### Evidence Report/Technology Assessment: Number 33

# Diagnosis and Management of Specific Breast Abnormalities

## Summary

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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

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## Overview

Each year, more than 170,000 women arediagnosed with breast cancer in the UnitedStates alone, and it is the most common formof cancer found in women worldwide. Theaverage lifetime risk of breast cancer in afemale infant born in the United States in theyear 2000 is 12 percent, or one in eight. Themost common cause of malpractice litigationis the missed or delayed diagnosis of breastcancer. Clearly, breast disease is a majorconcern for women, and it has a substantialeffect on both individual and societal healthcare resources.

When a woman presents to her health careprovider with a breast symptom, the initialmanagement will nearly always include, at aminimum, a clinical breast exam (CBE) andmammogram or ultrasound, depending onthe age of the patient. Controversies aboundconcerning the appropriate steps after theinitial imaging study. It is unclear whetherfurther management should be influenced bypatients' risk factors for breast cancer. Otherareas of controversy include management ofabnormal mammograms, management ofcertain pathological diagnoses, and whetherall women with breast cancer require a fullaxillary lymph node dissection (ALND).

These are but a few of the numerousunresolved issues regarding the diagnosis andmanagement of breast disease. In an effort toanswer some of these questions, the Agencyfor Healthcare Research and Quality(AHRQ) directed MetaWorks, Inc., Boston,MA, to undertake a systematic review of theEnglish-language literature since 1994pertinent to women with breast disease. Thistopic was nominated for review by KaiserPermanente.

This review focuses on women with breastsigns, symptoms, or mammographicabnormalities for whom specific risk factorsfor breast cancer are reported. Additionalareas of interest include specific biopsyfindings and initial management after breastcancer diagnosis.

The MetaWorks investigators haveassembled an evidence base that should beuseful to health care providers in developingevidence-based strategies to guide breastdisease management. It also will be useful toinvestigators planning new clinical trials andothers making regulatory decisions. Thissynthesis of the best available and most recentevidence is intended to serve as aninformation resource for local decisionmakersand developers of practice guidelines andrecommendations. It focuses attention ongaps in the literature and areas that warrantfuture research.

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## Reporting the Evidence

This report presents the results of asystematic review of published studies ofadult patients who were evaluated for breastsymptoms. The following key questionsguided this review:

- What are the recommendations forevaluation of breast symptoms,mammographic findings and othersuspicious findings based on menstrualstatus, use of hormone replacementtherapy (HRT), pregnancy, age, and familyhistory?
- How are lobular carcinoma in situ (LCIS)and atypical hyperplasia (AH) managed?
-  How are nonpalpable lesions andcalcifications managed?
- What are the indications for sentinel node biopsy?
- What costs are associated with diagnosis and managementof breast disease as outlined above?

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## Methodology

MetaWorks investigators applied methods derived fromthe evolving science of review research. The review followeda work plan that had been developed and shared withAHRQ, Kaiser Permanente, and a technical expert panel(TEP) that included gynecologists, family practitioners,internists, medical and surgical oncologists, radiologists, anda consumer representative who is a breast cancer survivor.

The work plan outlined the methods to be used for theliterature search, study eligibility criteria, data elements forextraction, and methodological strategies employed both tominimize bias and maximize precision during the process ofdata collection and synthesis.

The published English-language literature was searchedfrom January 1, 1994, to September 15, 1999, and theretrieval cutoff date was March 15, 2000. Different Medlinesearch strategies were employed for each question.

- Question 1 (management of symptomatic breast diseaseand suspicious findings): "breast neoplasms" AND"diagnosis."
- Question 2 (management of LCIS and AH): "breastneoplasms" 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 andcalcifications): "breast neoplasm" AND ("diagnosis" OR"pathology" OR "radiology" AND "mammography" OR"nonpalpable" OR "calcifications" OR"microcalcifications").
- Question 4 (indications for sentinel node biopsy): "breastneoplasm" 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. Theseelectronic searches were supplemented by a manual search ofthe reference lists of all accepted articles, review articles from1999, and relevant Internet sites.

Abstracts were screened using predefined exclusioncriteria, then full papers were reviewed and assessed for fitwith inclusion criteria. Only English-language studiesinvolving a minimum of 10 patients were eligible forinclusion. Only randomized controlled trials (RCTs),nonrandomized controlled trials (nRCTs), uncontrolled caseseries (UCSs), and observational studies were accepted.

After initial screening of abstracts, it became clear that theinclusion criteria needed to be refined in order to developevidence that addressed the specific questions that had beenposed. Questions 1 and 3 are actually facets of the samequestion; namely, what is the management of patients withrisk factors for breast cancer who present with abnormalclinical or mammographic findings? Thus, the refinedinclusion criteria for questions 1 and 3 included:

- Reporting of risk factors (age, menstrual status, pregnancyhistory, HRT use, or family history).
- Description of suspicious findings (palpable lesion, nippledischarge, or mammographic findings).
- Diagnosis of cancer at time of presentation and/orsubsequently.
- The inclusion criteria for question 2 included:Diagnosis of LCIS and/or AH.
- Management options (observation, excisional biopsy,magnetic resonance imaging [MRI], selective estrogenreceptor modulator [SERM] therapy, bilateralmastectomy).
- Diagnosis of cancer at time of presentation and/orsubsequently.

Initially, the review of AH was limited to atypical lobularhyperplasia (ALH). All studies that involved only atypicalductal hyperplasia (ADH) were rejected. Because of thescant literature available regarding ALH, the focus of thisreview was expanded to include both ALH and ADH.

Inclusion criteria for question 4 included:

- Indication for sentinel node biopsy (tumor size, tumorlocation, absence of palpable axillary nodes, no history ofbreast 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 wererejected because the questions for this review were focusedon patients with clinical or mammographic abnormalities inaddition to risk factors. Populations of interest would not berepresented in screening studies, which by definition consistof asymptomatic patients.

For questions 1 and 3, studies that involved only cancerpatients were rejected because the questions for this reviewaimed to determine the incidence of cancer in patients withspecific findings, not to determine the prevalence of specificfindings in cancer patients.

For question 2, studies of patients who had cancerconcurrently with LCIS or AH were rejected, as it would beimpossible to determine whether these patients' outcomeswere related to their cancer or their LCIS/AH.

Rejection of studies with cancer populations obviouslydid not apply to question 4, as sentinel node biopsy wouldbe done only in patients with a diagnosis of cancer.

Relevant data from all accepted studies were entered ontodata extraction forms (DEFs) designed specifically for thisproject. Results that required extrapolation from graphs orderivations from figures were not captured due to concernsabout accuracy. All data elements were extracted by oneinvestigator and reviewed by a second investigator; 100hundred percent agreement between the two reviewers wasrequired prior to entry of data elements into the database. Atleast one physician reviewed all data elements extracted fromevery study.

All accepted studies were evaluated for quality by usingthe previously published methods of Level of Evidence andthe Jadad Quality Score Assessment.

The elements extracted from each study varied,depending on the question. In general, the informationcaptured included date of publication, location and type ofstudy, primary objective of study, number of patients withvarious risk factors and clinical or mammographic findings,management of the abnormal findings, number of patientsdiagnosed with cancer, and any statistical measures reported.No quantitative analyses were performed beyond descriptivestatistics to summarize findings.

A group of 11 peer reviewers, drawn from consumergroups and professional organizations, was assembled toreview and provide suggestions for the draft final report ofthis project. Their comments, in addition to those of theTEP, were incorporated into the final report.

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## Findings

- 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).

Questions 1 and 3 (risk factors, abnormal clinical ormammographic findings):

- Risk factors were commonly reported, but age was theonly risk factor consistently reported in association withsymptoms and cancer diagnosis.
-  There was no evidence to support modifying the workupbased on risk factors other than age.
- The only age-related modification reported wasultrasound 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 ofpatients were diagnosed with breast cancer (k=5, n=1,014[of which 53 were diagnosed with cancer], overallincidence = 5.2 percent). In studies that followed patientsfor greater than 5 years, the incidence of cancer was 7.7-26.3 percent (k=3, n=421 [of which 77 were diagnosedwith cancer], overall incidence = 22.3 percent).
-  Within 5 years after AH diagnosis, 3.7-19.3 percent ofpatients 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 followedpatients for greater than 5 years, the incidence of cancerwas 13.6-33.6 percent (k=3, n=425 [of which 83 werediagnosed with cancer], overall incidence = 19.5 percent).
- When the diagnosis of ADH was made by stereotacticcore biopsy (SCBX), it generally was followed by opensurgical biopsy to confirm the diagnosis and rule outconcurrent carcinoma, LCIS, or ductal carcinoma in situ(DCIS). Forty-two percent of the ADH diagnoses werechanged as a result of excisional biopsy. Most changeswere to DCIS or invasive cancer, although approximately20 percent changed to more benign diagnoses. Only onestudy reported the incidence of diagnosis change afterALH (in one of four patients, the diagnosis of ALH waschanged 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 1.9-3.3percent. While both methods of sentinel node detection wereeffective, the combination of vital blue dye andradiocolloid mapping was more sensitive than eithermethod alone.
- Successful sentinel node detection was independent oftumor location, tumor size, and history of breast surgery.
- Approximately one-third of sentinel lymph nodes werepositive for metastatic disease. These patients required fullaxillary lymph node dissection (ALND) to determine theextent of their metastatic disease. The remaining two-thirdsof patients, however, could have been spared thisinvasive procedure at a cost of missing metastatic diseasein 2 to 3 percent of women with cancer.
- Long-term studies regarding the efficacy and safety ofsentinel node biopsy are lacking.

Question 5 (cost):

- Only six of the accepted studies addressed cost.
- Information was too disparate to draw any conclusionsregarding the actual costs of various interventions and/orthe long-term cost savings resulting from their use.

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## Future Research

Additional research is needed to more thoroughlyexamine risk factors and breast symptoms and how theyrelate to cancer diagnoses. Standardization of reportingresults is essential, particularly with regard to reportingnumbers of patients and not just numbers of lesions.Investigators should report baseline risk factors, presentingsymptoms, and followup data pertaining to which patientsdeveloped cancer.

Future research also should be undertaken to identifyadditional or new risk factors. If all of this information wereavailable, a comprehensive assessment of risk could becalculated. This, in turn, could lead to development of a riskmodel that could be used by doctors and patients to assessbreast cancer risk. Such a model could be an adjunct tomodels (such as the Gail model) that currently are in use,and it could include not only risk factors but also breastsymptoms and mammographic findings.

Further studies should be done to confirm and extend thepromising initial data that supports prophylactic SERMtherapy for patients with AH or LCIS. Although sentinelnode biopsy reportedly is effective in most patients, futurestudies should attempt to identify differences in sensitivitiesbased on tumor size, location, and history of breast surgeries.

Additionally, variations in success rates may depend on theexperience of the surgeon performing the procedure and theextent of the pathological investigation. These factors shouldbe addressed in future studies. Long-term cancer outcomesand survival data are required before sentinel node biopsycan be recommended for breast cancer patients.

The management of breast disease is changing, withimportant new developments in genetic susceptibility andpromising new imaging techniques. These changes will havea major impact on the diagnosis and management of breastdisease in the future.

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## Availability of the Full Report

The full evidence report from which this summary wastaken was prepared for the Agency for Healthcare Researchand Quality by MetaWorks, Inc., Boston, MA, undercontract 290-97-0016. Printed copies may be obtainedfree of charge from the AHRQ Publications Clearinghouseby calling 1-800-358-9295. Please request EvidenceReport/Technology Assessment  No. 33, *Diagnosis andManagement of Specific Breast Abnormalities* (AHRQPublication  No. 01-E046). 

 The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a set of PDF files or as a zipped file.

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*AHRQ Publication Number 01-E045Current as of April 2001*

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**Internet Citation:**

*Diagnosis and Management of Specific Breast Abnormalities*. Summary, Evidence Report/Technology Assessment: Number 33. AHRQ Publication  No. 01-E045, April 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/abnorsum.htm

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