0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Benefits, Harms, and Cost-Effectiveness of Supplemental Ultrasonography Screening for Women With Dense BreastsSupplemental Ultrasonography Screening for Women With Dense Breasts

Brian L. Sprague, PhD; Natasha K. Stout, PhD; Clyde Schechter, MD, MA; Nicolien T. van Ravesteyn, PhD; Mucahit Cevik, MS; Oguzhan Alagoz, PhD; Christoph I. Lee, MD, MSHS; Jeroen J. van den Broek, MS; Diana L. Miglioretti, PhD; Jeanne S. Mandelblatt, MD, MPH; Harry J. de Koning, MD, PhD; Karla Kerlikowske, MD, MS; Constance D. Lehman, MD, PhD; and Anna N.A. Tosteson, ScD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 9 December 2014.


From the University of Vermont, Burlington, Vermont; Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts; Albert Einstein School of Medicine, Bronx, New York; Erasmus Medical Center, Rotterdam, the Netherlands; University of Wisconsin–Madison, Wisconsin; University of Washington School of Medicine and Group Health Research Institute, Group Health Cooperative, Seattle, Washington; University of California, Davis, School of Medicine, Davis, California; Georgetown University, Washington, DC; University of California, San Francisco, California; and Dartmouth Institute for Health Policy and Clinical Practice and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

Acknowledgment: The authors thank the BCSC investigators, participating women, mammography facilities, and radiologists for the data they have provided for this study. A list of the BCSC investigators and procedures for requesting BCSC data for research purposes are provided at http://breastscreening.cancer.gov.

Grant Support: By the National Cancer Institute–funded BCSC (P01 CA154292, HHSN261201100031C) and the National Cancer Institute (U01 CA152958, U54 CA163303, and U54 CA163307). The collection of BCSC cancer and vital status data used in this study was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, visit http://breastscreening.cancer.gov/work/acknowledgement.html.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-0692.

Reproducible Research Statement:Study protocol: Not available. Statistical code: Available at http://cisnet.cancer.gov/breast/profiles.html. Data set: Available from Dr. Sprague (e-mail, bsprague@uvm.edu).

Requests for Single Reprints: Brian L. Sprague, PhD, Office of Health Promotion Research, 1 South Prospect Street, University Health Campus Room 4425, University of Vermont, Burlington, VT 05401; e-mail, Brian.Sprague@uvm.edu.

Current Author Addresses: Dr. Sprague: Office of Health Promotion Research, 1 South Prospect Street, University Health Campus Room 4425, University of Vermont, Burlington, VT 05401.

Dr. Stout: Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 133 Brookline Avenue, 6th Floor, Boston, MA 02215.

Dr. Schechter: Department of Family & Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Block Building 406, Bronx, NY 10461.

Drs. van Ravesteyn and de Koning and Mr. van den Broek: Department of Public Health, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.

Mr. Cevik and Dr. Alagoz: University of Wisconsin–Madison, 3242 Mechanical Engineering Building, 1513 University Avenue, Madison, WI 53706.

Drs. Lee and Lehman: Department of Radiology, University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, G2-600 Seattle, WA 98109.

Dr. Miglioretti: Department of Public Health Sciences, University of California–Davis School of Medicine, 1 Shields Ave, Medical Sciences 1C, Room 145, Davis, CA 95616.

Dr. Mandelblatt: Lombardi Comprehensive Cancer Center, 3300 Whitehaven Street Northwest, Suite 4100, Washington, DC 20007.

Dr. Kerlikowske: University of California, San Francisco, 4150 Clement Street, Veterans Affairs Medical Center (111A1), San Francisco, CA 94121.

Dr. Tosteson: Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive (HB7505), Lebanon, NH 03756.

Author Contributions: Conception and design: B.L. Sprague, N.K. Stout, C. Schechter, N.T. van Ravesteyn, M. Cevik, O. Alagoz, D.L. Miglioretti, J.S. Mandelblatt, K. Kerlikowske, C.D. Lehman, A.N.A. Tosteson.

Analysis and interpretation of the data: B.L. Sprague, N.K. Stout, C. Schechter, N.T. van Ravesteyn, M. Cevik, O. Alagoz, C.I. Lee, D.L. Miglioretti, J.S. Mandelblatt, H.J. de Koning, K. Kerlikowske, C.D. Lehman, A.N.A. Tosteson.

Drafting of the article: B.L. Sprague, N.K. Stout, O. Alagoz, C.I. Lee, D.L. Miglioretti, J.S. Mandelblatt, A.N.A. Tosteson.

Critical revision of the article for important intellectual content: N.K. Stout, C. Schechter, N.T. van Ravesteyn, O. Alagoz, C.I. Lee, D.L. Miglioretti, J.S. Mandelblatt, H.J. de Koning, K. Kerlikowske, C.D. Lehman, A.N.A. Tosteson.

Final approval of the article: B.L. Sprague, N.K. Stout, C. Schechter, N.T. van Ravesteyn, O. Alagoz, C.I. Lee, D.L. Miglioretti, J.S. Mandelblatt, H.J. de Koning, K. Kerlikowske, C.D. Lehman, A.N.A. Tosteson.

Provision of study materials or patients: C.I. Lee, K. Kerlikowske.

Statistical expertise: C. Schechter, O. Alagoz, J.J. van den Broek, D.L. Miglioretti, H.J. de Koning, A.N.A. Tosteson.

Obtaining of funding: B.L. Sprague, D.L. Miglioretti, J.S. Mandelblatt, K. Kerlikowske, A.N.A. Tosteson.

Administrative, technical, or logistic support: J.S. Mandelblatt, K. Kerlikowske.

Collection and assembly of data: B.L. Sprague, N.K. Stout, J.J. van den Broek, D.L. Miglioretti, K. Kerlikowske.


Ann Intern Med. 2015;162(3):157-166. doi:10.7326/M14-0692
Text Size: A A A

Background: Many states have laws requiring mammography facilities to tell women with dense breasts and negative results on screening mammography to discuss supplemental screening tests with their providers. The most readily available supplemental screening method is ultrasonography, but little is known about its effectiveness.

Objective: To evaluate the benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts.

Design: Comparative modeling with 3 validated simulation models.

Data Sources: Surveillance, Epidemiology, and End Results Program; Breast Cancer Surveillance Consortium; and medical literature.

Target Population: Contemporary cohort of women eligible for routine screening.

Time Horizon: Lifetime.

Perspective: Payer.

Intervention: Supplemental ultrasonography screening for women with dense breasts after a negative screening mammography result.

Outcome Measures: Breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, biopsies recommended after a false-positive ultrasonography result, and costs.

Results of Base-Case Analysis: Supplemental ultrasonography screening after a negative mammography result for women aged 50 to 74 years with heterogeneously or extremely dense breasts averted 0.36 additional breast cancer deaths (range across models, 0.14 to 0.75), gained 1.7 QALYs (range, 0.9 to 4.7), and resulted in 354 biopsy recommendations after a false-positive ultrasonography result (range, 345 to 421) per 1000 women with dense breasts compared with biennial screening by mammography alone. The cost-effectiveness ratio was $325 000 per QALY gained (range, $112 000 to $766 000). Supplemental ultrasonography screening for only women with extremely dense breasts cost $246 000 per QALY gained (range, $74 000 to $535 000).

Results of Sensitivity Analysis: The conclusions were not sensitive to ultrasonography performance characteristics, screening frequency, or starting age.

Limitation: Provider costs for coordinating supplemental ultrasonography were not considered.

Conclusion: Supplemental ultrasonography screening for women with dense breasts would substantially increase costs while producing relatively small benefits.

Primary Funding Source: National Cancer Institute.

Figures

Grahic Jump Location
Appendix Figure.

Model replication of U.S. incidence and mortality patterns for women aged 30 to 79 y during 1975–2000.

Model E = Erasmus University Medical Center, Rotterdam, the Netherlands; model G-E = Georgetown University Medical Center, Washington, DC, and Albert Einstein College of Medicine, Bronx, New York; model W = University of Wisconsin, Madison, Wisconsin, and Harvard Medical School, Boston, Massachusetts; SEER = Surveillance, Epidemiology, and End Results Program.

Grahic Jump Location
Grahic Jump Location
Figure 1.

Discounted QALYs versus costs by model and screening strategy.

A40–74 = annual screening for women aged 40–74 y; B50–74 = biennial screening for women aged 50–74 y; M = mammography; model E = Erasmus University Medical Center, Rotterdam, the Netherlands; model G-E = Georgetown University Medical Center, Washington, DC, and Albert Einstein College of Medicine, Bronx, New York; model W = University of Wisconsin, Madison, Wisconsin, and Harvard Medical School, Boston, Massachusetts. QALY = quality-adjusted life-year; SUSDB = supplemental ultrasonography screening for women with dense breasts (heterogeneously or extremely dense); SUSEDB = supplemental ultrasonography screening for women with extremely dense breasts.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Sensitivity analyses comparing costs per QALY gained for biennial mammography alone with mammography plus supplemental US for women aged 50 to 74 y with heterogeneously or extremely dense breasts.

The x-axis shows key variables that were changed. Diamonds show the median from the 3 simulation models. Error bars show the range across models. Dashed and dotted lines indicate $100 000 and $50 000 per QALY gained, respectively. The values explored for each variable are described in the Methods section and Tables 1 and 2. QALY = quality-adjusted life-year; US = ultrasonography.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment/Letter
Misleading Models On Sonography In Breast Cancer Screening
Posted on December 14, 2014
Elaine J. Schattner, MD
Clinical Associate Professor of Medicine, Weill Cornell Medical College
Conflict of Interest: None Declared
In their article on supplemental ultrasound screening in women with dense breasts, Sprague and colleagues used three simulations to assess benefits, harms and cost-effectiveness. Each calculation incorporates assumptions that diminish the validity of the findings.

The primary analysis involves “a hypothetical population of women aged 50 to 74 years.” But dense breasts predominantly affect younger women. Extremely dense breasts – the condition for which the authors’ models consistently found the greatest benefit – are unusual after menopause. For this reason, among women for whom breast cancer screening might be advisable, the most relevant cohort is those between ages 40 and 55 years.

By including women up to age 74, and neglecting those under 50 in the primary analysis, the authors simultaneously diluted the benefit of supplemental screening ultrasound, and exaggerated the costs. In a secondary analysis, the authors considered ultrasound given to women between the ages of 40 and 74 years, screened annually. That strategy doubles the attributable risks and costs, as compared to models for biennial screening, while maintaining the larger, dilutive age bracket of their primary analysis.

Perhaps a more useful set of models would evaluate the number of tumors found with ultrasound, expenses of early detection vs. treatment of later disease, and quality-adjusted life-years saved by adding ultrasound screening to women with dense breasts between the ages of 40 and 55 years.

Finally, I should acknowledge my potential bias: I’m a woman whose stage I, invasive breast cancer was found by a breast imaging specialist 12 years ago. I was 42 years old when a radiologist performed sonography in her office, immediately after an unclear mammogram suggested several areas of concern in dense breast tissue.
Comment
Posted on December 17, 2014
Wendie A. Berg, MD, PhD, FACR, David Gur, ScD
University of Pittsburgh
Conflict of Interest: None Declared

Breast density-inform legislation is motivated by the low sensitivity of mammography in women with dense breasts. Women diagnosed with advanced stage cancer after being adherent with annual screening commonly wonder how that was possible.

Models depend on the values of input parameters. For example, in the analysis by Sprague et al. (1) a lenient definition of “sensitivity” was used for mammography; only cancers detected clinically within 12 months following a mammographic screen were considered false negatives. However, many late stage cancers are detected on mammography after being masked on earlier screening rounds. Screening failures more appropriately are any diagnosis of advanced disease. When supplemental MRI screening is used, mammographic sensitivity averages under 40% (2), far less than the estimates used by Sprague et al. By overestimating mammographic sensitivity, the potential contribution of any supplemental screening is artificially reduced.

The sensitivity of mammography in ACRIN 6666 was 52% (59/111)where ultrasound was not limited to women with negative mammography (3). Sensitivity for invasive cancer was 46% (41/89) and 60% (53/89) for mammography and ultrasound, respectively, with 34% (30/89) of invasive cancers seen only on ultrasound. Parallel sensitivity inputs should be used for all considered modalities. The combination of mammography and ultrasound produces a low interval cancer rate of 1.1 to 1.2 per 1000 (3, 4). While supplemental ultrasound finds a similar number of additional invasive cancers as mammography, the modeled estimated life-savings ratio of mammography compared to ultrasound was unexpectedly very high at approximately 16 (1).

False positives for any screening modality decrease with subsequent screening rounds. Sprague et al (1) estimated a 6% false-positive biopsy rate for screening ultrasound. The observed false positive biopsy rate was 4.5% in ACRIN 6666 in years two and three (3). Weigert similarly reported a 135/4128 (3.3%) false positive biopsy rate in year 3 and only 42/3330 (1.3%) in year 4 while maintaining a 3.0/1000 additional cancer detection rate due to ultrasound (5).

In summary, the modeling of Sprague et al (1) likely substantially underestimates the benefit and overestimates the harms and costs of supplemental screening ultrasound, in particular during repeat screening and with increasing experience. A reduction in the detection of advanced disease is the primary goal of screening. Ultrasound is effective in that role. Notably, only 11/111 (9.9%) women in ACRIN 6666 were diagnosed with stage IIB or higher disease. Further reduction of avoidable false positives remains a desirable goal for any screening method.



References

1. Sprague BL, Stout NK, Schechter C, et al. Benefits, Harms, and Cost-Effectiveness of Supplemental Ultrasonography Screening for Women With Dense Breasts. Ann Intern Med. 2014.
2. Berg WA. Tailored supplemental screening for breast cancer: what now and what next? AJR Am J Roentgenol. 2009;192(2):390-9.
3. Berg WA, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394-404.
4. Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021-6.
5. Weigert JM. The Connecticut experiment continues: Ultrasound in the screening of women with dense breasts years 3 and 4. Radiologic Society of North America. Chicago, IL, November 30, 2014.


Wendie A. Berg, MD, PhD, FACR
Professor of Radiology

David Gur, ScD
Professor of Radiology

Department of Radiology
University of Pittsburgh School of Medicine
Pittsburgh, PA

Screening breast ultrasound and overdiagnosis
Posted on January 19, 2015
Brandon Hayse BS, Donald R. Lannin MD
Department of Surgery, Yale University School of Medicine
Conflict of Interest: None Declared
The recent article by Sprague et al (1) nicely describes the limited benefit of screening breast ultrasound as well as the high cost and the harm of false positives leading to unnecessary biopsies. However, the most serious harm of screening, overdiagnosis (2, 3) leading to unnecessary treatment of indolent cancers that would never become clinically apparent, was not mentioned. Our experience in Connecticut since enactment of the Breast Density Insurance and Notification Law of 2009 leads us to believe that screening breast ultrasound greatly increases the risk of overdiagnosis.

Out of 37 breast cancers treated at Yale that were diagnosed by screening ultrasound, 46% (17/37) were histologic grade 1, compared to 12% (78/649) diagnosed by self-examination (p<0.001), and 29% (295/1002) diagnosed by screening mammography (p<0.05). Since less that 5% of all breast cancer deaths in the SEER database are due to grade 1 cancer, it seems quite likely that many of these ultrasound detected cases represent overdiagnosis. The models in the Sprague article calculate the number of breast cancer deaths averted by ultrasound assuming that each cancer diagnosed by ultrasound has the same biology as a cancer diagnosed by self-examination or mammography. However, the actual reduction in mortality caused by the screening is unknown and may be quite a bit less than predicted by the models. It is clear that screening breast ultrasound can detect cancers not detected by mammography, but it is not clear whether this is a good thing or a bad thing.

Referrences

1.Sprague BL, Stout NK, Schechter C, van Ravesteyn NT, Cevik M, Alagoz O, et al. Benefits, Harms, and Cost-Effectiveness of Supplemental Ultrasonography Screening for Women With Dense Breasts. Ann Intern Med. 2014.

2.Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med. 2012;367(21):1998-2005.

3.Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ. 2014;348:g366.


Author's Response
Posted on March 31, 2015
Brian L. Sprague, Constance D. Lehman, Anna N.A. Tosteson
University of Vermont, University of Washington School of Medicine, Giesel School of Medicine at Dartmouth
Conflict of Interest: None Declared
Drs. Berg and Sur state that we overestimated the sensitivity of mammography screening and underestimated the specificity of ultrasound screening in our study. We used the definition of sensitivity published by the American College of Radiology Breast Imaging and Reporting and Data System (1), which states a false negative exam is one in which “there is a tissue diagnosis of cancer within one year of a negative examination.” We used Breast Cancer Surveillance Consortium data on the sensitivity of digital mammography among women with dense breasts who are not otherwise at high risk to inform our comparative effectiveness study of supplemental ultrasound for the general population of women with dense breasts (2). Our models were calibrated such that the sensitivity of digital mammography in simulated scenarios with no supplemental ultrasound screening matched the observed digital mammography sensitivity in community practice. Low estimates of mammography sensitivity have been reported when supplemental ultrasound or MRI imaging is used in high-risk populations, such as in the ACRIN 6666 trial. Indeed, more than half of women in the ACRIN 6666 trial had a personal history of breast cancer, among whom the sensitivity of mammography to detect subsequent breast cancer is lower than in the general population (3). Also, ACRIN 6666 included a mix of film and digital mammography, resulting in lower sensitivity because film is not as good as digital mammography in women with dense breasts (4). While the ACRIN 6666 trial suggests that improvements in specificity are possible in subsequent screening rounds, data remain sparse regarding the specificity of ultrasound screening in community practice. In sensitivity analyses, we found that even if ultrasound screening achieved 98% specificity, supplemental ultrasound screening for women with dense breasts undergoing digital mammography would still fail to achieve reasonable comparative effectiveness benchmarks.

We agree with Drs. Hayse and Lannin that overdiagnosis is an important harm to consider since the introduction of any supplemental screening modality may increase overdiagnosis. Given the already unfavorable results for supplemental ultrasound screening and the complexity of estimating overdiagnosis, we chose not to address this harm in our study. Hence, our study likely underestimates the harms of supplemental ultrasound screening.

We agree with Dr. Schattner that alternative supplemental ultrasound screening regimens should be considered that more specifically target women for whom the benefit to harm profile will be improved. This likely should entail consideration of both risk of cancer and risk of masking on mammography, rather than simply density and/or age. Strategies that focus on women aged 40-55 will suffer low cancer detection rates and elevated harms due to false positives because of the generally low breast cancer incidence in this age group. We also point out that the prevalence of dense breasts as defined by state laws (heterogeneously or extremely dense) exceeds 50% at ages 40-49 and remains above 25% up to age 74 years (5). Finally, we note that our study does not address the use of diagnostic ultrasound following inconclusive mammography as described by Dr. Schattner.

References

1. American College of Radiology. ACR BI-RADS® - Mammography. 5th Edition. ACR BI-RADS Atlas: Breast Imaging Reporting and Data System. Reston, VA: American College of Radiology; 2013.
2. Stout NK, Lee SJ, Schechter CB, Kerlikowske K, Alagoz O, Berry D, et al. Benefits, Harms, and Costs for Breast Cancer Screening After US Implementation of Digital Mammography. J Natl Cancer Inst. 2014;106(6):dju092.
3. Houssami N, Abraham LA, Miglioretti DL, Sickles EA, Kerlikowske K, Buist DS, et al. Accuracy and outcomes of screening mammography in women with a personal history of early-stage breast cancer. JAMA. 2011;305(8):790-9.
4. Kerlikowske K, Hubbard RA, Miglioretti DL, Geller BM, Yankaskas BC, Lehman CD, et al. Comparative effectiveness of digital versus film-screen mammography in community practice in the United States: a cohort study. Ann Intern Med. 2011;155(8):493-502.
5. Sprague BL, Gangnon RE, Burt V, Trentham-Dietz A, Hampton JM, Wellman RD, et al. Prevalence of mammographically dense breasts in the United States. J Natl Cancer Inst. 2014;106(10).
Submit a Comment/Letter

Summary for Patients

Clinical Slide Sets

Terms of Use

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.

Toolkit

Buy Now for $32.00

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)