Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force
Dense breasts are defined by mammographic appearance. The American College of Radiology's (ACR's) Breast Imaging Reporting and Data System (BI RADS) classifies breasts as almost entirely fatty (BI RADS category a) scattered areas of fibroglandular density (category b) heterogeneously dense (category c) or extremely dense (category d) About 27.6 million (43% women aged 40 to 74 years in the United States have dense breasts; most of these are classified as category c (1) Higher breast density is associated with decreased mammographic sensitivity and specificity and also with increased breast cancer risk. The relative hazard of breast cancer for women with dense breasts ranged from 1.50 (women aged 65 to 74 years) to 1.83 (women aged 40 to 49 years) in an analysis of 1169248 women enrolled in the Breast Cancer Surveillance Consortium (unpublished data) Increased breast density has been associated with hormone replacement therapy use, younger age, and lower body mass index (2) Data on breast density and race or ethnicity are limited. In the United States, Asian women have higher breast density (3) but lower than average incidence of breast cancer (4) Increased breast density is not associated with higher breast cancer mortality among women with dense breasts diagnosed with breast cancer, after adjustment for stage and mode of detection (5) Supplemental breast cancer screening with additional screening modalities has been proposed to improve the early detection of breast cancers. No clinical guidelines explicitly recommend use of supplemental breast cancer screening on women with dense breasts (69) but as of September 2015, 24 states had enacted legislation requiring that women be notified of breast density with their mammography results; 9 more states are considering mandatory notification (10) (Appendix Table 1) Most states require specific language distinguishing dense (BI RADS c and d) from nondense breasts, and 4 states require that insurers cover subsequent examinations and tests for women with dense breasts (1114) Federal legislation requiring breast density notification is pending (15) Appendix Table 1. Breast Density Legislation in the United States This report summarizes a systematic review of current evidence on the reproducibility of BI RADS breast density determinations and on test performance characteristics and outcomes of supplemental screening of women with dense breasts by using hand held ultrasonography (HHUS) automated whole breast ultrasonography (ABUS) breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT) Mandatory reporting laws frame notification of women as dense/nondense, so this review focused on this categorization. Methods The review protocol included an analytic framework with 4 key questions (KQs) (Appendix Figure 1) Detailed methods, including search strategies, detailed inclusion criteria, and excluded studies, are available in the full evidence report (16) Appendix Figure 1. Analytic framework. BI RADS Breast Imaging Reporting and Data System; DCIS ductal carcinoma in situ; KQ key question; MRI magnetic resonance imaging. Data Sources and Searches MEDLINE, PubMed, EMBASE, and the Cochrane Library were searched for relevant English language studies published between January 2000 and July 2015. We reviewed reference lists from retrieved articles and references suggested by experts. Study Selection Two investigators independently reviewed abstracts and full text articles for inclusion according to predetermined criteria (E.P.W. and J.H.T. for KQ 1, J.M. and J.J.F. for KQs 2 to 4) Included studies examining the reproducibility of BI RADS breast density categorization focused on asymptomatic women aged 40 years or older undergoing digital or film mammography. Included studies on supplemental screening with HHUS, ABUS, MRI, or DBT reported outcomes for asymptomatic women with dense breasts aged 40 years and older. In studies that focused primarily on women at high risk for breast cancer (including those with preexisting breast cancer or high risk breast lesions [such as ductal carcinoma in situ, atypical hyperplasia, and lobular carcinoma in situ] BRCA mutations, familial breast cancer syndromes, or previous chest wall radiation) and studies that included women with nondense breasts, we analyzed the relevant subset when available in the publication or provided by the authors. A priori inclusion criteria limited studies on BI RADS reproducibility to fair or good quality randomized, controlled trials; cohort studies; or test sets involving multiple blind readings by at least 3 readers. Studies on test performance characteristics and outcomes of supplemental screening modalities were limited to fair or good quality randomized, controlled trials; cohort studies; or diagnostic accuracy studies with reference standards applied to all participants. We examined sensitivity, specificity, positive predictive values (PPVs) negative predictive values (NPVs) and available clinical outcomes (including cancer detection rates, recall rates, and biopsy rates) We defined recall as the need for any additional diagnostic testing after supplemental screening, including imaging and biopsy. Data Extraction and Quality Assessment Two investigators (E.P.W. and J.H.T. for KQ 1, J.M. and J.J.F. for KQs 2 to 4) critically appraised all included studies independently using the U.S. Preventive Services Task Force's (USPSTF's) design specific criteria (17) supplemented with the National Institute for Health and Clinical Excellence methodology checklists (18) and the Quality Appraisal Tool for Studies of Diagnostic Reliability (19) According to USPSTF criteria, a good quality study generally met all prespecified criteria; fair quality studies did not meet all criteria but had no important limitations. Poor quality studies had important limitations that could invalidate results (inadequate or biased application of reference standard; population limited to very high risk patients) Data Synthesis and Analysis When available or provided by the authors, results of supplemental screening for subgroups of women with dense breasts were extracted; we excluded those with other risk factors for breast cancer. We calculated the sensitivity and specificity of the supplemental breast screening tests for women with negative mammography results. Only cancers detected by the supplemental test after negative mammography results and cancers found at interval follow up were included. Hence, the values reported represent the sensitivity and specificity for detection of additional cancer in women with negative mammography findings. Similarly, we defined cancer detection rates, recall rates, and biopsy rates to include only those cancer cases, recalls, and biopsies related to supplemental screening after negative results on mammography. Meta analysis was not performed because there were few good quality studies. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members to develop and refine the scope, analytic frameworks, and KQs. AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results The literature search yielded 2067 unique citations; 128 full text articles considered potentially relevant were reviewed to identify 24 unique studies meeting inclusion criteria (Appendix Figure 2) Table 1 (2043) provides the characteristics of included studies. No studies addressed the effect of supplemental screening (compared with women without supplemental screening) on breast cancer morbidity or mortality. Appendix Figure 2. Summary of evidence search and selection. KQ key question. Table 1. Characteristics of Included Studies Accuracy and Reliability of BI RADS Density Determination Absent a gold standard for breast density, studies could not evaluate the accuracy of BI RADS density determinations. Five studies reported repeated assignment of categorical BI RADS breast density classification by the same or different radiologists, altogether including more than 440000 women, almost all with data from 2 sequential screening mammograms. To reflect current U.S. practice, we included only studies based on the BI RADS density categories. The 3 largest studies were set in the United States. Two used data from the Breast Cancer Surveillance Consortium (20, 22) and the third presented findings from community radiologists conducting repeated readings of a large screening test set (24) Two other small studies (not discussed here) were based on mammographic screening programs in Spain (21) and Italy (23) All United Statesbased studies reflected community practice by use of clinical readings from community screening programs or test set readings by practicing community radiologists without additional training. Overall, group prevalence of BI RADS density ratings was similar across initial and subsequent examinations among community radiologists (Appendix Table 2) but there was greater disagreement at the individual level. On subsequent screening examinations, approximately 1 in 5 women (23% was placed in a different BI RADS density category (a, b, c, d) by the same radiologist, while approximately 1 in 3 was categorized differently when a different radiologist read the subsequent examination result (Table 2) Considering clinical interpretations that combine categories (dense representing those with BI RAD
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