Evidence Report/Technology Assessment

Number 33

Prepared for:
Agency for Healthcare Research and Quality
Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-0016

Prepared by:
MetaWorks, Inc., Boston, MA
Cindy Levine, MD
Katrina Armstrong, MD
Sameer Chopra, MA
Rhonda Estok, RN, BSN
Shuhuan Zhang, MS
Susan Ross, MD

AHRQ Publication No. 01-E046

September 2001

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care, and expands its role to improve patient safety and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

The Agency for Healthcare Research and Quality (AHRQ, formerly the Agency for Health Care Policy and Research, AHCPR), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

Robert Graham, M.D.	John M. Eisenberg, M.D.
Director, Center for Practice	Director, Agency for Healthcare
And Technology Assessment	Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

We are grateful to the following individuals for their diverse contributions throughout the course of developing this report: Elenie Chadbourne, Rebecca Cintron, Janet Connelly, Matthew Guldin, Veronica Ludensky, Luba Nalysnyk, Christopher Schmid, Sandy Schwartz, Marya Zilberberg, members of the TEP, peer reviewers, representatives from Kaiser, and representatives from AHRQ.

Over 170,000 women are diagnosed with breast cancer yearly in the United States, incurring enormous individual and societal costs. The objective of this systematic review is to assess the quantity and quality of published evidence regarding specific current issues of diagnosis and management of women with breast disease.

Literature published from January 1, 1994 to September 15, 1999 was searched using Medline and Current Contents databases. These searches were supplemented by manually reviewing bibliographies of all accepted studies and review articles.

Accepted studies included observational studies, randomized controlled trials (RCTs), non-randomized controlled trials (nRCTs), and uncontrolled case series (UCSs). All accepted publications were required to address the prospectively identified areas of interest and have a total sample size of at least 10 patients. Only English language studies were accepted.

Pertinent data were extracted from accepted studies by one researcher, and reviewed by a second. Studies were evaluated for quality and level of evidence. The data were summarized and synthesized qualitatively. A panel of multidisciplinary clinical experts provided recommendations throughout the project.

The database includes 51 studies (30,178 patients) regarding breast symptoms and risk factors, 20 studies (3,501 patients) pertinent to lobular carcinoma in situ (LCIS) or atypical hyperplasia (AH), and 39 studies (5,900 patients) regarding sentinel node biopsy.

Incomplete reporting of outcomes in patients with different risk factors precludes assessment of the relationship between risk factors, breast symptoms, and cancer incidence.

When managed by observation alone, LCIS was associated with a 4.2-9.3 percent incidence of cancer within 5 years and 7.7-26.3 percent incidence in studies that followed patients for at least 5 years. AH was associated with a 3.7-19.3 percent incidence of cancer within 5 years, and 13.6-33.6 percent incidence in longer-term studies. Selective estrogen receptor modulator (SERM) therapy with Tamoxifen markedly decreased the incidence of breast cancer following a diagnosis of LCIS or AH. After excisional biopsy was done, approximately half of the atypical ductal hyperplasias (ADHs) diagnosed by stereotactic core needle biopsy (SCBX) were changed, usually to a more worrisome diagnosis.

Regardless of tumor location, size, or history of breast surgery, sentinel node biopsy had a false negative rate of 1.9 to 3.3 percent. Sentinel nodes were positive for metastatic disease in approximately one third of cases.

The best available evidence suggests that breast symptoms are evaluated initially by clinical breast exam and imaging study, with supplemental studies when the diagnosis is unclear. There is no evidence to support modifying the work-up of breast symptoms or mammographic abnormalities based on risk factors other than age. Strong evidence supports the necessity of performing excisional biopsy following SCBX diagnosis of ADH, as excisional biopsy often leads to a change in diagnosis. Preliminary evidence strongly suggests that Tamoxifen therapy markedly decreases the incidence of cancer following a diagnosis of LCIS or AH, but it is associated with increased risk of endometrial cancer, thromboembolic disease, and other complications. While studies to date strongly suggest that sentinel node biopsy is successful in most breast cancer patients, long-term cancer outcomes and survival data are required before sentinel node biopsy could be considered the standard of care.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Levine C, Armstrong K, Chopra S, et al. Diagnosis and management of specific breast abnormalities. Evidence Report/Technology Assessment No. 33 (Prepared by MetaWorks, Inc., Boston, MA under Contract No. 290-97-0016). AHRQ Publication No. 01-E046. Rockville, MD: Agency for Healthcare Research and Quality. September 2001.

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 care resources.

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 Permanente.

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 cancer diagnosis.

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 future research.

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:

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 "diagnosis. "
• 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 "microcalcifications".
• 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, 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 subsequently.

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 mastectomy).
• Diagnosis of cancer at time of presentation and/or subsequently.

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 breast surgery).
• 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 every study.

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.

• 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), other (k=7).

• 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.

• 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 one 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.

• 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 method alone.
• 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 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.

• 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.

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 developed cancer.

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.