Digital Breast Tomosynthesis versus Digital Mammography for Detection of Early-Stage Cancers Stratified by Grade: A TOSYMA Subanalysis
Abstract
Background
Breast cancer screening with digital breast tomosynthesis (DBT) plus synthesized mammography (SM) increases invasive tumor detection compared with digital mammography (DM). However, it is not known how the prognostic characteristics of the cancers detected with the two screening approaches differ.
Purpose
To compare invasive breast cancers detected with DBT plus SM (test arm) versus DM (control arm) screening with regard to tumor stage, histologic grade, patient age, and breast density.
Materials and Methods
This exploratory subanalysis of the Tomosynthesis plus Synthesized Mammography (TOSYMA) study, which is a multicenter randomized controlled trial embedded in the German mammography screening program, recruited women aged 50–70 years from July 2018 to December 2020. It compared invasive cancer detection rates (iCDRs), rate differences, and odds ratios (ORs) between the arms stratified by Union for International Cancer Control (UICC) stage (I vs II–IV), histologic grade (1 vs 2 or 3), age group (50–59 vs 60–70 years), and Breast Imaging Reporting and Data System categories of breast density (A or B vs C or D).
Results
In total, 49 462 (median age, 57 years [IQR, 53–62 years]) and 49 669 (median age, 57 years [IQR, 53–62 years]) participants were allocated to DBT plus SM and DM screening, respectively. The iCDR of stage I tumors with DBT plus SM was 51.6 per 10 000 women (255 of 49 462) and with DM it was 30.0 per 10 000 women (149 of 49 669). DBT plus SM depicted more stage I tumors with grade 2 or 3 (166 of 49 462, 33.7 per 10 000 women) than DM (106 of 49 669, 21.3 per 10 000 women; rate difference, +12.3 per 10 000 women [95% CI: 0.3, 24.9]; OR, 1.6 [95% CI: 0.9, 2.7]). DBT plus SM achieved the highest iCDR of stage I tumors with grade 2 or 3 among women aged 60–70 years with dense breasts (41 of 7364, 55.4 per 10 000 women; rate difference, +21.6 per 10 000 women [95% CI: −21.1, 64.3]; OR, 1.6 [95% CI: 0.6, 4.5]).
Conclusion
DBT plus SM screening appears to lead to higher detection of early-stage invasive breast cancers of grade 2 or 3 than DM screening, with the highest rate among women aged 60–70 years with dense breasts.
Clinical trial registration no. NCT03377036
© RSNA, 2023
See also the editorial by Ha and Chang in this issue.
Summary
Digital breast tomosynthesis plus synthesized mammography screening showed higher detection rates for stage I breast cancers of grade 2 or 3 than digital mammography, particularly in women aged 60–70 years with dense breasts.
Key Results
■ In a subanalysis of 99 131 women from the randomized TOSYMA (Tomosynthesis plus Synthesized Mammography) trial, digital breast tomosynthesis (DBT) plus synthesized mammography (SM) helped detect more early-stage invasive breast cancers of histologic grade 2 or 3 (+12.2 per 10 000 women) than digital mammography.
■ DBT plus SM showed higher early-stage detection rates of grade 2 or 3 than of grade 1 cancer.
■ The highest detection rate for early-stage invasive breast cancers of grade 2 or 3 was achieved with DBT plus SM in women aged 60–70 years with dense breasts (55.4 per 10 000 women).
Introduction
Mammography screening is an effective tool for breast cancer mortality reduction; it reduces mortality by 22% among women invited to screening and by 33% among screening participants (1,2). As breast cancer is the leading cause of cancer-related mortality in women worldwide, the rationale for scientifically evaluating modified screening strategies is reasonable (3).
Compared with digital mammography (DM), digital breast tomosynthesis (DBT) reduces the likelihood of overlapping breast tissues that can radiologically conceal features of malignancy (4). The first phase of the German multicenter randomized controlled Tomosynthesis plus Synthesized Mammography (TOSYMA) screening trial (TOSYMA-1) found in women aged 50–70 years that the invasive cancer detection rate (iCDR) was significantly higher with DBT plus synthesized mammography (SM) (71 per 10 000 women screened) than with DM (48 per 10 000 women screened) (5). Subsequent exploratory analyses indicated that the iCDR was particularly increased in women aged 60–70 years with dense parenchyma (6). At present, clear evidence that DBT screening leads to benefits compared with DM screening, for example, by reducing breast cancer–specific mortality or lowering the incidence of interval cancers (ie, cancers occurring after a negative screening examination but before the next screening invitation) is still lacking in the literature (7–14).
In addition to long- and intermediate-term evaluations of the benefits of screening with DBT, a more timely evaluation based on early prognostic parameters of screen-detected cancers and assessment of how these relate to a woman’s individual characteristics, such as breast density and age, seems desirable.
The benefits of breast cancer screening result from the detection of small invasive tumors (1,2,15). Within the group of localized breast cancers of 20 mm or smaller, further prognostic differentiation is related to intrinsic factors such as the rate of cancer growth (16,17). Several studies have shown that histologic grade, an established indicator of tumor growth rate, is associated with patient outcomes (18–20). This prognostic significance is also reflected in the finding that early detection of grade 2 and 3 tumors reduced breast cancer–related mortality more than early detection of grade 1 tumors (relative rate among those screened vs those not screened, 0.68 and 0.65 vs 0.94, respectively) (20).
The present study is an exploratory subanalysis of the TOSYMA trial that aimed to compare screening with DBT plus SM versus DM with regard to the detection of early-stage invasive breast cancers, giving special consideration to histologic grade 2 or 3 cancers, and how detection is influenced by patient age and breast density.
Materials and Methods
Study Design
Recruitment for the multicenter, multivendor randomized controlled TOSYMA trial took place between July 2018 and December 2020. A total of 99 689 women underwent 1:1 randomization to DBT plus SM (test arm) or DM (control arm), both performed with the same imaging devices at 17 certified sites in the German mammography screening program (outpatient care). The protocol was approved by three ethics committees. Written informed consent was obtained from all participants (21).
The primary end point (iCDR) and four secondary end points (detection rate of cancers ≤ 20 mm, detection rate of ductal carcinoma in situ, recall rate, and positive predictive value of recall) of the TOSYMA trial have been reported (TOSYMA-1) (5). In addition, an exploratory analysis was published assessing the iCDR in relation to breast density (6).
Study Participants
Women aged 50–69 years and living in the catchment areas of TOSYMA sites received an invitation to participate in the trial with their biennial screening invitation letter. Due to time lags caused by the COVID-19 pandemic, women were up to 70 years of age at the time of screening. A previous breast cancer diagnosis within the past 5 years and a mammography examination within the past 12 months were exclusion criteria for mammography screening.
This subanalysis included 49 462 women allocated to DBT plus SM and 49 669 women allocated to DM; both arms had a median age of 57 years (IQR, 53–62 years). Breast implants and previous TOSYMA participation were trial-specific exclusion criteria. Subanalysis-specific exclusions comprised women with missing data for breast density assessment, missing data for screening results, and missing data for stage categorization as of September 2021 (Fig 1).
Figure 1: Flowchart shows randomized allocation of the Tomosynthesis plus Synthesized Mammography (TOSYMA) trial participants. DBT = digital breast tomosynthesis, DM = digital mammography, SM = synthetic mammography.
Imaging Procedures
Examinations in both arms included the craniocaudal and mediolateral oblique views of each breast. In the DBT plus SM arm, stacked sections of up to 1-mm thickness in addition to the synthesized mammograms were displayed for reading. Seven instruments from five vendors were used in the TOSYMA study (Table 1).
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Imaging Evaluations
Eighty-three readers (including S.W. and W.H.), each with experience reading more than 5000 screening mammograms per year, were involved (18 readers with 2–5 years of experience, 22 readers with 6–10 years of experience, and 43 readers with more than 10 years of experience). All readers participated in a training course at the Reference Center for Mammography Münster before the trial started. Readers were not blinded to imaging modality after retrieving the examination files from the digital storage systems.
Breast density for each participant was assessed independently by two readers using the Breast Imaging Reporting and Data System, or BI-RADS, categories, as follows: A, almost entirely fatty; B, scattered areas of fibroglandular density; C, heterogeneously dense; and D, extremely dense. If the two breasts differed, the denser category was recorded. If the categorization differed between the readers, the denser category was used. Categories A and B were considered “nondense,” and categories C and D were considered “dense” (22,23).
Histologic Assessment
Each of the 32 pathologists involved (all of them with at least 15 years of experience) made at least 100 screening diagnoses per year and attended a mandatory training course biennially in addition to following self-review procedures. The training (by T.D.) focused on the internationally recommended Nottingham grading system for invasive cancers (15,19,24), based on semiquantitative scoring of glandular differentiation, nuclear pleomorphism, and number of mitoses per square millimeter (G1, total score 3–5; G2, total score 6–7; G3, total score 8–9). Pathologists were not blinded to the trial arm as they had access to the screening software.
Outcome Parameters
The study outcome was the iCDR per 10 000 women screened. Based on medical records, cancers were staged according to the Union for International Cancer Control (UICC) TNM classification (25) using histologic results after surgery or imaging for participants receiving neoadjuvant treatment. In cases of multifocal or multicentric carcinomas, the largest tumor diameter was used for staging (25); in cases of bilateral breast cancers, the highest stage was used. UICC stage I is defined as tumor size up to 20 mm (T1), no axillary macrometastasis (pN0–pN1mi), and no distant metastasis (M0). Stage II+ encompasses the prognostically adverse UICC stages II, III, and IV (15,26). Women with stage I cancers were divided into groups based on tumors of histologic grade 1 versus grade 2 or 3. Age groups were 50–59 years and 60–70 years, and breast density groups were nondense (categories A and B) and dense (categories C and D).
Statistical Analyses
Descriptive analyses were performed, stratifying the iCDRs according to UICC stage, histologic grade, participant age, and breast density in each arm. Data are presented as absolute numbers of invasive breast cancers, iCDRs per 10 000 women screened, rate differences in the iCDR, and odds ratios (ORs) for detection of invasive breast cancer. Estimates are presented with Bonferroni-corrected 95% CIs. For calculating adjusted ORs of detection rates, we used generalized estimating equations to account for clustered data (correlation within centers), with a working correlation matrix with compound symmetry structure. The model included interaction terms for the study arm and subgroups of age and breast density.
The analyses were carried out by four authors (J.G., V.W.E., L.K., and H.W.H., with 19, 15, seven, and >30 years of experience, respectively). Analyses were performed using SAS version 9.4 (SAS Institute).
Results
Participant Characteristics
Of the 99 689 women randomized, 66 women who did not undergo either type of screening and 10 women who repeated TOSYMA participation were excluded from the analysis set. Specifically, for this subanalysis, women with missing data for breast density assessment (n = 317), screening results (n = 73), or stage categorization (n = 37) were excluded. Therefore, this exploratory subanalysis included 49 462 women allocated to DBT plus SM and 49 669 women allocated to DM (Fig 1).
For 8553 of 49 462 women (17.3%) in the DBT plus SM arm and 8610 of 49 669 women (17.3%) in the DM arm, this mammography screening was their first participation in the German mammography screening program; all others had participated in the screening program previously. Approximately two-thirds of the women in each study arm (30 766 and 30 910, respectively) were 50–59 years old (Table 2).
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Nondense (ie, categories A and B) and dense (ie, categories C and D) breasts were present in 26 758 and 22 704 women, respectively, screened with DBT plus SM and in 27 998 and 21 671 women screened with DM (Table 2).
Screen-detected Breast Cancers, Stratified by Stage and Grade
In the DM arm, the iCDR for UICC stage I tumors was 30.0 per 10 000 women screened (149 of 49 669) as compared with 51.6 per 10 000 women (255 of 49 462) in the DBT plus SM arm, yielding a difference in UICC stage I tumor detection rates between the study arms of +21.6 per 10 000 women (95% CI: 6.3, 36.9) (Table 3). UICC stage II+ invasive breast cancers were less often detected in both study arms and amounted to 71 cancers (14.3 per 10 000 women) in the DM arm and 82 cancers (16.6 per 10 000 women) in the DBT plus SM arm, yielding a rate difference of +2.3 per 10 000 women (95% CI: −7.2, 11.8) (Table 3).
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In both study arms, the iCDRs were highest for UICC stage I grade 2 or 3 tumors: 33.7 per 10 000 women (166 of 49 462) in the DBT plus SM arm and 21.3 per 10 000 women (106 of 49 669) in the DM arm, corresponding to a rate difference of +12.3 per 10 000 women (95% CI: 0.3, 24.9) and an OR of 1.6 (95% CI: 0.9, 2.7). By comparison, the iCDRs for UICC stage I grade 1 tumors were lower (18.0 [89 of 49 462] and 8.7 [43 of 49 669] per 10 000 women, respectively), corresponding to a rate difference of +9.3 per 10 000 women (95% CI: 0.5, 18.3) with DBT plus SM versus DM and an OR of 2.1 (95% CI: 1.2, 3.8) (Table 3).
Screen-detected Breast Cancers of UICC Stage I Stratified by Grade, Participant Age, and Breast Density
In age group–stratified analyses, the iCDR of UICC stage I tumors of grade 2 or 3 was highest for women aged 60–70 years (47.4 per 10 000 women, 89 of 18 700) in the DBT plus SM arm, which corresponded to a rate difference of +19.8 per 10 000 women (95% CI: −4.2, 43.9) compared with the DM arm and an OR of 1.6 (95% CI: 0.9, 3.1) (Table 4). The iCDR for DBT plus SM was lower in the age group 50–59 years (24.9 per 10 000 women, 77 of 30 822), corresponding to a rate difference compared with DM of +7.5 per 10 000 women (95% CI: −6.6, 21.6) and an OR of 1.4 (95% CI: 0.6, 3.0).
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Stratifying by breast density, the iCDR of UICC stage I cancers of grade 2 or 3 was highest in women with dense breasts screened with DBT plus SM (37.0 per 10 000 women, 84 of 22 605), corresponding to a rate difference compared with DM of +14.9 per 10 000 women (95% CI: −4.7, 34.6) and an OR of 1.7 (95% CI: 0.9, 3.2). In women with nondense breasts, the iCDR of UICC stage I tumors of grade 2 or 3 with DBT plus SM was 30.6 per 10 000 women (82 of 26 681), corresponding to a rate difference compared with DM of +10.0 per 10 000 women (95% CI: −6.6, 26.5) and an OR of 1.3 (95% CI: 0.7, 2.5) (Table 4, Fig 2).
Figure 2: Screen-detected invasive breast cancer in the dense breast tissue of a 59-year-old woman. A section in the mediolateral oblique view from a digital breast tomosynthesis examination of the left breast depicts an irregular mass with surrounding architectural distortion (circle). The participant had no history of breast cancer and had been screened previously in the German mammography screening program. Histologic analysis showed invasive carcinoma of no special type, grade 2, with tumor size of 18 mm.
Combining the stratification by age group and breast density, the highest iCDR of UICC stage I grade 2 or 3 tumors was seen in women aged 60–70 years with dense breasts when screened with DBT plus SM (55.4 per 10 000 women, 41 of 7364), corresponding to a rate difference compared with DM of +21.6 per 10 000 women (95% CI: −21.1, 64.3) and an OR of 1.6 (95% CI: 0.6, 4.5). The iCDR for UICC stage I grade 2 or 3 tumors in the older age group of women who had nondense breasts was slightly higher when screened with DBT plus SM (42.5 per 10 000 women, 48 of 11 238), and the corresponding rate difference was +18.7 per 10 000 women (95% CI: −10.6, 48.0), resulting in an OR of 1.7 (95% CI: 0.8, 3.8) (Table 4).
In each combination of age group and breast density category and in each screening arm, the detection rates of UICC stage I grade 1 tumors were generally lower than those of UICC stage I grade 2 and 3 tumors. Yet, the iCDRs of UICC I grade 1 cancers were consistently higher with DBT plus SM than with DM (Table 4, Fig 3).
Figure 3: Detection rates of Union for International Cancer Control (UICC) stage I breast cancers stratified by histologic grade (G), participant age, breast density category, and trial arm. Stage I is defined as tumor size up to 20 mm (T1), no axillary macrometastasis (pN0–pN1mi), and no distant metastasis (M0). Breast density categories are according to the Breast Imaging Reporting and Data System, or BI-RADS, 5th edition: A, almost entirely fatty; B, scattered areas of fibroglandular density; C, heterogeneously dense (which may obscure small masses); and D, extremely dense (which lowers the sensitivity of mammography). In this analysis categories A and B were combined (ie, nondense), and categories C and D were combined (ie, dense). DBT = digital breast tomosynthesis, DM = digital mammography, SM = synthetic mammography.
Discussion
Long-term results on the benefit of digital breast tomosynthesis (DBT) versus digital mammography (DM) in mammography screening do not exist. The present exploratory analyses of the randomized Tomosynthesis plus Synthesized Mammography (TOSYMA) trial specifically focused on the detection rates of early-stage invasive breast cancers (Union for International Cancer Control stage I) that were characterized as histologic grade 2 or 3, prognostically more aggressive grades than grade 1. Rates were compared in 99 131 women screened with either DBT plus synthesized mammography or with DM, additionally accounting for patient age and breast density.
We found that the detection rate of UICC I grade 2 or 3 cancers was generally higher in women screened with DBT plus SM than in women screened with DM (+12.3 per 10 000 women). Of note, the iCDRs with DBT plus SM were strongly raised compared to DM in older women (aged 60–70 years; rate difference, +19.8 per 10 000 women) and in women with dense breasts (Breast Imaging Reporting and Data System category C or D; rate difference, +14.9 per 10 000 women), and older women with dense breasts showed the highest rate difference: +21.6 per 10 000 women screened.
This finding is relevant as previous studies revealed that in particular the histologic grade of invasive breast cancers detected at screening is an independent predictor of breast cancer mortality reduction (18–20). This analysis appears to further confirm that screening with DBT plus SM not only increases the overall detection rate of early breast cancers (5), but also raises the early detection of prognostically adverse cancers with histologic grade 2 or 3 at an early stage (27).
This exploratory analysis suggests that the rates of screen-detected cancers of UICC stage I grade 2 or 3 surpass those of less progressive cancers of grade 1. Increased detection of ductal carcinoma in situ and invasive breast cancers of grade 1 with screening programs might especially enhance overdiagnosis, that is, the detection of cancers that never would have progressed to symptoms or life-threatening disease (28,29). As previously reported for the TOSYMA trial, the study arms had comparable recall rates (DBT plus SM, 4.9%; DM, 5.1%), and the detection rate of ductal carcinoma in situ did not notably differ between the arms for all breast density categories (5,6). The present subanalysis showed a higher rate of UICC stage I grade 1 cancer detection with DBT plus SM than with DM. However, the absolute rates and the absolute differences in rates between the screening arms were consistently higher for the more aggressive grade 2 and 3 cancers than for the less aggressive grade 1 cancers for all the women as well as for the age- and breast density–related strata. The TOSYMA trial now adds information on prognostic features, suggesting that in the test arm, the higher iCDR in women aged 60–70 years and with dense breasts was predominantly based on the detection of more relevant grade 2 or 3 cancers rather than grade 1 cancers (30,31). Thus, the detection of cancers suggestive of potential overdiagnosis increased with DBT plus SM but reached a lower detection level than that of the grade 2 or 3 tumors. These results are in line with the findings of a recent MRI screening trial that also found an increase in cancer detection involving all histologic grades (32). The TOSYMA results are in line with studies showing lower breast cancer screening detection rates in women with nondense breasts than in women with dense breasts (30,31). The applied stratifications demonstrated a similar pattern as previously described for women with dense breasts: higher iCDRs for early-stage grade 2 or 3 cancers than of grade 1 cancers and higher iCDRs with DBT plus SM than with DM, with a higher rate in the age group 60–70 years than in the age group 50–59 years. As the absolute benefit of breast cancer screening is known to be age dependent (1–3), DBT screening might further enhance screening advantages in the age group 60–70 years.
As a strength, the TOSYMA trial is presently the largest randomized controlled trial to our knowledge on the effect of DBT plus SM versus DM screening and allows various stratifications with sufficient numbers to provide precise comparative exploratory analyses, unlike one smaller randomized controlled study (33). The multicenter, multivendor approach, with a mix of readers and mammography devices, should confer high feasibility and external transferability of the employed methods, in contrast to a single-center and single-vendor approach (33). The proximity of the crude and statistically adjusted estimates of the ORs seems to support the view that the study design provided a balanced and stable basis for such analyses.
There are certain limitations. First, the analyses were exploratory and hypothesis-generating; thus, comparative statistical analyses in other study settings will need to be performed to validate the findings. Second, the study results are based on one DBT screening round in an ongoing DM screening program with a 2-year interval. Therefore, the results are probably not transferable to programs permanently operating with DBT or with different interval lengths (34). Third, the level of attention given to the unblinded images by the readers may have been increased in the test arm compared with the control arm. Furthermore, evidence that DBT screening lowers the rate of interval cancers compared with DM screening is lacking in the literature (11,33). However, the second phase of the TOSYMA trial (TOSYMA-2) will evaluate invasive interval cancer rates up to 24 months after trial participation in 2024–2025 (21).
In conclusion, screening with digital breast tomosynthesis (DBT) plus synthesized mammography (SM) appears to lead to a higher detection rate than digital mammography (DM) of prognostically relevant breast cancers of grade 2 or 3 at the earliest tumor stage. The findings were most pronounced among women aged 60–70 years with dense breasts. These results suggest that DBT plus SM screening might contribute to increased screening effectiveness by enhancing the early detection of prognostically unfavorable cancers compared with DM.
Acknowledgments
We especially thank the Deutsche Forschungsgemeinschaft (German Research Foundation) for funding this randomized controlled trial and all the women who participated. The authors acknowledge the support of the study centers (Niedersachsen Nordwest, Hannover, Niedersachsen Nord, Niedersachsen Mitte, Niedersachsen Nordost, Duisburg, Krefeld Mönchengladbach Viersen, Wuppertal Solingen, Aachen Düren Heinsberg, Köln Rechtsrheinisch, Münster-Süd Coesfeld, Bottrop Gelsenkirchen Recklinghausen, Minden Lübbecke Herford, Bielefeld Gütersloh, Hamm Unna Märkischer Kreis, Höxter Paderborn Soest, and Münster-Nord Warendorf), including the readers and the pathologists.
Author Contributions
Author contributions: Guarantors of integrity of entire study, S.W., W.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agree to ensure any questions related to the work are appropriately resolved, all authors; literature research, S.W., W.H., T.D., H.W.H.; clinical studies, S.W., W.H., T.D.; statistical analysis, V.W.E., L.K., J.G., H.W.H.; and manuscript editing, S.W., W.H., T.D., L.K., J.G., H.W.H.
* S.W. and W.H. contributed equally to this work.
Supported by Deutsche Forschungsgemeinschaft (grants 1646/5-1 and 1646/5-2).
Data sharing: All data generated or analyzed during the study are included in the published paper.
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Article History
Received: June 16 2023Revision requested: Aug 16 2023
Revision received: Oct 13 2023
Accepted: Oct 31 2023
Published online: Dec 05 2023
