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Original Contribution |

Detection of Breast Cancer With Addition of Annual Screening Ultrasound or a Single Screening MRI to Mammography in Women With Elevated Breast Cancer Risk FREE

Wendie A. Berg , MD, PhD; Zheng Zhang, PhD; Daniel Lehrer, MD; Roberta A. Jong, MD; Etta D. Pisano, MD; Richard G. Barr, MD, PhD; Marcela Böhm-Vélez, MD; Mary C. Mahoney, MD; W. Phil Evans, MD; Linda H. Larsen, MD; Marilyn J. Morton, DO; Ellen B. Mendelson, MD; Dione M. Farria, MD; Jean B. Cormack, PhD; Helga S. Marques, MS; Amanda Adams, MPH; Nolin M. Yeh, MS; Glenna Gabrielli, BS; for the ACRIN 6666 Investigators
[+] Author Affiliations

Author Affiliations: American College of Radiology Imaging Network, Philadelphia, Pennsylvania (Dr Berg and Ms Gabrielli); Center for Statistical Sciences, Brown University, Providence, Rhode Island (Drs Zhang and Cormack and Mss Marques, Adams, and Yeh); CERIM, Buenos Aires, Argentina (Dr Lehrer); Department of Radiology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada (Dr Jong); Department of Radiology, University of North Carolina, Chapel Hill (Dr Pisano); Radiology Consultants/Forum Health, Youngstown, Ohio (Dr Barr); Weinstein Imaging Associates, Pittsburgh, Pennsylvania (Dr Böhm-Vélez); Department of Radiology, University of Cincinnati Medical Center, Cincinnati, Ohio (Dr Mahoney); Department of Radiology, University of Texas Southwestern Medical Center, Dallas (Dr Evans); Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles (Dr Larsen); Department of Radiology, Mayo Clinic, Rochester, Minnesota (Dr Morton); Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (Dr Mendelson); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri (Dr Farria). Dr Berg is now with the Department of Radiology, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and Dr Pisano is now with the Department of Radiology, Medical University of South Carolina, Charleston.


JAMA. 2012;307(13):1394-1404. doi:10.1001/jama.2012.388.
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Published online

Context Annual ultrasound screening may detect small, node-negative breast cancers that are not seen on mammography. Magnetic resonance imaging (MRI) may reveal additional breast cancers missed by both mammography and ultrasound screening.

Objective To determine supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer.

Design, Setting, and Participants From April 2004-February 2006, 2809 women at 21 sites with elevated cancer risk and dense breasts consented to 3 annual independent screens with mammography and ultrasound in randomized order. After 3 rounds of both screenings, 612 of 703 women who chose to undergo an MRI had complete data. The reference standard was defined as a combination of pathology (biopsy results that showed in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes) and 12-month follow-up.

Main Outcome Measures Cancer detection rate (yield), sensitivity, specificity, positive predictive value (PPV3) of biopsies performed and interval cancer rate.

Results A total of 2662 women underwent 7473 mammogram and ultrasound screenings, 110 of whom had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Among 4814 incidence screens in the second and third years combined, 75 women were diagnosed with cancer. Supplemental incidence-screening ultrasound identified 3.7 cancers per 1000 screens (95% CI, 2.1-5.8; P < .001). Sensitivity for mammography plus ultrasound was 0.76 (95% CI, 0.65-0.85); specificity, 0.84 (95% CI, 0.83-0.85); and PPV3, 0.16 (95% CI, 0.12-0.21). For mammography alone, sensitivity was 0.52 (95% CI, 0.40-0.64); specificity, 0.91 (95% CI, 0.90-0.92); and PPV3, 0.38 (95% CI, 0.28-0.49; P < .001 all comparisons). Of the MRI participants, 16 women (2.6%) had breast cancer diagnosed. The supplemental yield of MRI was 14.7 per 1000 (95% CI, 3.5-25.9; P = .004). Sensitivity for MRI and mammography plus ultrasound was 1.00 (95% CI, 0.79-1.00); specificity, 0.65 (95% CI, 0.61-0.69); and PPV3, 0.19 (95% CI, 0.11-0.29). For mammography and ultrasound, sensitivity was 0.44 (95% CI, 0.20-0.70, P = .004); specificity 0.84 (95% CI, 0.81-0.87; P < .001); and PPV3, 0.18 (95% CI, 0.08 to 0.34; P = .98). The number of screens needed to detect 1 cancer was 127 (95% CI, 99-167) for mammography; 234 (95% CI, 173-345) for supplemental ultrasound; and 68 (95% CI, 39-286) for MRI after negative mammography and ultrasound results.

Conclusion The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings.

Trial Registration clinicaltrials.gov Identifier: NCT00072501

Figures in this Article

Six previous single-center studies16 and 3 multicenter trials79 have shown supplemental screening breast ultrasound significantly increases detection of node-negative invasive breast cancer in women with mammographically dense breast tissue on the first prevalence screen, consistently increasing cancer detection (yield) by 3.5 per 1000 in single-center studies and from 4.2 to 4.4 per 1000 in multicenter trials. The vast majority of cancers detected only by ultrasound have been node-negative invasive breast cancers. Until now, it was unclear whether continuing ultrasound screening annually (ie, incidence screening) would result in a detection benefit.

A substantial majority of American College of Radiology Imaging Network (ACRIN) 6666 participants were at intermediate risk for breast cancer, with more than half having a personal history of breast cancer.7 Although there was evidence from prior studies1013 that magnetic resonance imaging (MRI) provided considerable detection benefit beyond what combined ultrasound and mammography screens could discover in high-risk women, the combination of ultrasound and mammography might still identify the vast majority of cancers when they are node negative at a much lower cost to the health care system than the cost of an MRI, particularly when screening women with a lower prevalence of disease. A substudy of ACRIN 6666 participants was therefore undertaken to assess the rate and stage of cancers detected with a single screening MRI.

Study Design

Study participants included women who were asymptomatic, presenting for routine annual mammography with heterogeneously dense or extremely dense breast tissue,14 and who had at least 1 other risk factor for breast cancer (Table 1). Race/ethnicity was self-assigned based on fixed categories.

Each participant underwent mammographic and physician-performed ultrasonographic screening examinations in randomized order, with the interpreting radiologist for each examination masked to results of the other study, at 0 months (first screening), 12 months (second screening), and 24 months (third screening). The randomization process has been previously described,7 and initial randomization order was maintained for subsequent screening rounds. If recommendation from either screening test was other than routine annual screening, the test was considered positive for purposes of analysis and a qualified site investigator then recorded an integrated interpretation by reviewing study mammogram and ultrasound together. Clinical management was based on integrated interpretation. If both modalities recommended routine annual follow-up, no integration was performed. Cancers positive only on a given modality refers to those not visible on any other modality. Sensitivity of a modality alone refers to the number of cancers that would have been detected if only that modality had been used and includes some cancers that were also visible on the other modality.

To be eligible for the MRI substudy, women had to have completed the third round of annual ultrasound and mammography screenings per protocol7 and had agreed to undergo contrast-enhanced breast MRI within 8 weeks of the 24-month screening mammogram. Interpretation of each of the 3 screening approaches was blinded to results of the other examinations. A separate integrated breast-level interpretation across all 3 modalities was then performed, which determined clinical management. Women who accepted MRI had higher risk and were younger than those who declined.15 Women enrolled at sites in the MRI substudy were less likely to have had a personal history of breast cancer; no other systematic differences were noted across sites.

Web-based data capture and quality monitoring were conducted by the ACRIN biostatistics and data management center. The study was compliant with the Health Insurance Portability and Accountability Act, received institutional review board approval from all participating sites and from ACRIN, and received approval from the National Cancer Institute Cancer Imaging Program. The study underwent data and safety monitoring committee review every 6 months.

Participants

Among the 21 sites, 2809 women were recruited between April 2004 and February 2006, 2725 of whom were eligible (Figure 1). Women aged at least 25 years presenting for routine mammography were eligible to participate if they met study definitions of elevated risk (Table 1) and had heterogeneously dense or extremely dense parenchyma14 in at least 1 quadrant, either by prior mammography report or review of prior mammograms. Women were excluded if they were pregnant or lactating or if they had known metastatic disease, signs or symptoms of breast disease, breast surgery within prior 12 months, or breast implants.

Place holder to copy figure label and caption
Figure 1. Flowchart of Protocol
Graphic Jump Location

Participants with negative results on both mammography and ultrasound were imputed as having negative results on integrated reading of mammography plus ultrasound: 1844 for the first screening, 1922 for the second screening, and 1912 for the third screening. The reference standard was the most severe of biopsy results within 365 days of mammographic screening, on clinical follow-up at 1 year, or both. Biopsies prompted by an early subsequent screening examination were attributed to that subsequent screen.

aAll participants in the magnetic resonance imaging (MRI) analysis set are also in the screen 3 analysis set.

For the MRI substudy, women also could not have contraindications to MRI (have a pacemaker, aneurysm clip, or other metallic implant; weigh >135 kg; or have renal impairment [have a glomerular filtration rate of <30 mL/min per 1.73 m2 or were undergoing a dialysis regimen]). Participants provided written informed consent at their initial visit. Those participating in the MRI screening provided a second consent at MRI registration.

Screening methods are detailed in the eAppendix. The expanded 7-point Breast Imaging-Reporting and Data System (BI-RADS)14,16,17 assessment scale was used: a score of 1 is negative; 2, benign; 3, probably benign; 4a, low suspicion; 4b, intermediate suspicion; 4c, moderate suspicion; and 5, highly suggestive of malignancy.

Reference Standard

We defined the reference standard, which could be cancer or not, to be the most severe of biopsy results within 365 days of mammographic screening, clinical follow-up at 1 year, or both. Each mammographic screening was targeted for 365 days after the previous mammographic screening. A complete examination of all study breasts performed more than 11 full months after the previous screen was considered the next annual screen; only 88 of 7473 visits (1.2%) occurred before 11 months. The absence of a known diagnosis of cancer for a participant report at interview, review of medical records, or both at least 11 full months (330 days) after mammographic screening was considered disease negative, as were 7 cases of prophylactic mastectomies with no evidence of cancer at pathology. Biopsy results showing breast cancer (in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma) in the breast or axillary lymph nodes were considered disease positive.

Statistical Methods

The primary unit of analysis was the participant. A participant's BI-RADS score was derived as the maximum breast level BI-RADS or the score from the breast with cancer when only 1 breast had cancer. In keeping with planned revisions to BI-RADS (Edward A. Sickles, MD, Professor of Radiology, University of California, San Francisco, written communication, November 29, 2009), a screening BI-RADS assessment score of 3, 4a, 4b, 4c, or 5 was considered test positive, provided that the recommendation was for other than routine screening. This differs from the definition of positive test results that we used in our initial publication of the first screening, wherein an assessment of 4a or higher was considered a positive test result7: results of the first screen have been reanalyzed and included herein. For a participant diagnosed with cancer, the breast(s) with cancer were excluded from analysis for the next annual screen.

The cancer detection rate (ie, the proportion of women with a positive screen result and a positive reference standard); sensitivity; specificity; recall rate, which is the proportion of women with a positive screen result; positive predictive value (PPV1), which is the malignancy rate among cases that test positive on screening; short-term follow-up rate; biopsy rate; and area under the empirical receiver operating characteristic (ROC) curve (AUC) using BI-RADS scores were reported. PPV3 is defined as the rate of malignancy among cases with positive results on screening who underwent biopsy of the same lesion.14 Interval cancers were defined as those diagnosed because of a clinical abnormality such as a lump, skin thickening, or pathologic nipple discharge occurring in the interval between prescribed screenings (ie, less than 365 days after the last screening mammogram and before the next screen; cancers detected on an early screen performed at least 11 months after the previous screen were considered screen detected).

Single-year estimates of yield, sensitivity, specificity, recall rate, PPV1, short-term follow-up rate, biopsy rate, and PPV3, were determined as simple proportions with exact 95% CIs (Clopper-Pearson). The 95% CIs for differences in yield, sensitivity, specificity, recall rate, short-term follow-up rate, and biopsy rate were calculated per Fleiss et al.18P values for the above comparisons were based on the McNemar test statistic. The 95% CIs and P values for differences in PPV1 and PPV3 were calculated using the bootstrap-resampling method.19 All inferences for incidence screens were based on the bootstrap-resampling method. Estimates, 95% CIs, and P values related to AUC were derived by using the method of Delong et al20 for empirical ROC curves. Results for participants with a personal history of breast cancer were compared with those who had no such history by the bootstrap method. All P values were reported as 2-sided, with .05 set as threshold for significance. All analyses were performed by SAS 9.2 statistical software (SAS Institute Inc).

Participant Demographic Information

A total of 2659 eligible women with reference standard completed the first annual mammogram and ultrasound screenings; 2493, the second; and 2321, the third (Figure 1 and Figure 2, Table 1). Participant demographics at enrollment were previously reported.7 Median age at enrollment was 55 years (range, 25-91 years). Approximately 29% of women were younger than 50 years at enrollment, and 23% were premenopausal (Table 1). Nearly 54% of women had a personal history of breast cancer. The median age of the 612 women in the MRI group was 57 years (range, 27-87 years); 21% were younger than 50 years at the time of the screening, 25% were premenopausal, and 45% had personal history of breast cancer. Time between screens (eTable 1) and time to perform ultrasound (eTable 2).

Place holder to copy figure label and caption
Figure 2. Outcomes of 3 Rounds of Annual Screening Mammography Plus Ultrasound
Graphic Jump Location

Outcomes of screening 2662 participants are detailed for mammography alone compared with integrated tests, mammography plus ultrasound, for each of the 3 screening years and also for 612 women in the MRI substudy compared with mammography alone or compared with integrated tests, mammography plus ultrasound, in year 3.

Cancer Detection

A total of 110 participants were diagnosed with breast cancer during the 3-year study. One woman diagnosed by mammography in the first year was diagnosed again in the third year in the contralateral breast by MRI only. Each diagnosis was counted as a separate event, for a total of 111 participant-cancer events. Of 111 diagnoses, 89 (80%) were invasive (Table 2). Fifty-nine cancers (53%) were detected by mammography, including 33 (30%) that were detected by mammography only; 32 (29%) by ultrasound only; and 9 (8%) by MRI only after both mammography and ultrasound screens failed to detect cancer. Eleven cancers (10%) were not detected by any imaging screen. Of 32 cancers seen only on ultrasound, 30 (94%) were invasive, with median size of 10 mm (range, 2-40 mm), and 26 of 27 (96%) of those staged were node negative.

Table Graphic Jump LocationTable 2. Summary of Cancer Detection and Characteristics for 2662 Unique Participants Screened 3 Years With Mammography and Physician-Performed Ultrasound and 612 Participants Screened With MRI in Year 3

A total of 16 of 612 women (2.6%) in the MRI substudy were diagnosed with breast cancer, 12 of 16 (75%) of whom had invasive cancer. Nine of 16 cancers (56%) were seen only on MRI after negative mammography and ultrasound results: 8 of 9 (89%) were invasive, with median size of 8.5 mm (range, 1-25 mm), and all 7 cancers that were staged were node negative (Table 2). Two invasive cancers that had been detected by ultrasound but not by mammography in the MRI substudy were also detected by MRI.

Supplemental Cancer Detection Yield

Supplemental ultrasound increased cancer detection with each annual screen beyond that of mammography, adding detection of 5.3 cancers per 1000 women in the first year (95% CI, 2.1-8.4; P < .001); 3.7 women per 1000 per year in each of the second and third years (95% CI, 2.1-5.8, P < .001; Table 3); and averaging 4.3 per 1000 for each of the 3 rounds of annual screening. Supplemental yield results of ultrasound after digital mammography are shown in the eAppendix. The addition of MRI screening further increased cancer detection with a supplemental cancer detection yield of 14.7 per 1000 women (95% CI, 3.5-25.9; P = .004 vs mammogram plus ultrasound; Table 4). The number of screens needed to detect 1 cancer was 127 (95% CI, 99-167) for mammography; 234 (95% CI, 173-345) for supplemental ultrasound, and 68 (95% CI, 39-286) for supplemental MRI after negative mammography plus ultrasound screening results.

Table Graphic Jump LocationTable 3. Screening Performance in 2662 Unique Participants Screened 3 Years With Mammography and Physician-Performed Ultrasound
Table Graphic Jump LocationTable 4. Screening Performance in 612 Participants Screened by Magnetic Resonance Imaging After 3 Annual Mammography and Ultrasound Screenings
Sensitivity, Specificity, and AUC

Among 4814 incidence screens in years 2 and 3 combined, 75 women were diagnosed with cancer. Sensitivity of combined mammography plus ultrasound was 57 of 75 (0.76; 95% CI, 0.65-0.85) for incidence screening, higher than mammography alone, which was 39 of 75 (0.52; 95% CI, 0.40-0.64; P < .001). Specificity of combined mammography and ultrasound was 3987 of 4739 (0.84; 95% CI, 0.83 to 0.85) for incidence screens, lower than the specificity of mammography alone, which was 4325 of 4739 (0.91; 95% CI, 0.90-0.92; P < .001; Table 3).

For 612 MRI participants, sensitivity increased from 7 of 16 (0.44; 95% CI, 0.20-0.70) with combined mammography and ultrasound to 16 of 16 (1.00; 95% CI, 0.79-1.00) with the addition of MRI (P = .004). Specificity was reduced to 390 of 596 (0.65; 95% CI, 0.61-0.69) after MRI vs combined mammography plus ultrasound at 503 of 596 (0.84; 95% CI, 0.81-0.87, P < .001; Table 4).

Overall AUC increased each year when ultrasound was added to mammography (Table 3). Adding MRI lowered apparent performance of mammography plus ultrasound because more cancers were identified by MRI (Table 4).

Additional Biopsies and PPV3

The PPV3 for biopsies resulting from combined mammography plus ultrasound was 31 of 272 (0.11; 95% CI, 0.08-0.16) for the first screen and was 55 of 339 (0.16; 95% CI, 0.12 to 0.21) for incidence screens. These values were significantly lower than those of mammography alone (19 of 65 [0.29; 95% CI, 0.19-0.42, first screening] and 37 of 97 [0.38; 95% CI, 0.28-0.49 incidence screening]; P < .001 for both; Table 3). The percentage of women undergoing biopsy after mammography and ultrasound decreased from 272 of 2659 (10.2%; 95% CI, 9.1%-11.4%) in year 1 to 339 of 4814 (7.0%; 95% CI, 6.3%-7.8%) for incidence screens (P < .001). The biopsy rates after mammography alone were 65 of 2659 (2.4%; 95% CI, 1.9%-3.1%) in year 1 and 97 of 4814 (2.0%; 95% CI, 1.6%-2.5%) for incidence screens. There were 242 of 4814 (5%) incidence screens resulting in biopsy due to addition of ultrasound, with 18 of 242 (7.4%) of these women found to have cancer.

For 612 MRI participants, the rate of biopsy after a full workup of mammography plus ultrasound was 38 of 612 (6.2%; 95% CI, 4.4%-8.4%), which increased to 81 of 612 (13.2%; 95% CI,10.7%-16.2%) with the addition of MRI (P < .001). The PPV3 after mammography plus ultrasound was 7 of 38 (0.18; 95% CI, 0.08-0.34) and with addition of MRI, it was 15 of 81 (0.19; 95% CI, 0.11-0.29, P = .98; Table 4). There were 43 of 612 (7.0%) participants biopsied only because of MRI, 8 (19%) of whom were found to have cancer.

Interval Cancers

Of 20 women with cancer not seen on either mammography or ultrasound in 3 annual rounds, 9 women in the MRI cohort had their cancer detected by MRI. Another 9 cancers were identified because of clinical abnormalities found during the intervals between screens (interval cancer rate 8.1%): 2 had clinical findings in the first year; 4 in the second year; and 3 in the third year. One participant was found to have high-grade ductal carcinoma in situ because of off-study computer-assisted detection applied to mammogram (revealing calcifications) after the year-3 interpretation had been recorded. One participant with a BRCA 1 mutation had an MRI screening off study 6 months after the third screen and was found to have a 7 mm node-negative grade III invasive ductal carcinoma.

Women With Personal History of Breast Cancer

A total of 1426 of 2659 participants (54%) had a personal history of breast cancer at study entry and underwent 4010 screens; 59 of 1426 (4.1%) were diagnosed with cancer (28 only ipsilateral and 29 only contralateral to the original cancer; 2 bilateral). Supplemental yield of ultrasound was the same in women with a personal history of breast cancer as in women without a personal history of breast cancer (eTable 3A), as was the absolute increase insensitivity due to added ultrasound. Supplemental ultrasound was less likely to prompt unnecessary recall or biopsy in women with a personal history of breast cancer than those without (eTable 3A). The supplemental yield of MRI screening in women with or without a personal history of breast cancer in the MRI substudy is detailed (eTable 3B. The supplemental MRI was less likely to prompt unnecessary recall or biopsy in women with a personal history of breast cancer than those without (eTable 3B).

In this study, annual supplemental incidence screening ultrasound detected an additional 3.7 cancers per 1000 women per year screened beyond mammography alone. The majority of cancers seen only on ultrasound were node-negative invasive cancers. Invasive lobular carcinoma and low-grade invasive ductal carcinoma were overrepresented among such cancers.

One of the major concerns about screening is the harm of extra testing and biopsies for women who do not have cancer.21 As has been observed with mammography22 and MRI,11,2325 the risk of false positives decreased significantly with annual screening ultrasound in this study compared with the first screen. However, there still remained a substantial rate of biopsies prompted only by incidence screening ultrasound, averaging 5.0% of women screened.

In a separate analysis of ACRIN 6666 participants, MRI was significantly less tolerable than mammography or ultrasound. Only 58% of ACRIN 6666 participants who were offered a screening MRI at no out-of-pocket cost accepted the invitation.15 These barriers are in addition to high costs of MRI equipment, contrast, and examination, as well as the high rates of induced testing including biopsy, with 7% of women in this study biopsied only because of MRI findings.

Contrast-enhanced MRI has been recommended for supplemental screening of women at high risk of breast cancer, defined as those women with a lifetime risk of 20% to 25% or greater based on family history, known or suspected BRCA or other high-risk genetic mutations, or prior mantle radiation to the chest.26 Across 9 series, the supplemental yield of MRI after mammography in high-risk women was 11 per 100027 and was 14 per 1000 among the subset who also had screening ultrasound.1113,25 Similar results were observed in this study of women who were mostly at intermediate risk of breast cancer.

Fewer studies have evaluated MRI in women at intermediate risk, including women with a personal history of breast cancer, prior atypical biopsy or lobular carcinoma in situ, intermediate family history of breast cancer (lifetime risk of 15%-20% per the American Cancer Society guidelines26), or women whose only risk factor is dense breasts. Recent studies collectively suggest that supplemental MRI screening may be reasonable for women with a personal history of breast cancer and also found false positives to be less frequent than for women with a family history of breast cancer.2830

For high-risk women unable to undergo MRI,15 and for intermediate-risk women with dense breasts, including those with a personal history of breast cancer, this study supports the use of supplemental screening with ultrasound in addition to mammography. With either MRI or ultrasound, the risks of false positives, including unnecessary biopsies, were lower for supplemental screening in women with a personal history of breast cancer than in women without. The outcomes in terms of staging, node-positive disease, and interval cancer rates achieved in this study after 3 years of programmatic screening with both ultrasound and mammography were comparable with benchmarks from studies that included MRI.1013,25

If screening ultrasound were to be adopted for women with dense breasts who are not candidates for MRI, there would be obstacles to its implementation. These include the availability of only 1 current procedural terminology (CPT) code, 76645, for breast ultrasound, with low reimbursement (2010 Medicare reimbursement averaged a global fee of $89.85 to $91.83,31 which does not cover the costs of physicians performing and interpreting a thorough screening examination). While supplemental cancer detection rates with technologist-performed screening ultrasound were similar to physician-performed ultrasound in one series,4 there remains a shortage of qualified breast ultrasound technologists.

There are a few limitations to this study. Additional node-negative invasive cancers were found by adding screening ultrasound to mammography in each incidence screen, and increasing detection of such cancers correlates with mortality reduction.32 However, we did not have a control group with no ultrasound performed with which we could compare clinical outcomes, and mortality was not assessed. In Japan, the ongoing Japan Strategic Anti-Cancer Randomized Trial ( J-START) of biennial mammography, with or without technologist-performed screening ultrasound does have such a control group.33 We only performed a single screening MRI, and false positives would be expected to decrease in subsequent years.11,23 Not all sites in the original ACRIN 6666 protocol were able to offer MRI.

The cancer detection benefit from supplemental screening ultrasound seen on the first screening persisted with each annual screening. Rates of biopsy for findings seen only on ultrasound remained substantial on incidence screens, representing 5% of women, with only 7.4% of those women found to have cancer. Risks of false-positives were lower in women with a personal history of breast cancer than in women without.

As has been seen in other studies,10,11,25,34 MRI significantly increased detection of early breast cancer beyond that seen with mammography or mammography combined with ultrasound. The 56% absolute increase in cancer detection seen in the MRI substudy (16 of 16 vs 7 of 16) was greater than the 34% absolute increase in invasive cancer detection (71 of 89 vs 41 of 89) seen by adding annual ultrasound to mammography in the main ACRIN 6666 study. However, given the low clinically detected interval cancer rate of 8% in the main ACRIN 6666 protocol and given the fact that all interval cancers remained node-negative at diagnosis, it is unclear that the added cost and reduced tolerability of screening MRI are justified in women at intermediate risk for breast cancer in lieu of supplemental screening with ultrasound. Despite its higher sensitivity, the addition of screening MRI rather than ultrasound to mammography in broader populations of women at intermediate risk with dense breasts may not be appropriate, particularly when the current high false-positive rates, cost, and reduced tolerability of MRI are considered.

Corresponding Author: Wendie A. Berg, MD, PhD, Department of Radiology, Magee-Womens Hospital, 300 Halket St, Pittsburgh, PA 15213 (wendieberg@gmail.com).

Author Contributions: Drs Zhang and Cormack had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Berg, Zhang, Mendelson, Pisano.

Acquisition of data: Berg, Mendelson, Lehrer, Böhm-Vélez, Pisano, Jong, Evans, Morton, Mahoney, Hovanessian-Larsen, Barr, Farria, Gabrielli.

Analysis and interpretation of data: Berg, Zhang, Cormack, Pisano, Marques, Adams, Yeh.

Drafting of the manuscript: Berg, Zhang.

Critical revision of the manuscript for important intellectual content: Berg, Zhang, Mendelson, Lehrer, Böhm-Vélez, Pisano, Jong, Evans, Morton, Mahoney, Hovanessian-Larsen, Barr, Farria, Gabrielli.

Statistical analysis: Zhang, Cormack, Marques, Adams, Yeh.

Obtained funding: Berg.

Administrative, technical, or material support: Berg, Mendelson, Gabrielli.

Study supervision: Berg, Zhang.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Berg reports that she has served as a consultant to Naviscan Inc and SuperSonic Imagine, has received research support from Naviscan Inc, has prepared educational materials for Gamma Medica, has a research grant from Hologic Inc, and is on the medical advisory board of Philips. Dr Mendelson reports that she is a member of the scientific advisory boards of MediPattern, Hologic, and Siemens and has received equipment support from Philips and research support from SuperSonic Imagine and Siemens. Dr Böhm-Vélez reports that she is a member of the scientific advisory board of Philips, does clinical validation studies for Philips Ultrasound, and is on the speakers bureau of Dilon. Dr Pisano reports that her laboratory received research support from GE Healthcare, Konica Minolta, Sectra AB, Naviscan Inc, Koning, Zumatek, Inc, equipment grants from R2 and iCAD, is a board member of ACR Imaging Metrix and NextRay Inc, and a stockholder in NextRay Inc. Dr Jong reports that she is a consultant to and receives research support from GE Healthcare. Dr Evans reports that he is a member of the scientific advisory board of Hologic. Dr Mahoney reports that she is a consultant to Ethicon EndoSurgery and SenoRx and on the scientific advisory board of Hologic and receives research support from Naviscan Inc. Dr Larsen reports that she receives equipment support from Naviscan Inc. Dr Barr reports that he is a member of the ultrasound advisory boards of and has received equipment support, research support, and speakers fees from Siemens and Philips, an equipment grant from SuperSonic Inc, and a research grant from Bracco. The remaining coauthors report no financial disclosures.

ACRIN 6666 Site Investigators and Research Assistants:Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania: William R. Poller, MD, principal investigator (PI), and Michelle Huerbin; American Radiology Services–Johns Hopkins Green Spring, Baltimore, Maryland: Wendie A. Berg, MD, PhD (PI), Barbara E. Levit, RT, and Kathy Wetzel; Beth Israel Deaconess Medical Center, Boston, Massachusetts: Janet K. Baum, MD, and Valerie J. Fein-Zachary, MD (PIs), and Suzette M. Kelleher, BA; CERIM, Buenos Aires, Argentina: Daniel E. Lehrer, MD (PI), and Maria S. Ostertag; Duke University Medical Center, Durham, North Carolina: Mary Scott Soo, MD (PI), and Brenda N. Prince, RT; Mayo Clinic, Rochester, Minnesota: Marilyn J. Morton, DO (PI), and Lori M. Johnson, AAS; Feinberg School of Medicine, Northwestern University, Chicago, Illinois: Ellen B. Mendelson, MD (PI), and Marysia Kalata, AA; Radiology Associates of Atlanta, Atlanta, Georgia: Handel Reynolds, MD (PI), and Y. Suzette Wheeler, RN, MSHA; Radiology Consultants/Forum Health, Youngstown, Ohio: Richard G. Barr, MD, PhD (PI), and Marilyn J. Mangino, RN; Radiology Imaging Associates, Denver, Colorado: A. Thomas Stavros, MD (PI), and Margo Valdez; Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada: Roberta A. Jong, MD (PI), and Julie H. Lee, BSC; Thomas Jefferson University Hospital, Philadelphia, Pennsylvania: Catherine W. Piccoli, MD, and Christopher R. B. Merritt, MS, MD (PIs), and Colleen Dascenzo; David Geffen School of Medicine at University of California Los Angeles Medical Center, Los Angeles: Anne C. Hoyt, MD (PI), and Roslynn Marzan, BS; University of Cincinnati Medical Center, Cincinnati, Ohio: Mary C. Mahoney, MD (PI), and Monene M. Kamm, AS; University of North Carolina, Chapel Hill: Etta D. Pisano, MD (PI), and Laura A. Tuttle, MA; Keck School of Medicine, University of Southern California, Los Angeles: Linda H. Larsen, MD (PI), and Christina E. Kiss, AA; University of Texas MfD Anderson Cancer Center, Houston: Gary J. Whitman, MD (PI), and Sharon R. Rice, AA; University of Texas Southwestern Medical Center, Dallas: W. Phil Evans, MD (PI), and Kimberly T. Taylor, AA; Washington University School of Medicine, St Louis, Missouri: Dione M. Farria, MD, MPH (PI), and Darlene J. Bird, RT, AS; and Weinstein Imaging Associates, Pittsburgh, Pennsylvania: Marcela Böhm-Vélez, MD, (PI), and Antoinette Cockroft.

Funding/Support: The study was funded by the Avon Foundation and grants CA 80098 and CA 79778 from the National Cancer Institute.

Role of the Sponsors: The Avon Foundation was not involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. The trial was conducted by the American College of Radiology Imaging Network, a member of the National Cancer Institute's Clinical Trials Cooperative Groups Program, and was developed and carried out adhering to the standard cooperative group processes. These processes include review of and input about the trial design from the NCI's Cancer Therapy Evaluation Program (CTEP). Upon CTEP's approval of the research protocol, the NCI was not involved in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Previous Presentation: Presented at the 2009 Radiologic Society of North America Scientific Assembly, Chicago, Illinois, December 1, 2009.

Online-Only Material: The Author Video Interview is available The Author Audio Inverview is available here . The full protocol is available online at http://acrin.org/Portals/0/Protocols/6666/Protocol-ACRIN%206666%20Admin%20Update%2011.30.07.pdf.

Additional Contributions: We thank Jeffrey Blume, PhD, Vanderbilt University, Nashville, Tennessee, for his contributions to initial study design and supervision and Robert A. Smith, PhD, American Cancer Society, Atlanta, Georgia, for review and helpful discussions. We especially thank Marydale DeBor, JD, Chief Advisor Avon Breast Cancer Crusade 1993-2003, who was instrumental in securing the support within the Avon Foundation that made this study possible, and Marc Hurlbert, PhD, of the Avon Foundation for his continued vision and unwavering support. We are indebted to the many investigators, coinvestigators, and research assistants at the clinical sites. We appreciate the efforts of ACRIN Data Management and Imaging staff, and we especially thank Cynthia Olson, MBA, MHS, for administrative oversight. We thank Eric Berns, PhD, University of Colorado, Denver, for ultrasound image quality control and R. Edward Hendrick, PhD, University of Colorado, for MRI imaging quality control. No one was compensated beyond their usual salary for their efforts for this study. We are especially grateful to the 2809 women who enrolled in this study.

Buchberger W, Niehoff A, Obrist P, DeKoekkoek-Doll P, Dünser M. Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography.  Semin Ultrasound CT MR. 2000;21(4):325-336
PubMed   |  Link to Article
Crystal P, Strano SD, Shcharynski S, Koretz MJ. Using sonography to screen women with mammographically dense breasts.  AJR Am J Roentgenol. 2003;181(1):177-182
PubMed   |  Link to Article
Gordon PB, Goldenberg SL. Malignant breast masses detected only by ultrasound.  Cancer. 1995;76(4):626-630
PubMed   |  Link to Article
Kaplan SS. Clinical utility of bilateral whole-breast US in the evaluation of women with dense breast tissue.  Radiology. 2001;221(3):641-649
PubMed   |  Link to Article
Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them.  Radiology. 2002;225(1):165-175
PubMed   |  Link to Article
Leconte I, Feger C, Galant C,  et al.  Mammography and subsequent whole-breast sonography of nonpalpable breast cancers: the importance of radiologic breast density.  AJR Am J Roentgenol. 2003;180(6):1675-1679
PubMed   |  Link to Article
Berg WA, Blume JD, Cormack JB,  et al; ACRIN 6666 Investigators.  Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer.  JAMA. 2008;299(18):2151-2163
PubMed   |  Link to Article
Corsetti V, Ferrari A, Ghirardi M,  et al.  Role of ultrasonography in detecting mammographically occult breast carcinoma in women with dense breasts.  Radiol Med. 2006;111(3):440-448
PubMed   |  Link to Article
Tohno E, Ueno E, Watanabe H. Ultrasound screening of breast cancer.  Breast Cancer. 2009;16(1):18-22
PubMed   |  Link to Article
Kuhl C, Weigel S, Schrading S,  et al.  Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer.  J Clin Oncol. 2010;28(9):1450-1457
PubMed   |  Link to Article
Kuhl CK, Schrading S, Leutner CC,  et al.  Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer.  J Clin Oncol. 2005;23(33):8469-8476
PubMed   |  Link to Article
Lehman CD, Isaacs C, Schnall MD,  et al.  Cancer yield of mammography, MR, and US in high-risk women.  Radiology. 2007;244(2):381-388
PubMed   |  Link to Article
Sardanelli F, Podo F, D’Agnolo G,  et al; High Breast Cancer Risk Italian Trial.  Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study).  Radiology. 2007;242(3):698-715
PubMed   |  Link to Article
D'Orsi CJ, Bassett LW, Berg WA,  et al.  Breast Imaging Reporting and Data System, BI-RADS: Mammography. 4th ed. Reston, VA: American College of Radiology; 2003
Berg WA, Blume JD, Adams AM,  et al.  Reasons women at elevated risk of breast cancer refuse breast MR imaging screening.  Radiology. 2010;254(1):79-87
PubMed   |  Link to Article
Mendelson EB, Baum JK, Berg WA, Merritt CRB, Rubin E. Breast Imaging Reporting and Data System, BI-RADS: Ultrasound. Reston, VA: American College of Radiology; 2003
Ikeda DM, Hylton NM, Kuhl CK.et al. Breast Imaging Reporting and Data System, BI-RADS: Magnetic Resonance Imaging. Reston, VA: American College of Radiology; 2003
Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. Hoboken, NJ: Wiley-Interscience; 2003
Efron B. Bootstrap methods: another look at the jackknife.  Ann Stat. 1979;7(1):1-26
Link to Article
DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves.  Biometrics. 1988;44(3):837-845
PubMed   |  Link to Article
Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for breast cancer.  Ann Intern Med. 2009;151(10):727-737
PubMed   |  Link to Article
Schell MJ, Yankaskas BC, Ballard-Barbash R,  et al.  Evidence-based target recall rates for screening mammography.  Radiology. 2007;243(3):681-689
PubMed   |  Link to Article
Kriege M, Brekelmans CT, Boetes C,  et al; Dutch MRI Screening (MRISC) Study Group.  Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition.  Cancer. 2006;106(11):2318-2326
PubMed   |  Link to Article
Leach MO, Boggis CR, Dixon AK,  et al; MARIBS study group.  Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer.  Lancet. 2005;365(9473):1769-1778
PubMed   |  Link to Article
Warner E, Plewes DB, Hill KA,  et al.  Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.  JAMA. 2004;292(11):1317-1325
PubMed   |  Link to Article
Saslow D, Boetes C, Burke W,  et al; American Cancer Society Breast Cancer Advisory Group.  American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.  CA Cancer J Clin. 2007;57(2):75-89
PubMed   |  Link to Article
Berg WA. Tailored supplemental screening for breast cancer.  AJR Am J Roentgenol. 2009;192(2):390-399
PubMed   |  Link to Article
Brennan ME, Houssami N, Lord S,  et al.  Magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer.  J Clin Oncol. 2009;27(33):5640-5649
PubMed   |  Link to Article
Brennan S, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer.  AJR Am J Roentgenol. 2010;195(2):510-516
PubMed   |  Link to Article
Demartini WB, Kalish GM, Peacock S, Eby PR, Gutierrez RL, Lehman CD. Screening MRI for high risk women. Paper presented at: Radiologic Society of North America; November 28, 2010; Chicago, IL
Centers for Medicare & Medicaid Services.  Physician fee schedule search page. http://www.cms.gov/apps/physician-fee-schedule. Accessed March 9, 2012
Smith RA, Duffy SW, Gabe R, Tabar L, Yen AM, Chen TH. The randomized trials of breast cancer screening.  Radiol Clin North Am. 2004;42(5):793-806
PubMed   |  Link to Article
Ohuchi N, Ishida T, Kawai M,  et al.  Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40–49 (J-START).  Jpn J Clin Oncol. 2011;41(2):275-277
Link to Article
Sardanelli F, Podo F, Santoro F,  et al; High Breast Cancer Risk Italian 1 (HIBCRIT-1) Study.  Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study).  Invest Radiol. 2011;46(2):94-105
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 2. Outcomes of 3 Rounds of Annual Screening Mammography Plus Ultrasound
Graphic Jump Location

Outcomes of screening 2662 participants are detailed for mammography alone compared with integrated tests, mammography plus ultrasound, for each of the 3 screening years and also for 612 women in the MRI substudy compared with mammography alone or compared with integrated tests, mammography plus ultrasound, in year 3.

Place holder to copy figure label and caption
Figure 1. Flowchart of Protocol
Graphic Jump Location

Participants with negative results on both mammography and ultrasound were imputed as having negative results on integrated reading of mammography plus ultrasound: 1844 for the first screening, 1922 for the second screening, and 1912 for the third screening. The reference standard was the most severe of biopsy results within 365 days of mammographic screening, on clinical follow-up at 1 year, or both. Biopsies prompted by an early subsequent screening examination were attributed to that subsequent screen.

aAll participants in the magnetic resonance imaging (MRI) analysis set are also in the screen 3 analysis set.

Tables

Table Graphic Jump LocationTable 4. Screening Performance in 612 Participants Screened by Magnetic Resonance Imaging After 3 Annual Mammography and Ultrasound Screenings
Table Graphic Jump LocationTable 3. Screening Performance in 2662 Unique Participants Screened 3 Years With Mammography and Physician-Performed Ultrasound
Table Graphic Jump LocationTable 2. Summary of Cancer Detection and Characteristics for 2662 Unique Participants Screened 3 Years With Mammography and Physician-Performed Ultrasound and 612 Participants Screened With MRI in Year 3

References

Buchberger W, Niehoff A, Obrist P, DeKoekkoek-Doll P, Dünser M. Clinically and mammographically occult breast lesions: detection and classification with high-resolution sonography.  Semin Ultrasound CT MR. 2000;21(4):325-336
PubMed   |  Link to Article
Crystal P, Strano SD, Shcharynski S, Koretz MJ. Using sonography to screen women with mammographically dense breasts.  AJR Am J Roentgenol. 2003;181(1):177-182
PubMed   |  Link to Article
Gordon PB, Goldenberg SL. Malignant breast masses detected only by ultrasound.  Cancer. 1995;76(4):626-630
PubMed   |  Link to Article
Kaplan SS. Clinical utility of bilateral whole-breast US in the evaluation of women with dense breast tissue.  Radiology. 2001;221(3):641-649
PubMed   |  Link to Article
Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them.  Radiology. 2002;225(1):165-175
PubMed   |  Link to Article
Leconte I, Feger C, Galant C,  et al.  Mammography and subsequent whole-breast sonography of nonpalpable breast cancers: the importance of radiologic breast density.  AJR Am J Roentgenol. 2003;180(6):1675-1679
PubMed   |  Link to Article
Berg WA, Blume JD, Cormack JB,  et al; ACRIN 6666 Investigators.  Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer.  JAMA. 2008;299(18):2151-2163
PubMed   |  Link to Article
Corsetti V, Ferrari A, Ghirardi M,  et al.  Role of ultrasonography in detecting mammographically occult breast carcinoma in women with dense breasts.  Radiol Med. 2006;111(3):440-448
PubMed   |  Link to Article
Tohno E, Ueno E, Watanabe H. Ultrasound screening of breast cancer.  Breast Cancer. 2009;16(1):18-22
PubMed   |  Link to Article
Kuhl C, Weigel S, Schrading S,  et al.  Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer.  J Clin Oncol. 2010;28(9):1450-1457
PubMed   |  Link to Article
Kuhl CK, Schrading S, Leutner CC,  et al.  Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer.  J Clin Oncol. 2005;23(33):8469-8476
PubMed   |  Link to Article
Lehman CD, Isaacs C, Schnall MD,  et al.  Cancer yield of mammography, MR, and US in high-risk women.  Radiology. 2007;244(2):381-388
PubMed   |  Link to Article
Sardanelli F, Podo F, D’Agnolo G,  et al; High Breast Cancer Risk Italian Trial.  Multicenter comparative multimodality surveillance of women at genetic-familial high risk for breast cancer (HIBCRIT study).  Radiology. 2007;242(3):698-715
PubMed   |  Link to Article
D'Orsi CJ, Bassett LW, Berg WA,  et al.  Breast Imaging Reporting and Data System, BI-RADS: Mammography. 4th ed. Reston, VA: American College of Radiology; 2003
Berg WA, Blume JD, Adams AM,  et al.  Reasons women at elevated risk of breast cancer refuse breast MR imaging screening.  Radiology. 2010;254(1):79-87
PubMed   |  Link to Article
Mendelson EB, Baum JK, Berg WA, Merritt CRB, Rubin E. Breast Imaging Reporting and Data System, BI-RADS: Ultrasound. Reston, VA: American College of Radiology; 2003
Ikeda DM, Hylton NM, Kuhl CK.et al. Breast Imaging Reporting and Data System, BI-RADS: Magnetic Resonance Imaging. Reston, VA: American College of Radiology; 2003
Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. Hoboken, NJ: Wiley-Interscience; 2003
Efron B. Bootstrap methods: another look at the jackknife.  Ann Stat. 1979;7(1):1-26
Link to Article
DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves.  Biometrics. 1988;44(3):837-845
PubMed   |  Link to Article
Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L. Screening for breast cancer.  Ann Intern Med. 2009;151(10):727-737
PubMed   |  Link to Article
Schell MJ, Yankaskas BC, Ballard-Barbash R,  et al.  Evidence-based target recall rates for screening mammography.  Radiology. 2007;243(3):681-689
PubMed   |  Link to Article
Kriege M, Brekelmans CT, Boetes C,  et al; Dutch MRI Screening (MRISC) Study Group.  Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition.  Cancer. 2006;106(11):2318-2326
PubMed   |  Link to Article
Leach MO, Boggis CR, Dixon AK,  et al; MARIBS study group.  Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer.  Lancet. 2005;365(9473):1769-1778
PubMed   |  Link to Article
Warner E, Plewes DB, Hill KA,  et al.  Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.  JAMA. 2004;292(11):1317-1325
PubMed   |  Link to Article
Saslow D, Boetes C, Burke W,  et al; American Cancer Society Breast Cancer Advisory Group.  American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.  CA Cancer J Clin. 2007;57(2):75-89
PubMed   |  Link to Article
Berg WA. Tailored supplemental screening for breast cancer.  AJR Am J Roentgenol. 2009;192(2):390-399
PubMed   |  Link to Article
Brennan ME, Houssami N, Lord S,  et al.  Magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer.  J Clin Oncol. 2009;27(33):5640-5649
PubMed   |  Link to Article
Brennan S, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer.  AJR Am J Roentgenol. 2010;195(2):510-516
PubMed   |  Link to Article
Demartini WB, Kalish GM, Peacock S, Eby PR, Gutierrez RL, Lehman CD. Screening MRI for high risk women. Paper presented at: Radiologic Society of North America; November 28, 2010; Chicago, IL
Centers for Medicare & Medicaid Services.  Physician fee schedule search page. http://www.cms.gov/apps/physician-fee-schedule. Accessed March 9, 2012
Smith RA, Duffy SW, Gabe R, Tabar L, Yen AM, Chen TH. The randomized trials of breast cancer screening.  Radiol Clin North Am. 2004;42(5):793-806
PubMed   |  Link to Article
Ohuchi N, Ishida T, Kawai M,  et al.  Randomized controlled trial on effectiveness of ultrasonography screening for breast cancer in women aged 40–49 (J-START).  Jpn J Clin Oncol. 2011;41(2):275-277
Link to Article
Sardanelli F, Podo F, Santoro F,  et al; High Breast Cancer Risk Italian 1 (HIBCRIT-1) Study.  Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study).  Invest Radiol. 2011;46(2):94-105
PubMed   |  Link to Article

Letters

July 18, 2012
Tetsuji Fujita, MD
JAMA. 2012;308(3):236. doi:10.1001/jama.2012.7545.
July 18, 2012
Steven A. Narod, MD
JAMA. 2012;308(3):236. doi:10.1001/jama.2012.7547.
July 18, 2012
Wendie A. Berg, MD, PhD; Richard G. Barr, MD, PhD; Zheng Zhang, PhD
JAMA. 2012;308(3):236. doi:10.1001/jama.2012.7549.
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