Joy Melnikow, MD, MPH; Joshua J. Fenton, MD, MPH; Evelyn P. Whitlock, MD, MPH; Diana L. Miglioretti, PhD; Meghan S. Weyrich, MPH; Jamie H. Thompson, MPH; Kunal Shah
Disclaimer: This review was conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center with the University of California Davis Center for Healthcare Policy and Research under contract to AHRQ. AHRQ staff provided oversight for the project and assisted in the external review of the companion draft evidence synthesis. The analytic framework, review questions, and methods for locating and qualifying evidence were posted on the USPSTF Web site for public comment before the review began; final versions reflect public input. The authors of this report are responsible for its content, including any clinical treatment recommendations. No statement in this article should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the following for their contributions to this project: AHRQ staff; the USPSTF; Joann Elmore, MD, MPH, Elizabeth Rafferty, MD, Jeffrey Tice, MD, Edward Sickles, MD, Barnett Kramer, MD, MH, Gretchen Gierach, PhD, and Gwendolyn Bryant-Smith, MD, who provided expert and federal partner review of the report; Wendie Berg, MD, PhD, and Christiane Kuhl, MD, for providing unpublished subgroup data; and Bruce Abbott, MLS, and Guibo Xing, PhD, at the University of California, Davis.
Financial Support: By AHRQ (contract HHSA-290-2012-00015-I), Rockville, Maryland.
Disclosures: Dr. Melnikow reports a contract with the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Miglioretti reports grants from the Agency for Healthcare Research and Quality and the National Cancer Institute during the conduct of the study. Ms. Weyrich reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Ms. Thompson reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1789.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Reprints are available from the AHRQ Web site (www.ahrq.gov).
Current Author Addresses: Drs. Melnikow and Fenton and Ms. Weyrich: Center for Healthcare Policy and Research, University of California, Davis, 2103 Stockton Boulevard, Sacramento, CA 95817.
Dr. Whitlock and Ms. Thompson: Kaiser Permanente Center for Health Research, 3800 North Interstate Avenue, Portland, OR 97227.
Dr. Miglioretti: Department of Public Health Sciences, University of California Davis School of Medicine, One Shields Avenue, Med Sci 1C, Room 145, Davis, CA 95616.
Mr. Shah: Columbia University, 6380 Lerner Hall, 2920 Broadway, New York, NY 10027.
Author Contributions: Conception and design: J. Melnikow, J.J. Fenton, E.P. Whitlock, D.L. Miglioretti, K. Shah.
Analysis and interpretation of the data: J. Melnikow, J.J. Fenton, E.P. Whitlock, D.L. Miglioretti, M.S. Weyrich, J.H. Thompson, K. Shah.
Drafting of the article: J. Melnikow, J.J. Fenton, M.S. Weyrich, J.H. Thompson, K. Shah.
Critical revision of the article for important intellectual content: J. Melnikow, J.J. Fenton, E.P. Whitlock, D.L. Miglioretti, M.S. Weyrich, J.H. Thompson, K. Shah.
Final approval of the article: J. Melnikow, J.J. Fenton, E.P. Whitlock, D.L. Miglioretti, M.S. Weyrich, J.H. Thompson, K. Shah.
Statistical expertise: D.L. Miglioretti.
Obtaining of funding: J. Melnikow, E.P. Whitlock.
Administrative, technical, or logistic support: J. Melnikow, D.L. Miglioretti, M.S. Weyrich, J.H. Thompson, K. Shah.
Collection and assembly of data: J. Melnikow, J.J. Fenton, E.P. Whitlock, D.L. Miglioretti, M.S. Weyrich, J.H. Thompson, K. Shah.
Melnikow J, Fenton JJ, Whitlock EP, Miglioretti DL, Weyrich MS, Thompson JH, et al. Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:268-278. doi: 10.7326/M15-1789
Download citation file:
Published: Ann Intern Med. 2016;164(4):268-278.
Published at www.annals.org on 12 January 2016
Screening mammography has lower sensitivity and specificity in women with dense breasts, who experience higher breast cancer risk.
To perform a systematic review of reproducibility of Breast Imaging Reporting and Data System (BI-RADS) density categorization and test performance and clinical outcomes of supplemental screening with breast ultrasonography, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT) in women with dense breasts and negative mammography results.
MEDLINE, PubMed, EMBASE, and Cochrane database from January 2000 to July 2015.
Studies reporting BI-RADS density reproducibility or supplemental screening results for women with dense breasts.
Quality assessment and abstraction of 24 studies from 7 countries; 6 studies were good-quality.
Three good-quality studies reported reproducibility of BI-RADS density; 13% to 19% of women were recategorized between “dense” and “nondense” at subsequent screening. Two good-quality studies reported that sensitivity of ultrasonography for women with negative mammography results ranged from 80% to 83%; specificity, from 86% to 94%; and positive predictive value (PPV), from 3% to 8%. The sensitivity of MRI ranged from 75% to 100%; specificity, from 78% to 94%; and PPV, from 3% to 33% (3 studies). Rates of additional cancer detection with ultrasonography were 4.4 per 1000 examinations (89% to 93% invasive); recall rates were 14%. Use of MRI detected 3.5 to 28.6 additional cancer cases per 1000 examinations (34% to 86% invasive); recall rates were 12% to 24%. Rates of cancer detection with DBT increased by 1.4 to 2.5 per 1000 examinations compared with mammography alone (3 studies). Recall rates ranged from 7% to 11%, compared with 7% to 17% with mammography alone. No studies examined breast cancer outcomes.
Good-quality evidence was sparse. Studies were small and CIs were wide. Definitions of recall were absent or inconsistent.
Density ratings may be recategorized on serial screening mammography. Supplemental screening of women with dense breasts finds additional breast cancer but increases false-positive results. Use of DBT may reduce recall rates. Effects of supplemental screening on breast cancer outcomes remain unclear.
Agency for Healthcare Research and Quality.
Appendix Table 1. Breast Density Legislation in the United States
BI-RADS = Breast Imaging Reporting and Data System; DCIS = ductal carcinoma in-situ; KQ = key question; MRI = magnetic resonance imaging.
Summary of evidence search and selection.
KQ = key question.
Table 1. Characteristics of Included Studies
Appendix Table 2. Consistency of Breast Imaging Reporting and Data System Density Categories and Population Categorization
Table 2. Potential Misclassification of Breast Imaging Reporting and Data System Density Categorization by Density Categories
Sensitivity of supplemental screening with HHUS, ABUS, and MRI in detecting breast cancer.
These estimates include ductal carcinoma in situ and invasive cancers. ABUS = automated whole-breast ultrasonography; HHUS = hand-held ultrasonography; MRI = magnetic resonance imaging.
* Good-quality study.
Specificity of supplemental screening with HHUS, ABUS, and MRI in detecting breast cancer.
These estimates include ductal carcinoma in situ and invasive cancer. ABUS = automated whole-breast ultrasonography; HHUS = hand-held ultrasonography; MRI = magnetic resonance imaging.
Table 3. Test Performance Characteristics for Supplemental HHUS, ABUS, and MRI
Table 4. Breast Cancer Detection Outcomes for Supplemental HHUS, ABUS, MRI, and DBT
Breast cancer detection rates of supplemental screening with HHUS, ABUS, MRI and DBT.
These estimates include ductal carcinoma in situ and invasive cancer. ABUS = automated whole-breast ultrasonography; DBT = digital breast tomosynthesis; HHUS = hand-held ultrasonography; MRI = magnetic resonance imaging.
The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.
Stéphanie V. de Lange MD, Marije F. Bakker PhD, Ruud M. Pijnappel MD PhD, Wouter B. Veldhuis MD PhD, Carla H. van Gils PhD
The Julius Center for Health Sciences and Primary Care (S.V.d.L, M.F.B, C.H.v.G) and Department of Radiology (R.M.P, W.B.V.), University Medical Center Utrecht. Utrecht, the Netherlands
February 10, 2016
Conflict of Interest:
Stéphanie V. de Lange: disclosed no relevant relationships<br/><br/>Marije F. Bakker: disclosed no relevant relationships<br/><br/>Ruud M. Pijnappel: Activities related to the present article: none to disclose. Activities not related to the present article: none to disclose. Other relationships: is a non-compensated member of the scientific board of Hologic.<br/> <br/>Wouter B. Veldhuis: disclosed no relevant relationships<br/><br/>Carla H. van Gils: C. van Gils reports a grant from the European Union’s Seventh Framework Programme (FP7), a grant from Bayer Healthcare and a personal grant from the Dutch Cancer Society during the conduct of the study. She also reports non-financial support from Volpara Solutions. <br/><br/>The DENSE trial is supported by the University Medical Center Utrecht (project number UMCU DENSE), the Netherlands Organization for Health Research and Development (project number ZONMW-200320002-UMCU), the Dutch Cancer Society (project numbers DCS-UU-2009-4348 and UU-2014-6859), the Dutch Pink Ribbon/A Sister's Hope (project number Pink Ribbon-10074), Bayer HealthCare Medical Care (project number BSP-DENSE), and Stichting Kankerpreventie Midden-West. For research purposes, Matakina (Wellington, New Zealand) provided Volpara Imaging Software, version 1.5 for installation on servers in the screening units of the Dutch screening program.
Supplemental breast cancer screening in women with dense breasts
TO THE EDITOR:Melnikow et al. conclude that although supplemental screening of women with dense breasts finds additional breast cancer, the effects on breast cancer outcomes remain unclear (1). The authors mention a lack of comparative studies with interval breast cancer rates, stage at diagnosis or breast cancer mortality as the outcome. We know of two randomized controlled trials on supplemental ultrasound screening. As mentioned in the accompanying editorial (2), the Japanese multicenter J-START study was probably too recent to have been included. In this RCT, with approximately 60% of participants having dense breasts, cancer detection rates were higher and interval cancer rates statistically significantly lower in the ultrasound plus mammography group, compared to the mammography-only group (3). A Chinese RCT (4) included women that were not specifically selected on breast density either, but more than 65% was expected to have dense breasts. In the group with ultrasound and mammography, significantly more breasts cancers were detected than in the mammography-only group. No interval tumors were observed in either group, which may be partly explained by the combination of a relatively low overall breast cancer incidence rate and loss-to-follow-up. Together with clinicians and researchers from 8 hospitals, we are currently conducting a third RCT, DENSE. This trial investigates the value of additional MRI compared to usual screening practice, in women with extremely dense breasts and a negative digital mammography. A description of its design has been published last year (5). It has many of the characteristics called for by Melnikow (1) and Berg (2). Women are included solely on the basis of their breast density. A fully automatic and validated method was used to estimate mammographic density (Volpara Imaging Software; Matakina). The primary outcome is the difference in interval cancer rates between the two arms, as the best proxy for a difference in breast cancer mortality. Information on molecular phenotypes, cancer stage and other outcomes is being collected, as well as information on potential harms, including impact of MRI screening on quality of life. Influence of age and other breast cancer risk factors on performance of supplemental screening MRI will be examined.Currently all participants have been recruited. More than 4,700 MRI examinations have been carried out, and results on interval cancers are expected in 2018. These results will provide comparative evidence on the benefits and harms of supplemental MRI breast cancer screening in women with extremely dense breasts. References1. Melnikow J, Fenton JJ, Whitlock EP, Miglioretti DL, Weyrich MS, Thompson JH, et al. Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task ForceSupplemental Breast Cancer Screening in Women With Dense Breasts. Ann Intern Med [Internet]. 2016;N/A(N/A):N/A – N/A. Available from: http://dx.doi.org/10.7326/M15-17892. Berg WA. Supplemental Breast Cancer Screening in Women With Dense Breasts Should Be Offered With Simultaneous Collection of Outcomes Data. Ann Intern Med [Internet]. 2016;(9):9–10. Available from: http://annals.org/article.aspx?doi=10.7326/M15-29773. Ohuchi N, Suzuki A, Sobue T, Kawai M, Yamamoto S, Zheng Y-F, et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet [Internet]. Elsevier Ltd; 2015;6736(15):1–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S01406736150077464. Shen S, Zhou Y, Xu Y, Zhang B, Duan X, Huang R, et al. A multi-centre randomised trial comparing ultrasound vs mammography for screening breast cancer in high-risk Chinese women. Br J Cancer [Internet]. 2015 Feb 10 [cited 2015 Feb 11];(February):998–1004. Available from: http://www.ncbi.nlm.nih.gov/pubmed/256680125. Emaus MJ, Bakker MF, Peeters PH, Loo CE, Lobbes MBI, Pijnappel RM, et al. MR imaging as an additional screening modality for the detection of breast cancer in women aged 50-75 years with extremely dense breasts: the DENSE trial study design. Radiology. 2015;277(2):527–37.
Hematology/Oncology, Breast Cancer, Cancer Screening/Prevention, Prevention/Screening.
Results provided by:
Copyright © 2016 American College of Physicians. All Rights Reserved.
Print ISSN: 0003-4819 | Online ISSN: 1539-3704
Conditions of Use
This PDF is available to Subscribers Only