although data are available from only 1 study of 13,175 patients, those patients with LCIS or AH who received tamoxifen therapy had a markedly decreased subsequent incidence of cancer, compared with patients who were treated by observation alone (1.9 percent vs. 4.4 percent in LCIS, 0.5 percent vs. 3.7 percent in AH). However, the risks associated with tamoxifen therapy must be considered, including an increased risk of endometrial cancer and thromboembolic disease.
Question 4 (sentinel node biopsy):
- Sentinel node biopsy had a false negative rate of 1.9-3.3
percent. While both methods of sentinel node detection were
effective, the combination of vital blue dye and
radiocolloid mapping was more sensitive than either
- Successful sentinel node detection was independent of
tumor location, tumor size, and history of breast surgery.
- Approximately one-third of sentinel lymph nodes were
positive for metastatic disease. These patients required full
axillary lymph node dissection (ALND) to determine the
extent of their metastatic disease. The remaining two-thirds
of patients, however, could have been spared this
invasive procedure at a cost of missing metastatic disease
in 2 to 3 percent of women with cancer.
- Long-term studies regarding the efficacy and safety of
sentinel node biopsy are lacking.
Question 5 (cost):
- Only six of the accepted studies addressed cost.
- Information was too disparate to draw any conclusions
regarding the actual costs of various interventions and/or
the long-term cost savings resulting from their use.
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Additional research is needed to more thoroughly
examine risk factors and breast symptoms and how they
relate to cancer diagnoses. Standardization of reporting
results is essential, particularly with regard to reporting
numbers of patients and not just numbers of lesions.
Investigators should report baseline risk factors, presenting
symptoms, and followup data pertaining to which patients
Future research also should be undertaken to identify
additional or new risk factors. If all of this information were
available, a comprehensive assessment of risk could be
calculated. This, in turn, could lead to development of a risk
model that could be used by doctors and patients to assess
breast cancer risk. Such a model could be an adjunct to
models (such as the Gail model) that currently are in use,
and it could include not only risk factors but also breast
symptoms and mammographic findings.
Further studies should be done to confirm and extend the
promising initial data that supports prophylactic SERM
therapy for patients with AH or LCIS. Although sentinel
node biopsy reportedly is effective in most patients, future
studies should attempt to identify differences in sensitivities
based on tumor size, location, and history of breast surgeries.
Additionally, variations in success rates may depend on the
experience of the surgeon performing the procedure and the
extent of the pathological investigation. These factors should
be addressed in future studies. Long-term cancer outcomes
and survival data are required before sentinel node biopsy
can be recommended for breast cancer patients.
The management of breast disease is changing, with
important new developments in genetic susceptibility and
promising new imaging techniques. These changes will have
a major impact on the diagnosis and management of breast
disease in the future.
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Availability of the Full Report
The full evidence report from which this summary was
taken was prepared for the Agency for Healthcare Research
and Quality by MetaWorks®, Inc., Boston, MA, under
contract 290-97-0016. Printed copies may be obtained
free of charge from the AHRQ Publications Clearinghouse
by calling 1-800-358-9295. Please request Evidence
Report/Technology Assessment No. 33, Diagnosis and
Management of Specific Breast Abnormalities (AHRQ
Publication No. 01-E046).
The Evidence Report is also online on the National Library of Medicine Bookshelf.
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AHRQ Publication Number 01-E045
Current as of April 2001