Coverage Policy Manual
Policy #: 2011005
Category: Radiology
Initiated: March 2011
Last Review: August 2018
  Digital Breast Tomosynthesis

Description:
Digital breast tomosynthesis uses modified digital mammography equipment to obtain additional radiographic data that are used to reconstruct cross-sectional “slices” of breast tissue. Tomosynthesis may improve the accuracy of digital mammography by reducing problems caused by overlapping tissue. Tomosynthesis typically involves additional imaging time and radiation exposure, although a recently improved modification may change this.
 
Background
Conventional mammography produces two-dimensional (2D) images of the breast. Overlapping tissue on a 2D image can mask suspicious lesions or make benign tissue appear suspicious, particularly in women with dense breast tissue. As a result, women may be recalled for additional mammographic spot views. Inaccurate results may lead to unnecessary biopsies and emotional stress, or to a potential delay in diagnosis. The spot views are often used to evaluate microcalcifications, opacities or architectural distortions or to distinguish masses from overlapping tissue, as well as to view possible findings close to the chest wall or in the retro-areolar area behind the nipple (Tagliafico, 2012). The National Cancer Institute (NCI) reports that approximately 20% of cancers are missed at mammography screening (NCI, 2012). Average recall rates are approximately 10%, with an average cancer detection rate of 4.7 per 1,000 screening mammography examinations (Rosenberg, 2006).  The Mammography Quality Standards Act audit guidelines anticipate 2-10 cancers detected per 1,000 screening mammograms (Brandt, 2013). Interval cancers, which are detected between screenings, tend to have poorer prognoses (Shen, 2005).
 
Digital breast tomosynthesis was developed to improve the accuracy of mammography by capturing three-dimensional (3D) images of the breast, further clarifying areas of overlapping tissue. Developers proposed that its use would result in increased sensitivity and specificity, as well as fewer recalls due to inconclusive results (Smith, 2008). Digital breast tomosynthesis produces a 3D image by taking multiple low-dose images per view along an arc over the breast. During breast tomosynthesis, the compressed breast remains stationary while the x-ray tube moves approximately 1 degree for each image in a 15-50 degree arc, acquiring 11-49 images (Alakhras, 2013). These images are projected as cross-sectional “slices” of the breast, with each slice typically 1-mm thick. Adding breast tomosynthesis takes about 10 seconds per view. In one study in a research setting, the mean time to interpret the results was 1.22 (standard deviation [SD]=1.15) minutes for digital mammography and 2.39 (SD=1.65) for combined digital mammography and breast tomosynthesis (Gur, 2009).
 
With conventional 2D mammography, breast compression helps decrease tissue overlap and improve visibility. By reducing problems with overlapping tissue, compression with breast tomosynthesis may be reduced by up to 50%. This change could result in improved patient satisfaction (Alakhras, 2013).
 
A machine equipped with breast tomosynthesis can perform 2D digital mammography, 3D digital mammography, or a combination of both 2D and 3D mammography during a single compression. The radiation exposure from tomosynthesis is roughly equivalent to a mammogram. Therefore, adding tomosynthesis to mammography doubles the radiation dose, although it still is below the maximum allowable dose established in the U.S. Mammography Quality Standards Act.
 
Studies typically compare one- or more commonly, two-view breast tomosynthesis alone or combined with standard 2D mammography to standard 2D mammography alone. The assessment focuses on two-view tomosynthesis. According to the FDA Radiological Devices Panel, which reviewed this new modality: “2D [full-field digital mammography] plus a single [digital breast tomosynthesis] view (3D MLO) could be another exam option, but the full 2-view [digital breast tomosynthesis] protocol (MLO [mediolateral oblique view] and CC [cranio-caudal view]) would be recommended” (FDA, 2011).
 
In May 2013, the FDA approved new tomosynthesis software that will permit creation of a 2D image (called C view) from the tomosynthesis images (Hologic, 2013).  As a result, the 2D mammography may become unnecessary, thereby lowering the radiation dose. In other words, only the tomosynthesis procedure will be needed and both 2D and 3D images will be created from them. It is too early to gauge how traditional mammography plus tomosynthesis compares to the C view plus 3D images. The study submitted to the FDA was a noninferiority trial that compared the combined C view and 3D reconstruction to digital tomosynthesis alone, so it does not provide information on the comparison of greater interest.
 
Regulatory Status
The Selenia® Dimensions® 3D System manufactured by Hologic, Inc. achieved U.S. Food and Drug Administration (FDA) approval on February 11, 2011 through the premarket application (PMA) approval process. It is currently the only tomosynthesis system with FDA approval on the market. This system is a software and hardware upgrade of the Selenia Dimensions 2D full-field digital mammography system, which the FDA approved in 2008. Facilities using a digital breast tomosynthesis system must apply to the FDA for a certificate extension covering the use of the breast tomosynthesis portion of the unit. The Mammography Quality Standards Act requires the interpreting physicians, radiologic technologists, and medical physicists to complete 8 hours of digital breast tomosynthesis training and mandates a detailed mammography equipment evaluation prior to use. In May 2013, the FDA also approved Hologic's C-View 2D imaging software. This software is used to create 2D images from the tomosynthesis results, rather than performing a separate mammogram.
 
Several other manufacturers are working toward FDA approval of their digital breast tomosynthesis systems. GE Healthcare is seeking FDA PMA for breast tomosynthesis, specifically as an add-on option for the Senographe™ Essential mammography device. The FDA has agreed to a modular PMA submission, which means that GE Healthcare will submit the request in different sections. The first of 4 sections was submitted in November 2011. Three completed trials sponsored by GE are listed at online site clinicaltrials.gov. They focus on the use of breast tomosynthesis in routine screening (NCT00535678), in women undergoing diagnostic mammography (NCT00535327), and in women referred for breast biopsy (NCT00535184). The results do not appear to have been published to date.
 
Coding
At this time, there are no specific CPT codes for this testing. The testing would be reported with the appropriate breast mammography code (77055-77057 or G0202-G0206) along with an unlisted code (e.g., 76499) for the additional views.
  

Policy/
Coverage:
Effective August 2017
For health plans insured or administered by Arkansas Blue Cross and Blue Shield or its affiliates that are not subject to Arkansas Act 708 of 2017, codified as A.C.A. §23-79-140, digital breast tomosynthesis in the screening or diagnosis of breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness because this technology is currently being studied in clinical trials (NCT01091545, NCT00723541); OR for those members with contracts without primary coverage criteria, digital breast tomosynthesis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.
 
However, beginning August 1, 2017 individual and group insurance policies and HMO contracts, Arkansas Blue Cross and Health Advantage will cover and administer benefits for digital breast tomosynthesis (DBT) in accordance with Arkansas Act 708 of 2017, codified at A.C.A. §23-79-140, enacted by the General Assembly of the State of Arkansas which mandates coverage both for screening and diagnosis.
 
Effective Prior to August 2017
Digital breast tomosynthesis in the screening or diagnosis of breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness because this technology is currently being studied in clinical trials (NCT01091545, NCT00723541, NCT00721435).
 
For contracts without primary coverage criteria, digital breast tomosynthesis is considered investigational.  Investigational services are contract exclusions in most member benefit certificates of coverage.
 

Rationale:
The premarket approval (PMA) by the FDA was based on review of two multi-reader case studies supported by the sponsor, Reader 1 and Reader 2, and a separate publication referred to as the Pittsburgh study. The studies varied in the number of tomosynthesis views that were used (one or two). The studies were enriched, in that additional cases of patients with cancer were added to the study population. Radiologists knew or learned that the case set is highly enriched with cancer cases. These were not prospective evaluations of this technology in a clinical setting.
 
This study compared the accuracy of 2-view 2D FFDM with the 2-view 2D FFDM supplemented by 2-view 3D digital breast tomosynthesis. The study involved interpretation of a sample of 312 sets of images, 222 from a screening group and 90 (29%) from a biopsy group. Of the cases in the study, 48 (15%) had biopsy-proven cancer; 5 cancers were from the screening group and 43 were from the biopsy group; 16 were DCIS only and 32 cancers were invasive. Images for the screening patients were selected randomly from a larger cohort of 1083 subjects. This interpretation was not done as part of clinical care. In addition, copies of prior studies were not available to the readers. Fourteen radiologists participated in this study. However, only the results of the 12 radiologists who successfully completed the reader training were included in the analysis (2 did not complete training). The 12 readers, included: 5 highly experienced, 2 experienced, and 5 less experienced radiologists.
 
Scores were compiled for each reader for each of the 312 sets of images. For all readers, using ROC (receiver-operator characteristics) analysis, the AUC (area under the curve) was superior with 2D plus 3D imaging (i.e., FFDM plus DT) compared with 2D (i.e., FFDM) alone. The average increase in AUC was 0.072 (95% confidence interval [CI]: 0.037 to 0.107, p=0.0001) using the measure “probability of malignancy.”
 
Estimates of sensitivity and specificity were calculated based on “forced BIRADS” scores. Using BIRADS 3, 4, or 5 as positive, the sensitivity increased 8.0% (from 70.8% to 78.8%) and specificity increased 8.7% (from 76.9% to 85.6%) with the addition of the 3D tomosynthesis images. Using BIRADS 4 or 5 as positive, sensitivity increased 10.7 % (65.5% to 76.2%) and specificity increased 5.1% (84.1% to 89.2%). Improvements with use of 3D images were more modest in patients with calcifications; this occurred in 83 of the study patients.
 
There was a significant reduction in the recall rate among the screening cases. For screening cases the recall rate decreased from 51.5% with 2D to 12.9% with 2D plus 3D.
 
Reader Study 2
Reader Study 2 was conducted in response to deficiencies noted from the FDA.  In particular, the results of Reader Study 2 were provided to support a lower dose tomosynthesis protocol (i.e., 2D plus one 3D-view, the 3D MLO image) as well as to address concerns with the reader scoring methodology (identification of the correct location of a malignant lesion was not required for crediting readers with a true positive result). Reader Study 2 used new readers and a new random selection of only non-cancer cases. Reader Study 2 reused the cancer cases from Reader Study 1 with the addition of three more cancers. This again represented an enriched sample of cases.
 
The study involved interpretation of a sample of images from 310 cases, 220 selected from a screening group and 90 (29%) from a biopsy group. In this set there were 51 cases with cancer. Images for these patients were selected randomly from a larger cohort of 1083 subjects. Again, this interpretation was not done as part of clinical care. In addition, copies of prior studies were not available to the readers. Fifteen new radiologists (5 highly experienced, 6 experienced, and 4 less experienced) were used in this study. Readers received additional 3D training based on the types of errors made during Reader Study 1. In Reader Study 1, the readers were trained not to dismiss lobulated masses even if they were circumscribed; however, based upon review of the dismissed cancer cases approximately half of the readers did not adhere to that. In Reader Study 2, the readers were again trained not to dismiss lobulated circumscribed masses and their training was reinforced in written format and with further examples.
This study compared the accuracy of 2-view 2D FFDM with the 2-view 2D FFDM supplemented by 1-view 3D digital breast tomosynthesis (MLO-view) and with 2-view 3D digital breast tomosynthesis (as in Reader Study 1).
 
For ROC-AUC results, the best reader performance was achieved when using 2D plus 3D (all views). The lower dose 2D plus 3D MLO option was also superior to 2D alone. The following are the results using the probability of malignancy scores; the 2D plus 3D mode was superior to 2D alone; ROC AUC improved by 0.068 (95% CI 0.041 to 0.095); the 2D plus 3D MLO mode was superior to 2D alone; ROC AUC improved by 0.036 (95% CI 0.009 to 0.063); the 2D plus 3D mode was superior to 2D plus 3D MLO; ROC AUC improved by 0.032 (95% CI 0.005 to 0.059). These differences were all statistically significant with p-value <0.025.
 
For Reader Study 2, when taking BIRADS 3, 4, or 5 as positive, the sensitivity increased 12.0% and specificity increased 1.7% when comparing 2D plus 3D with using 2D alone. For Reader Study 2, when BIRADS scores of 4 and 5 were considered positive, the sensitivities for the 3 groups were 62.7%, 71.4%, and 78.7% for 2D, 2D plus MLO, and 2D plus 3D, respectively. (Presumably the analysis for Study 2 was based on 51 cancers.) Specificities for the 3 groups were 86.2%, 86.0%, 84.5%, respectively.
 
Again, the recall rate decreased for the screening group with use of the 3D digital breast tomosynthesis, dropping from 44.2% to 24.0%.
 
Pittsburgh Reader Study
As part of the PMA process, the company (sponsor) also submitted a research study performed by the University of Pittsburgh (Gur, 2009). The study was felt to be relevant to the review, but it was not designed or intended for the PMA submission. The study used different cancer cases than Reader Study 1 and Reader Study 2 above.
 
In this study, 8 readers read 125 cases in each of four display conditions: 2-view FFDM alone, 11 low-dose projections, reconstructed digital breast tomosynthesis images (MLO and CC), and a combined display mode of FFDM and digital breast tomosynthesis images. The cases were read in four reading sessions separated by at least one month. A single mode was used in each reading session. Two readers initially read by FFDM alone, two readers began with the frames, two readers began with the digital breast tomosynthesis images, and two readers began with the combined FFDM and tomosynthesis display. This also was an enriched case sample, with 35 of 125 cases (28%) having cancer.
 
Consistent with the two prior studies, this study also showed that ROC AUC increased with use of 3D tomosynthesis. This study also showed a decrease in the recall rate around 12 percentage points for non-cancer patients, a smaller reduction than noted in the other two studies.
 
Other Studies/Literature
The literature review (through January 2011) identified other studies which were comparisons made between FFDM with and without DBT. Some of these studies had results similar to those described above. In others, there was no change in the sensitivity for detecting breast cancer.
 
Radiation Dose
The Executive Summary of the FDA Advisory Panel Meeting (September 2010) included information about radiation dosage. The Mammography Quality Standards Act (MQSA) states: “The average glandular dose delivered during a single craniocaudal view of an FDA-accepted phantom simulating a standard breast shall not exceed 3.0 milligray (mGy) (0.3 rad) per exposure.”[21 CFR 900.12(e)(5)(vi)] The total dose for both the 2D FFDM and 3D DBT was measured using an ACR breast phantom that simulates a 4.2 cm thick, 50% fat / 50% glandular equivalent compressed breast. The total dose to the phantom for the 2D plus 3D (4-views total) is approximately 5 mGy. The total dose to the phantom for the 2D plus 3D MLO (3-views total) in Reader Study 2 is approximately 3.5 mGy. The total dose for 2-D alone (2-view FFDM) is approximately 2.0 mGy.
 
Summary
There are no studies currently published that provide adequate information about outcomes (sensitivity, specificity, accuracy, recall rate) when DBT is used in clinical practice. This contrasts to other breast imaging technologies such as computer aided detection (CAD) and full-field digital mammography (FFDM) where large clinical studies have demonstrated effectiveness in clinical care. The reader studies described here should be viewed as hypothesis-generating. There also are concerns about determining the impact on recall rates when studies with enriched numbers of cancers are used.
 
In addition, there still seem to be open questions about the number of DBT views that are needed. A related question is how the impact of using additional views from standard mammography would compare with the impact from digital breast tomosynthesis. Questions also still remain about the impact of calcifications on interpretation. Finally, more information is needed about the learning curve regarding interpretation of these studies. (Two of 14 radiologists were not able to participate in Reading Study 1.)
 
In summary, Studies of outcomes (including accuracy and recall rate) with use in clinical practice are needed. In addition, there are unanswered questions about the number of images needed as well as concerns about radiation dose and time for interpretation.
 
2012 Update
A search of the MEDLINE database was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key literature identified.
 
Gennaro and colleagues reported on a study of 200 women from Italy who had at least one breast lesion discovered by mammography and/or ultrasound classified as doubtful or suspicious or probably malignant (Gennaro, 2010). The patients underwent tomosynthesis with one view (mediolateral oblique [MLO]) of both breasts at a radiation dose noted to be comparable to that of standard screen-film mammography in 2 views (craniocaudal [CC] and MLO). They used a prototype tomosynthesis system by GE Healthcare that is not FDA-approved as of June 2012. Images were rated by 6 breast radiologists using the breast imaging reporting and data system (BIRADS) score. Ratings were compared with the truth established according to the standard of care. A multiple-reader multiple-case (MRMC) receiver-operating characteristic (ROC) analysis was performed. Clinical performance of digital breast tomosynthesis (DBT) compared with that of FFDM (digital mammography) was evaluated in terms of the difference between areas under ROC curves (AUCs) for BIRADS scores. Overall clinical performance with DBT and FFDM for malignant versus all other cases was not significantly different (AUCs 0.851 vs. 0.836, p=0.645). The authors concluded that the clinical performance of tomosynthesis in 1 view at the same total dose as standard screen-film mammography is not inferior to digital mammography in 2 views. Another study used a digital tomosynthesis prototype developed by Siemens, which is not FDA-approved, to compared single-view tomosynthesis and 2-view mammography (Svahn, 2012). The researchers reported that the sensitivity using tomosynthesis was statistically significantly higher than for mammography, but there was no statistically significant difference in the specificity, which varied across readers.
 
In another study from Europe, Teertstra et al.evaluated mammography and tomosynthesis in 513 women with an abnormal screening mammogram or with clinical symptoms (Teertstra, 2010). The tomosynthesis was performed using prototype equipment by Hologic, which manufacturers the mammography/tomosynthesis equipment the FDA approved for marketing. Cases were prospectively classified according to the American College of Radiology (ACR) BI-RADS criteria. In 112 newly detected cancers, tomosynthesis and mammography were each false-negative in 8 cases (7%). In 3 patients, both mammography and tomosynthesis missed detecting the carcinoma. The sensitivity of both techniques for the detection of breast cancer was 92.9%, and the specificity of mammography and tomosynthesis was 86.1 and 84.4%, respectively. The authors noted that tomosynthesis can be used as an additional technique to mammography in patients referred with an abnormal screening mammogram or with clinical symptoms. They also comment that the additional lesions detected by tomosynthesis are also likely to be detected by other techniques used in the clinical work-up of these patients.
 
In a retrospective European study by Wallis et al., ten experienced mammography readers read mammograms and tomosynthesis results for women with breast density of 2-4 (using ACR criteria) who had breast symptoms or were recalled after routine screening (Wallis, 2012). Of the 130 women, 64 had abnormal images, 40 of which turned out to be malignant, and 66 had normal images. The reference standard was cytology or pathology reports or one-year follow-up. The tomosynthesis was performed on a device not approved by the FDA, and two of the authors are employees of the equipment’s manufacturer. The readers had a minimum of 2 hours of tomosynthesis training. Two-view mammography (film or digital) was compared to both single- and double-view tomosynthesis. Only the area under the receiver operator characteristic curve was reported. Subgroup analyses were performed (e.g., masses vs. calcifications and readers with >10 years of experience reading mammograms vs. <10 years). According to the authors, mammographers in Europe typically read a higher volume of mammograms than those in the U.S., and all of the readers would be considered high-volume readers. The researchers found that diagnostic performance was better for 2-view tomosynthesis than 2-view mammography (average area under the ROC curve [AUC]: 0.772 for mammography, 0.851 for 2 -view tomosynthesis; average difference: –0.078 [95% CI: –0.144, –0.0129], p=0.021). The result was similar among relatively less experienced readers (<10 years; AUC difference: –0.110 [95% CI: –0.204, –0.015], p=.03) but not among more experienced readers (> 10 years; AUC difference: –0.047 [95% CI: –0.135, 0.040], p=0.25)). For all other comparisons (e.g., single-view tomosynthesis vs. 2-view mammography, masses vs. calcifications) the difference in accuracy between tomosynthesis and mammography was not statistically significant. No statistical adjustment for multiple comparisons was reported. It took about twice as long for readers to review 2-view tomosynthesis results vs. mammography (124 seconds on average [range, 97-158 sec] vs. 67 seconds [range, 46-91 sec], respectively; 97 seconds [range, 73-136] for single-view tomosynthesis), but the readers were clearly much more experienced in reading mammograms. The precise location of the findings identified using each modality were not compared.
 
In a study from the U.K. in an unblinded clinical setting, Michel et al. reported on women recalled after routine screening (Michel, 2012). The reference standard was histology for women undergoing biopsy or surgery and clinical evaluation and other imaging results for women who did not. Film mammograms were read first, then with digital mammograms; and then breast tomosynthesis results were evaluated. Readers could change the thickness of the reconstructed section. The results are reported per lesion (n=792; 26.8% were malignant) rather than per person (n=738). The overall accuracy for breast tomosynthesis was increased compared to film and digital mammography. On AUC analysis the mean AUC was 0.7882+0.0198 [95% CI: 0.74945, 0.82702] for film mammography alone; 0.8949+0.0124 [95% CI: 0.87061, 0.91915] for combined film and digital mammography; and 0.9671+0.0050 [95% CI: 0.95732, 0.97683] for both types of mammography plus breast tomosynthesis. The difference in AUC between the 3 modalities, including tomosynthesis, and both types of mammography was 0.0722 (p=0.0001), and the difference in AUC between the 3 modalities and film mammography alone was 0.1789 (p=0.0001). However, it is not clear whether this accuracy applies to detection of lesions, or to detection of malignant lesions. The increased accuracy was limited to “soft-tissue” lesions (difference in AUC: 0.0704; p=0.0001) and not to microcalcifications (difference in AUC: 0.0077; p=0.3182). No difference across modalities was found based on breast density. No statistical adjustment for multiple comparisons was reported. Assuming that ratings of suspicion of malignancy of 3 (probably benign), 4 (suspicious), and 5 (malignant) using the rating system of the Royal College of Radiologists indicate malignancy, the sensitivity of film and digital mammography is 97.5%; the addition of breast tomosynthesis increases the sensitivity to 100%. The values for specificity are 51% and 74%, respectively, yielding positive predictive values of 42.3% and 58.8%, and negative predictive values of 98.3% and 100%, respectively. The use of rating 3 is open to question, given that it indicates that the finding is probably benign. The sensitivity is also reported using only rating 5 as an indication of malignancy, and the results are 39.7% for digital mammography and 58.3% for tomosynthesis. No statistical results were reported for these comparisons. The authors note the inherent bias in selecting the cases based on mammography, which is one of the modalities being compared. They state “[T]these potential improvements in specificity and sensitivity will need to be carefully examined in large-scale trials.”
 
Bernardi et al. compared recall rates using tomosynthesis and mammography in a population of 158 consecutive cases of women in Italy recalled for a diagnostic workup based on mammography results (Bernardi, 2012). Tomosynthesis was performed using an FDA-approved Selenia Dimensions unit. Before the diagnostic workup, radiologists reviewed the tomosynthesis results and indicated whether or not the workup was necessary or unnecessary. The reference standard was the diagnostic workup performed on all study patients; ultrasound and biopsy results were included when those procedures were used. Twenty-one of the women (13.2%) had confirmed carcinoma. The 7 radiologists involved in the study were experienced mammographers who took a short course on interpreting tomosynthesis results taught by one of the study authors. Based on the tomosynthesis results, the radiologists found recall to be unnecessary in 102 (64.5%) of the cases; the remainder were deemed necessary. The necessary cases included all 21 cancer cases, as well as 35 false-positive cases. All 102 cases deemed unnecessary had benign outcomes. The positive predictive value of using the tomosynthesis to identify cancer in this population was 37.5%. This study was intended to be exploratory, and the researchers note the need for further research, which is already under way in other studies.
 
In a retrospective study, Spangler et al. compared the performance of full-field digital mammography and digital breast tomosynthesis for detecting and characterizing calcifications (malignant and benign), using 100 paired cases (FFDM and tomosynthesis on the same patient) and 5 readers (Spangler, 2011). The cases included 20 biopsy-proven malignancies, 40 biopsy-proven non-cancer cases, and 40 randomly selected screening cases with normal results (i.e. a BIRADS rating of 1). The results yielded a sensitivity in detecting calcifications of 84% (95% CI: 79%, 88%) for FFDM and 75% (95% CI: 70%, 80%) for tomosynthesis. The specificity was 71% (95% CI: 64%, 77%) and 64% (95% CI: 56%, 70%), respectively. According to the authors, the FFDM results served as the reference standard. The difference in the area under the receiver operating characteristic (ROC) curve between the 2 modalities was not statistically significant (p=0.13). However, the tomosynthesis procedures were performed on a research system, which may not be FDA-approved. Also, the researchers note that the cases with positive findings were initially identified using FFDM, so the results are biased in favor of that modality. The readers were also able to determine the thickness of the reconstructed section, and the location of the findings identified for each modality were not compared.
 
Another study by Noroozian and colleagues compared the performance of tomosynthesis and spot views on mammography in characterizing masses as benign or malignant (Noroozian, 2012). The tomosynthesis was performed on a combined tomosynthesis and whole breast ultrasound research system developed with GE Global Research, which is not FDA-approved. The mammographic spot views included digital, analog, spot compression, and spot magnification. The initial sample was composed of 260 consecutive women who had undergone tomosynthesis and who were referred for an interventional procedure and had clinical diagnostic breast imaging findings with a BIRADS rating of 4 or 5. Cases with microcalcifications only were excluded (n=31), and a random sample of 108 benign cases were excluded to enrich the sample; 31 were excluded for other reasons. In selecting the cases from the resulting sample of 90, 20 were excluded because of issues with the tomosynthesis results, including truncated project artifacts (n=6), mass not included in field of view due to its location (n=13), and technical failure (n=1); 3 were excluded for other reasons. Four readers reviewed the results of mammographic spot views and tomosynthesis for 67 women with masses in random order. The readers had median breast imaging experience of 13.5 years (range, 3-20 yrs); one reader had no experience reading tomosynthesis, while the others had participated in another reader study. The reference standard was histopathologic results. Thirty (45%) of the masses were malignant. There was no statistically significant difference in the area under the ROC curve for the likelihood of malignancy (on a 12-point scale) between tomosynthesis and mammographic spot view results (average AUC: 0.91 for tomosynthesis and 0.90 for mammographic spot views; p=0.60 [95% CI: -0.7, 0.04]). The researchers note that wide confidence intervals indicate that the study had insufficient power. They also report that the readers would have recommended biopsy for 7 more cancers and 5 more benign lesions based on tomosynthesis versus mammographic spot views. Changes in recommendations for biopsy based on the 2 modalities were not statistically significant for any reader. However, all of these cases had been selected for an interventional procedure in the clinical setting.
 
Hendrick estimated the lifetime attributable risk (LAR) of fatal breast cancer associated with several types of breast imaging (Hendrix, 2010). Using an estimate of mean glandular dose for 2-view digital mammography of 3.7 mGy, the LAR is 1.7 fatal breast cancers per 100,000 women aged 40 at exposure and less than 1 fatal breast cancer per 1 million women aged 80 at exposure. For women screened annually between ages 40 and 80 with film or digital mammography, the LAR for fatal breast cancer is estimated to be 20-25 fatal breast cancers per 100,000. Most of the risk is associated with screening at younger ages in this range. Hendrick also estimates that the mean glandular dose and therefore the LAR for fatal breast cancer associated with digital breast tomosynthesis is one to two times that for mammography, depending on how many tomosynthesis views are used. The risk would also presumably vary depending on how tomosynthesis is used, e.g., as a substitute or add-on to screening or diagnostic mammography.
 
Ongoing Research
There are 12 ongoing research studies on breast tomosynthesis with an expected enrollment of more than 100 patients listed at online site clinical trials.gov (last accessed June 2012). Hologic, Inc., is listed as a collaborator on 4 of the 12 studies. Six of the studies have a target enrollment of more than 1,000 patients. They include
 
  • two studies of tomosynthesis versus mammography for routine screening (sponsor: Region Skane; n=15,000; NCT01091545; and sponsor: Oslo University Hospital; n=25,000; NCT01248546);
  • a comparison of tomosynthesis with mammography versus mammography alone in routine screening (sponsor: Case Comprehensive Cancer Center; n=12,000; NCT01593384);
  • two comparisons of recall rates of tomosynthesis with or without mammography to mammography alone (sponsor: Rose Imaging Specialists, P.A.; n=10,000; NCT01569802; and sponsor: University of Pittsburgh; n=1,080; NCT01106911); and
  • one study comparing tomosynthesis to mammography among women with histologically proven breast cancer, those with a history of treated cancer, or those with a detected anomaly requiring diagnosis (sponsor: Centre Oscar Lambret; n=1,172; NCT01612650).
 
Most of the other studies with sample sizes between 100 and 1,000 also examine the use of breast tomosynthesis in routine screening, including an ACRIN multicenter trial (sponsor: American College of Radiology Imaging Network [ACRIN]; n=550; NCT01236781), which has a particular focus on recall rates. One of the other studies focuses on its use in younger symptomatic women (sponsor: Liz Coote, NHS Tayside; n=200; NCT01241981); and another compares breast tomosynthesis reconstructed slice thickness of 1 mm versus 5 mm (sponsor: Emory University; n=180; NCT00957567). NCT01524029, a national multicenter trial sponsored by the Medical University of Vienna compares digital breast tomosynthesis to digital mammography. Another study on the use of tomosynthesis among women with a finding of BIRADS 3 (probably benign finding) has been completed, but the results apparently have not been published yet (sponsor: WellSpan Health; PI: Joanne Trapeni; n=690; NCT00763100). NCT00776126 has also been completed but not published. This trial compared digital breast tomosynthesis to digital mammography.
 
Four additional trials are listed that are examining new modalities that incorporate breast tomosynthesis, including the use of computer-aided detection (sponsor: University of Michigan; n=800; NCT00723541), contrast-enhanced mammography and contrast-enhanced tomosynthesis versus contrast-enhanced MRI (sponsor: Hologic, Inc.; n=70; NCT01433640); and a combined tomosynthesis and ultrasound device (sponsor: University of Michigan; n=260; NCT00721435).
 
2013 Update
A search of the MEDLINE database through September 2013 did not reveal any new information that would prompt a change in the coverage statement.
 
Two new studies addressed the use of mammography with or without digital breast tomosynthesis for screening. The strongest evidence for using mammography and breast tomosynthesis for screening women for breast cancer comes from the interim results of a large trial in Norway (Skaane, 2013).  The sample consisted of 12,621 women with 121 screening-detected cancers who underwent routine screening. The cancer detection rate was 6.1 per 1000 screenings for mammography alone and 8.0 per 1000 screenings for mammography plus digital breast tomosynthesis. After adjusting for reader differences, the ratio of cancer detection rates for mammography versus mammography plus breast tomosynthesis was 1.27 (98.5% confidence interval [CI]: 1.06 to 1.53; p=0.001). The authors note that they did not ascertain any improvement in detecting ductal carcinoma in situ (DCIS) by adding breast tomosynthesis; the additional cancers detected were largely invasive. The false-positive rate was 61.1 per 1,000 screenings for mammography alone and 53.1 per 1,000 screenings for mammography plus breast tomosynthesis. A reduction in the false-positive rate would decrease the number of women recalled after screening for additional imaging or biopsy. In Norway, as in much of Europe, women are screened every other year, and 2 readers independently interpret the images, which differs from usual practice in the U.S. After adjusting for differences across readers, the ratio of false-positive rates for mammography alone versus mammography plus breast tomosynthesis was 0.85 (98.5% CI: 0.76 to 0.96; p<0.001). The authors note that for this interim analysis, only limited data were available about interval cancers so they could not estimate “conventional absolute sensitivity and specificity.” Additional information will be available when the trial is completed.
 
The second study examined comparative cancer detection for traditional mammography with or without breast tomosynthesis in a general Italian, asymptomatic screening population of 7,292 women (Ciatto, 2013). The reference standard was pathology for women undergoing biopsies; women with negative results on both mammography and breast tomosynthesis were not followed up, so neither the sensitivity nor specificity could be calculated. Mammography plus breast tomosynthesis revealed all 59 cancers, while 20 of them were missed by traditional mammography (p<0.0001). The incremental cancer detection of using both modalities was 2.7 cancers per 1,000 screens (95% CI: 1.7 to 4.2). There were 395 false-positive results: 181 were false positive using either mammography or both imaging modalities together; an additional 141 occurred using mammography only and 73 occurred using mammography and breast tomosynthesis combined (p<0.0001). In preplanned analyses, the researcher found that the combined results of mammography and digital breast tomosynthesis yielded more cancers in both age groups (<60 versus >60 years) and breast density categories (1, least dense, and 2 versus 3 and 4, most dense).
 
Diagnosis: Six studies address the use of breast tomosynthesis in the diagnostic setting, i.e., if there are suspicious findings on screening mammography or if the woman is symptomatic. The studies vary considerably in the types of suspicious mammographic findings (e.g., calcifications versus noncalcifications); the patient population; and the comparators to breast tomosynthesis, e.g., two-view mammography, mammographic spot views, ultrasound. One study had a medium risk of bias; the remainder, a high risk of bias using the QUADAS-2 tool.
 
In a study of 158 women consecutively recalled after screening mammography, breast tomosynthesis was evaluated as a possible triage tool to reduce the number of false-positive results (Bernardi, 2012). The results of the diagnostic assessment (including ultrasound and needle biopsy where performed) were used as the reference standard. Breast tomosynthesis eliminated 102 of the 158 recalls, all of which were unnecessary (i.e., false-positive results on mammography). No cancers were missed on breast tomosynthesis. The performance of breast tomosynthesis did not vary by breast density or age group, but the reduction in recalls was greater for asymmetric densities and distortions, and nodular opacities with regular margins. The authors note that the decline in recall rates following the use of breast tomosynthesis was higher in this study than in blinded comparisons of digital mammography and breast tomosynthesis.
 
Another study compared the performance of mammographic spot views versus tomosynthesis among 52 consecutive recalled women with a BI-RADS rating on initial screening of 0 (which means “Need Additional Imaging Evaluation and/or Prior Mammograms for Comparison”) (Tagliafico, 2012). Women with calcifications were excluded. The study was designed as a noninferiority analysis for areas under the receiver operating characteristic (ROC) curve, sensitivity, and specificity, with a noninferiority margin of delta=0.05, so that if breast tomosynthesis were noninferior to mammographic spot views, breast tomosynthesis could be performed right after screening mammography to avoid a recall. The sensitivity and specificity were extremely high for both modalities, and there was no statistically significant difference between them.
 
A third study compared diagnostic mammography to breast tomosynthesis among women with abnormalities on screening mammography with no calcifications in a “simulated clinical setting” (Brandt, 2013). The breast tomosynthesis rating was based on both readers’ ratings and their confidence that no additional studies were needed, as well as ultrasound results in some cases. The reference standard was either the results of the entire clinical workup, including biopsy if performed, or follow-up for women not undergoing biopsy (86.1% of entire sample).There was not a statistically significant difference between diagnostic mammography and breast tomosynthesis in sensitivity or specificity.
 
Two of the these 3studies found no difference in sensitivity and specificity between breast tomosynthesis and a clinical workup that consisted of diagnostic mammographic images or a more comprehensive diagnostic work-up. The third study examined the use of breast tomosynthesis to triage women recalled after screening and substantially reduced the recall rate.
 
Another study evaluated 738 women with 759 lesions recalled after screening with film mammography. In this unblinded study, the incremental value of breast tomosynthesis added to film and digital mammography was assessed (Michell, 2012). The reference standard consisted of pathology results or follow-up for 18 to 36 months. Adding breast tomosynthesis to film and digital mammography results increased the area under the ROC curve from 0.895 (0.871-0.919) to 0.967 (0.957-0.977) (p=0.001). The complete sensitivity (counting ratings of 3-5 as positive) increased from 39.7% for digital mammography to 58.3% when breast tomosynthesis was added; no confidence intervals or p values were reported. The specificity increased from 51% to 74.2% when breast tomosynthesis was added to digital mammography. The difference in areas under the ROC curve after the addition of breast tomosynthesis was statistically significant for soft-tissue lesions, but not for microcalcifications.
 
One study compared diagnostic mammography images to dual-view breast tomosynthesis in 217 lesions (72 [33%] malignant) among 182 women (Zuley, 2013). In this retrospective study, women who had undergone diagnostic mammography and breast tomosynthesis were included. The sample included women with clinical symptoms such as a palpable lump, or findings on mammograms, ultrasound, or magnetic resonance imaging (MRI). Women with only calcifications were excluded. The area under the ROC curve for diagnostic mammography was 0.83 (95% CI: 0.77 to 0.83; range across readers = 0.74-0.87), while for tomosynthesis, it was 0.87 (95% CI: 0.82 to 0.92; range across readers = 0.80-0.92; p<0.001). .
 
The authors of the Norse trial also wrote another article on their initial experience with digital breast tomosynthesis in a clinical setting (Skaane, 2012).
 
This mixed set of articles provides evidence of either a similar diagnostic performance between breast tomosynthesis and other approaches or an advantage for breast tomosynthesis. The mixed patient populations, differences in references standard, use of different imaging tests to compare to breast tomosynthesis, and variations in follow-up make it difficult to draw a conclusion from these studies.
 
Conclusions
 
Screening: The Norse and Italian screening studies published in 2013 provide the strongest evidence available to date on the use of mammography plus digital breast tomosynthesis versus mammography alone for screening women for breast cancer. This evidence suggests that the use of the mammography plus breast tomosynthesis may modestly increase the number of cancers detected, while having a large impact on decreasing the number of women who undergo unnecessary recalls or biopsies. For example, the interim results of the Norway screening trial reported that the ratio of cancer detection rates per 1,000 screens for mammography versus mammography plus breast tomosynthesis was 1.27 (98.5% CI: 1.06 to 1.53; p=0.001). The ratio of false-positive rates for mammography alone versus mammography plus breast tomosynthesis was 0.85 (98.5% CI: 0.76 to 0.96; p<0.001). Even if adding breast tomosynthesis simply maintained the same sensitivity as for mammography, a decline in the false-positive rate would reduce the substantial number of unnecessary diagnostic work-ups in the U.S. and spare women the psychological stress these engender.
 
Completion of the Norse trial and additional studies are needed to confirm these findings, as well as studies that indicate whether the use of breast tomosynthesis should be targeted at certain subgroups, e.g., by age and breast density. The configuration of mammography and breast tomosynthesis used in these studies roughly doubled the radiation dose of mammography alone, but the exposure was still lower than the guideline established in the Mammography Standards and Quality Act. On May 20, 2013, the U.S. Food and Drug Administration approved new tomosynthesis software from Hologic that would create a 2d image from the tomosynthesis images and obviate the need for a separate mammogram. This approach would reduce the radiation dose of the combination, but studies are needed to compare its performance to traditional mammography plus breast tomosynthesis, since the study submitted to the FDA only compared C view and 3D tomosynthesis to tomosynthesis alone.
 
Diagnosis: The potential of digital breast tomosynthesis, as an addition to diagnostic mammography (such as spot views), is primarily to reduce the number of women who are biopsied by screening out some fraction of women with false-positive results. The body of evidence on the use of breast tomosynthesis to evaluate women who are recalled for a diagnostic work-up after a suspicious finding on screening mammography is weaker than that on adding breast tomosynthesis to mammography for screening. Confounding this analysis is the fact that diagnostic mammography is not the only imaging modality used during the diagnostic work-up. Ultrasound is also commonly used and less often, MRI. As a result, the study designs are more complicated in terms of how they incorporate ultrasound into the comparison between diagnostic mammography and breast tomosynthesis. A different research design would be needed to assess the incremental value of tomosysnthesis compared to the set of diagnostic tests currently used. In addition, some of the studies focused on one type of finding, e.g., masses versus calcification. They do not provide data on the accuracy of breast tomosynthesis for the full range of findings.
 
Ongoing Research
Digital breast tomosynthesis continues to be an active field of investigation. According to online site clinicaltrials.gov (http://clinicaltrials.gov/ct2/results?term=breast+tomosynthesis), there were 15 trials on breast tomosynthesis enrolling subjects and 7 that were active but not recruiting. All but 2 of the studies had sample sizes larger than 100, and 6 studies were larger than 1,000—e.g., studies had estimated sample sizes of 10,000 (NCT01569802); 15,000 (NCT01091545); and 25,000 (the study whose interim analysis is reported by Skaane et al; NCT01248546) (Skaane, 2013). A study comparing screening recall rates for digital mammography versus breast tomosynthesis is being conducted by the American College of Radiology Imaging Network (ACRIN) and has a sample size of 550 (NCT01236781). One large study with target enrollment of 12,000 was suspended due to funding unavailability (NCT01593384).
 
Several studies have also been conducted using different breast tomosynthesis equipment, including one using the Siemens Inspiration Digital Breast Tomosynthesis system (NCT01373671) and 3 completed studies sponsored by GE Healthcare that have not yet been published (NCT NCT00535184, NCT NCT00535327, NCT00535678).
 
Practice Guidelines and Position Statements
The American College of Radiology does not include digital breast tomosynthesis in its Appropriateness Criteria for breast imaging (available online at: http://www.acr.org/Quality-Safety/Appropriateness-Criteria/Diagnostic/Breast-Imaging). However, in a joint news release with the Society of Breast Imaging following the release of the interim analysis by Skaane et al., (Skaane, 2013) discussed below, the organizations stated that “While the study results are promising, they do not provide adequate information to define the role of tomosynthesis in clinical practice” (ACR, 2013). They also noted that while cancer detection was greater with tomosynthesis, it is not known whether the incremental benefit would be the same during a second round of screening. Furthermore, they note “[h]ow the technology will affect screening accuracy among women of different ages, risk profiles and parenchymal density is uncertain. In addition, how this technology would affect reader performance among U.S. radiologists with varying practice patterns and expertise is also uncertain. Other questions include whether computer aided detection will provide any further benefit, and if reconstructed images (presumably 2D) can be used, in lieu of standard full field digital images, to reduce radiation dose.”
 
In its practice bulletin on breast cancer screening, the American College of Obstetricians and Gynecologists notes that digital breast tomosynthesis is one of several screening techniques that were considered but not recommended for routine screening (ACOG, 2011). According to the National Comprehensive Cancer Network, “Early studies show promise for tomosynthesis mammography. Currently, there is insufficient evidence to recommend routine use for screening or diagnosis at this time” (NCCN, 2013).
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Lång and colleagues reported exploratory results from the first half of the Malmö Breast Tomosynthesis Screening Trial (MBTST) comparing 1-view DBT (lower radiation dose than digital mammography) (MLO) with 2-view digital mammography (DM). The MBTST is a 1-arm, single-institution, prospective study (Lang, 2015). Randomly selected women in Malmö, Sweden aged 40 to 74 years were offered 1-view DBT and 2-view DM. A sample size of 15,000 was specified to detect an improvement in cancer detection sensitivity from 63% to 88% (power of 80%); 7,500 were included in the exploratory analysis. In Sweden, breast cancer screening is offered every 18 months between ages 40 and 55 and biannually thereafter to age 74. The primary outcomes were cancer detection rates, recall rates, and positive predictive values. Six experienced readers interpreted images (mean 26 years experience, range 8 to 41). Blinded double reading was carried out for DBT and DM with rule-based arbitration for disagreements. Pathologic findings after abnormal imaging (additional DM, ultrasound, and indicated biopsy) were the basis for outcomes. Women in this exploratory analysis were followed at least 1 year for development of cancer ascertained through the South Swedish Cancer Registry. Of women invited, 71.1% participated with 20% undergoing their first screening test. Cancers were detected in 47 of the DM and 67 DBT studies (21 by DBT alone and 1 by DM alone; 46 by both modalities); detection rates were 8.9/1000 (95% CI, 4.6 to 8.3) for DBT and 6.3/1000 (95% CI, 4.6 to 8.3) for DM, p<0.001. DCIS detection rates were similar. Following arbitration, the recall rate was lower for DM (2.6%; 95% CI, 2.3 to 3.0) than following DBT (3.8%; 95% CI, 3.3 to 4.2), p <0.001. Positive predictive values were similar for both at 24%.
 
In these partial MBTST results, DBT achieved a higher cancer detection rate. In contrast to other studies recall rates were lower for digital mammography. Tomosynthesis-detected cancers were generally smaller, of lower grade, more often node negative, and women somewhat younger. Regarding this finding the authors noted, “It is not clear whether this represents earlier diagnosis and/or overdiagnosis from DBT screening, since the present study was not designed to address these issues.” Additionally, DBT-alone detected cancers tended to be in women with dense and fatty breasts. Although the results are preliminary, the authors concluded “...that one-view DBT may be feasible as a stand-alone technique for breast cancer screening.” The preliminary results include only half of the planned sample accrual with follow-up insufficient to assess interval cancer rates. Readers were highly experienced, and all studies read independently by 2 highly experienced readers. Final results will require consideration of broader applicability.
 
Cornford and colleagues compared the accuracy of tomosynthesis (GE) with supplementary 2 view mammographic views in the diagnosis of screen-detected abnormalities (Cornford, 2015). From 322 patients, 342 abnormalities were studied in a prospective analysis. Microcalcifications were uncommon (3.8%) owing to women not invited to participate if they were the main mammographic finding. Overall discrimination of the modalities was not statistically different (p=0.12) with AUCs of 0.946 (95% CI, 0.917 to 0.968) for tomosynthesis versus 0.922 (95% CI, 0.889 to 0.948).
 
The evidence for digital breast tomosynthesis for breast cancer screening in average risk women includes results from 3 studies in which women served as their own control, and observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy, test validity, change in disease status, and treatment-related morbidity. Norse and Italian screening studies published in 2013 provide the strongest evidence available to date on the use of mammography plus digital breast tomosynthesis (DBT) versus mammography alone for screening women for breast cancer. Partial results (50% of anticipated enrollment) from the Malmö Breast Tomosynthesis Screening Trial (MBTST) utilizing 1-view DBT offers similar evidence. In these studies, participants served as their own controls. This evidence suggests that use of mammography plus breast tomosynthesis may modestly increase the number of cancers detected, with a decrease in the number of women who undergo unnecessary recalls or biopsies. For example, in interim analysis of the Norse screening trial, the ratio of cancer detection rates per 1000 screens for mammography plus breast tomosynthesis versus mammography alone was 1.27 (98.5% confidence interval [CI], 1.06 to 1.53; p=0.001). The ratio of false-positive rates for mammography plus breast tomosynthesis versus mammography alone was 0.85 (98.5% CI, 0.76 to 0.96; p<0.001). Results from half the anticipated sample of the MBTST, demonstrated improved sensitivity with 1-view DBT, but not lower recall rates. A decrease in the false-positive rate would reduce unnecessary diagnostic workups and their consequences. However, the potential for overdiagnosis cannot be ascertained given the study designs. Interval cancer rates, which may provide useful evidence on overdiagnosis, are not yet available. Other studies were retrospective case reviews; patients had mixed or unclear indications for screening. More recently, prospective and large retrospective studies have reported cancer detection rates with reduced false recall rates. The nonrandomized designs lack long-term follow-up to assess false-negative results. Long-term effects of additional radiation exposure also are unknown. Adding tomosynthesis to mammography may increase the radiation dose depending on the specific equipment and protocols used, although it still is below the maximum allowable dose established in the U.S. Mammography Quality Standards Act. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
The evidence for digital breast tomosynthesis in women with abnormal findings on breast imaging or clinical exam includes multiple observational studies and one meta-analysis. Relevant outcomes are test accuracy, test validity, and treatment-related morbidity. Studies show either a similar diagnostic performance between breast tomosynthesis and other approaches or an advantage for breast tomosynthesis; 2-view DBT having better performance characteristics that single view DBT. Some concerns have been raised regarding classification of microcalcification clusters with DBT alone. Mixed patient populations, differences in references standard, use of different imaging tests to compare wit breast tomosynthesis, and variations in follow-up make it difficult to draw conclusions from these studies.
The evidence is insufficient to determine the effects of the technology on health outcomes.
 
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
DBT as an Adjunct to Mammography
 
Characteristics of Detected Cancers
Yun et al published a meta-analysis of the characteristics of cancers detected with DM alone vs DM plus DBT during routine breast cancer screening (Yun, 2017) Eleven studies were included in the meta-analysis, 4 prospective and 7 retrospective observational studies.  Reviewers evaluated study quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool and found an overall satisfactory risk of bias, but all studies had a high risk of bias concerning the reference standard as well as flow and timing because patients who were not recalled did not have a reference standard test.
 
In a pooled analysis, the overall cancer detection rate was significantly higher with DM plus DBT than with DM alone (relative risk [RR], 1.29; 95% CI, 1.16 to 1.43; I2=0%). Moreover, the detection of invasive cancer was significantly higher in the DM plus DBT group compared with DM-alone group (RR=1.33; 95% CI, 1.17 to 1.51; I2=7%). The rate of carcinoma in situ detection did not differ significantly between the DM plus DBT group and the DM-alone group (RR=1.20; 95% CI, 0.94 to 1.52; I2=29%). Fewer studies reported on cancer detection by T and/or N stage. In a pooled analysis of 5 studies, there was a significantly higher rate of detecting T1 cancers with DM plus DBT than with DM alone (RR=1.39; 95% CI, 1.14 to 1.70; I2=0%), but no significant difference for detecting stage T2 or larger cancer (RR=1.39l 95% CI, 0.90 to 2.16; I2=0%). Similarly, there was a significantly higher rate of detection of stage N0 cancers with DM plus DBT than with DM alone (RR=1.45; 95% CI, 1.21 to 1.74; I2=0%) and no significant difference in the detection of stage N1 or higher cancers (RR=1.34; 95% CI, 0.92 to 1.99; I2=0%). The numbers of more advanced cancers were relatively small, and the pooled analyses of T2 or higher, and N1 or higher cancers may have been underpowered. The findings of this meta-analysis were limited by the potential biases of the included studies (eg, many are retrospective and studies had insufficient confirmatory data on negative imaging results).
 
DBT Plus Synthesized 2D Mammography
 
Clinical Validity
In a single-center study published in 2016, Zuckerman et al compared the performance of DBT with s2D mammography to a historical control group that received DBT plus 2D mammography (Zuckerman, 2016). In the analysis, DBT with synthesized 2D mammography had a similar cancer detection as DBT with acquired mammography (5.03 per 1000 vs 5.45 per 1000, respectively) and a lower recall rate (8.8% vs 7.1%, respectively; p<0.001).
 
Aujero et al compared the diagnostic accuracy of s2D plus DBT, DBT-DM, and DM alone in a retrospective analysis of breast cancer screening data from a single institution in the United States (Aujero, 2017). The study took place during the institution’s transition from DM to DBT and then DBT plus synthesized 2D between 2011 and 2016. Single reading was done for mammography images. All DBT plus synthesized 2D images were acquired between 2015 and 2016 after radiologists had several years of experience with DBT and thus interpretation of those images may have been impacted by the learning curve effect. The cancer detection rate did not differ significantly among the 3 groups. The recall rates were significantly lower in both DBT groups compared with DM alone, and significantly lower in the DBT plus synthesized 2D group compared with the DBT plus DM group. The database used to collect study data did not include the reasons for recalls. Moreover, data on confirmation of negative findings using a reference standard test or long-term follow-up to assess false-negative results were not available.
 
A second single institution retrospective study was published by Freer et al, who reported on the diagnostic accuracy of synthesized 2D plus DBT, DBT plus DM, and DM alone for screening breast cancer (Freer, 2017). In this study, the cancer detection rate did not differ significantly between the DBT plus synthesized 2D and either of the other groups. The recall rate was significantly lower in the DBT plus s2D group than in the mammography alone group and was similar in the DBT plus synthesized 2D group and the DBT plus mammography groups. As with the Aujero study, data on confirmation of negative findings were not available.
 
Clinical Utility
Direct Evidence
There are is no direct evidence from trials comparing health outcomes in patients screened for breast cancer using DBT and mammography.
 
Chain of Evidence
Given that the utility of breast cancer screening with mammography has been established, a chain of evidence should demonstrate that DBT plus synthesized 2D is equivalent to screening performance of standard mammography alone. Available studies have reported that replacing mammography with DBT plus synthesized 2D might increase cancer detection and reduce recall rates. However, performance characteristics are uncertain due to limitations described above in the section on the clinical utility of DBT plus acquired mammography, and thus it is not possible to construct a chain of evidence
.
Section Summary: Screening With DBT Plus Synthesized 2D Mammography
One prospective and 3 retrospective studies assessed DBT plus synthesized 2D mammography, which has lower radiation exposure than DBT plus DM. Two studies found higher detection rates with DBT plus synthesized 2D compared with DM, one found similar detection rates with DBT plus synthesized 2D compared with DM, and one found similar detection rates with DBT plus synthesized 2D compared with DBT plus DM. When comparing the recall rate of DBT plus synthesized 2D with DM alone, the prospective study found a higher recall rate in the former, while the retrospective studies had mixed findings. However, the potential for over diagnosis cannot be ascertained because of the study designs, and interval cancer rates are not yet available. The nonrandomized designs lack long-term follow-up to assess false-negative results.
 
There is a lack of direct evidence on the clinical utility of DBT from screening trials comparing health outcomes in patients screened for breast cancer with DBT vs mammography. Due to limitations in the studies on diagnostic accuracy, it is not possible to construct a chain of evidence.
 
U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
In 2016, the U.S. Preventive Services Task Force (USPSTF) updated its recommendations on breast cancer screening (USOSTF, 2016). USPSTF recommended biennial screening mammography in women ages 50 to 74 years (grade B recommendation) and that the decision to start screening mammography before age 50 should be individualized (grade C recommendation).
 
For all women, USPSTF stated, “...the current evidence is insufficient to assess the benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer” (grade I recommendation). For women with dense breasts, USPSTF stated “…the current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using… DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram” (grade I recommendation).

CPT/HCPCS:
77061Digital breast tomosynthesis; unilateral
77062Digital breast tomosynthesis; bilateral
77063Screening digital breast tomosynthesis, bilateral (List separately in addition to code for primary procedure)
G0279Diagnostic digital breast tomosynthesis, unilateral or bilateral (List separately in addition to 77065 or 77067)

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