Radiological Tumor Signs of Breast Cancer in UICC Stage I: Subanalysis of the Randomized Controlled Trial TOSYMA

Abstract

Purpose

The randomized controlled, multicenter TOSYMA study showed a superiority of the combination of digital breast tomosynthesis and synthetic mammography (DBT+SM) over digital mammography (DM) in the detection rate of invasive breast cancer at stage UICC I. In this subanalysis, we compared the mammographic tumor signs of UICC I stage breast cancers detected in each study arm and stratified according to histological grade.

Materials and Methods

This subanalysis included 49,462 women in the DBT+SM arm and 49,669 women in the DM arm after 1:1 randomization from July 2018 to December 2020. The mammographic abnormalities documented at the consensus conference were collected for breast cancers in stage UICC I based on various tumor signs (such as masses, microcalcifications, architectural distortions, or their combinations). The detection rates (per 10,000 screened women) were calculated with differentiation of grade 1 and grade 2 or 3 cancers.

Results

Grade 1 cancers were detected using DBT+SM in 6.5/10,000 screened women only by masses (+1.5/10,000 versus DM), in 2.4/10,000 (+1.6/10,000) by architectural distortions, and in 1.2/10,000 (+0.8/10,000) by microcalcifications. Combinations of tumor signs were present in 7.9/10,000 (+6.1/10,000) screened women. Grade 2 or 3 cancers were detected by DBT+SM in 13.7/10,000 by masses (+2.6/10,000 versus DM), in 4.9/10,000 by microcalcifications (+2.3/10,000), and in 3.6/10,000 by architectural distortions (+2.0/10,000). Combinations were present in 10.1/10,000 (+6.3/10,000) screened women.

Conclusion

In DBT+SM screening, the detection rate of UICC I breast cancers is higher compared to DM: both, individual tumor signs and their combinations contribute to this finding. The detection rate of UICC I grade 2 or 3 cancers is higher in DBT+SM screening than in DM screening mainly due to the combination of tumor signs.

Key Points

• DBT+SM detects more grade 2 or 3-UICC I breast cancers than DM.

• This increase in detection rate results mainly from a combination of tumor signs.

• Nearly half of the increase relates to individual signs: masses, microcalcifications, and architectural distortions.

Citation Format

• Weigel S, Hense HW, Weyer-Elberich V et al. Radiological Tumor Signs of Breast Cancer in UICC Stage I: Subanalysis of the Randomized Controlled Trial TOSYMA. Rofo 2025; DOI 10.1055/a-2544-9085

Keywords

breast - digital radiography - screening - breast cancer - digital breast tomosynthesis - digital mammography

Introduction

Previous randomized controlled trials (RCT) on mammography screening have found that breast cancer mortality was reduced by 20–25% among women between ages 50 and 69 who were invited to screenings [1]. These effects have been confirmed by major systematic reviews of prospective observational studies [2] [3].

The benefits of breast cancer screening programs result from detecting tumors at an early stage, when therapy is often less invasive and the prognosis is significantly better [4] [5] [6]. Within this group of early-detected, non-metastatic breast cancers, the prognosis depends mainly on intrinsic factors, especially histological grading [7] [8]. For example, the detection of grade 2 or 3 breast cancer reduces breast cancer-related mortality more than that of grade 1 breast cancer (risk reduction 0.68 or 0.65 vs. 0.94) [9].

From the perspective of radiology, digital breast tomosynthesis (DBT) reduces tumor masking by overlying breast tissue compared to digital mammography (DM) [10]. The randomized controlled TOSYMA trial (TOmosynthesis plus SYnthesized MAmmography Screening Study) embedded in the German Mammography Screening Program (MSP) demonstrated in women of ages 50 to 70 years that the detection rate for invasive breast cancer is significantly higher with screening using DBT plus synthesized mammography (DBT+SM) (71/10,000 screened women) compared to DM (48/10,000) [11]. A subsequent subanalysis showed that with DBT+SM, the rate of detecting breast cancer in UICC stage I (tumor size up to 20 mm without regional metastasis or distant metastasis) was significantly increased, and this increase was mainly due to the detection of stage I carcinomas of grades 2 or 3 (+12.3 per 10,000 compared to DM) [12].

To sharpen the focus to diagnose such breast cancers, knowledge and expertise of the leading mammographic tumor signs are important. For this reason, this exploratory subanalysis of the TOSYMA study compares the frequency of the individual mammographic tumor signs – and their combinations – that enabled detection of stage I breast cancer in the screening group with DBT+SM and the group with DM, and examines whether the morphological criteria differ in light of the histological grade.

Materials and Methods

Study design

Phase 1 of the TOSYMA study was conducted from July 2018 to December 2020 in 17 screening units in the German states of North Rhine-Westphalia and Lower Saxony. In the process, a total of 99,689 women were randomized 1:1 to the test arm (DBT+SM) or the control arm (DM). The study protocol was approved by the responsible ethics committee and rated positively by two other ethics committees. All study participants provided their written consent. The study protocol, the results of the first primary endpoint – including some secondary endpoints – and several exploratory sub-analyses have already been published [11] [12] [13] [14] [15] [16].

Study participants

Women ages 50 to 69 were invited by letter every two years to participate in the German MSP, temporarily up to the age of 70 due to a COVID-19 regulation. In the catchment areas of the study centers, a personal invitation to the TOMSYA study was added to the regular invitation letter. Women who had been diagnosed with breast cancer up to five years previously or who had had a mammogram within the last 12 months were not eligible. Breast implants or repeated TOSYMA participation were specific exclusion criteria of the study [13] [15].

Preparing the screening examination

The opportunity to participate in the study was offered at 21 locations (Northwest Lower Saxony (Wilhelmshaven), Hanover, North Lower Saxony (Stade), Central Lower Saxony (Vechta), Northeast Lower Saxony (Lüneburg), Duisburg, Krefeld/Mönchengladbach/Viersen, Wuppertal/Solingen (Bergisches Land/Mettmann district), Aachen-Düren-Heinsberg, Cologne rechtsrheinisch (Bergisch Gladbach), Münster-South/Coesfeld, Bottrop, Gelsenkirchen, Recklinghausen, Minden-Lübbecke/Herford, Bielefeld/Gütersloh, Hamm/Unna/Märkischer Kreis (Schwerte), Höxter, Paderborn, Soest (Lippstadt), Münster-North/Warendorf).

Seven different mammography device manufacturers were used to prepare the DBT+SM or DM examination: Amulet Innovality (Fujifilm Cooperation, Tokyo, Japan; n=10,075 examinations), Class Tomo (IMS Giotto, Sasso Marconi, Italy; n=7,970), Lorad Selenia 3Dimensions (Hologic, Malborough, USA; n=10,955), Lorad Selenia Dimensions (Hologic, Malborough, USA; n=40,645), MAMMOMAT Inspiration (Siemens Healthineers, Erlangen, Germany; n=6,759), MAMMOMAT Relevation (Siemens Healthineers, Erlangen, Germany; n=12,917), Senographe Essential (GE Healthcare, Chicago, USA; n=10,237).

In both study arms, the examinations included the cranio-caudal and the medio-lateral-oblique projection for each breast. In the test arm, in addition to the synthesized mammograms (SM), stacked slices of ≤ 1 mm thickness were reconstructed to view the findings [11] [13] [15].

Mammographic findings

As in the ongoing MSP, an independent double reading was performed in both study arms by the same certified physicians. A total of 83 experienced readers participated, each of whom had previous screening experience of at least two years with at least 5,000 screening examinations per year. Before the start of the TOSYMA study, DBT training was conducted for all study physicians by the Reference Center for Mammography in Münster.

In case of abnormalities, the results were discussed with the physician responsible for the program in the consensus conference in order to decide on further diagnostic assessment. During the consensus conference, mammographic abnormalities that prompted a recall were documented digitally and used in the current subanalysis.

The diagnostic assessment of study participants did not differ from the established MSP procedure and included, depending on the findings, a clinical examination and, if necessary, further mammographic projections (e.g. magnification mammograms or DBT), sonography, MR scans, or minimally invasive diagnostic procedures.

All screening data were stored centrally and electronically in the MaSc documentation system (KV-IT GmbH, Dortmund, Germany) [15].

Histological assessment

The 32 pathologists involved, all with at least 15 years of experience, made at least 100 histopathological diagnoses annually as part of the MSP, and they attended mandatory training every two years, in addition to self-assessment procedures. The study training focused on the Nottingham grading system for invasive carcinomas, based on a semiquantitative assessment (1 to 3) of glandular differentiation, nuclear pleomorphism, and the number of mitoses per square millimeter (G1: ScoreΣ 3–5, G2: ScoreΣ 6–7, G3: ScoreΣ 8–9) [4] [8] [12] [17].

Study data

The stages of breast cancer were classified based on postoperative histological findings or, in case of neoadjuvant treatment, clinical imaging according to the TNM classification of the Union for International Cancer Control (UICC) [18]. In multifocal or multicentric carcinomas, the largest tumor diameter was used for staging [18]; in bilateral breast cancer, the side with the highest TNM classification was used. UICC stage I is defined as a tumor size ≤ 20 mm (T1), no regional metastases (N0, N1mi) and no distant metastases (M0). Women with stage I breast cancer were divided into two groups, those with histological grade 1 and those with grades 2 or 3. In case of multifocality or multicentricity, the highest grade was used.

Previously published results from the TOSYMA study reported the detection rates of invasive breast cancer (iCDR) per 10,000 examined women stratified by stage and histological grade based on the aforementioned grouping [12]. This group also forms the basis of this subanalysis. Of the 99,689 randomized women, 66 women who had not undergone any study examination and 10 women who repeatedly participated in the TOSYMA study were excluded from the analysis set. In addition, we excluded women with missing data regarding screening results, breast density, and UICC stage. Accordingly, the current subanalysis included 49,462 women in the DBT+SM arm and 49,669 women in the DM arm [12].

Tumor signs

The frequencies of tumor signs documented during the consensus conference and leading to diagnostic assessment with detection of stage I invasive breast cancer after independent double reading were collected from the screening software. These were: masses, microcalcifications, architectural distortions, asymmetries, densities, or their combinations [19].

Statistical analysis

The descriptive subanalysis included the assessment of tumor signs for screening-detected stage I breast cancer at the time of the consensus conference, which the callback for diagnostic assessment was based on. For these categorical variables, the absolute frequencies were determined for each study arm overall and stratified by histological grade, i.e. grade 1 versus grade 2 or 3. These were determined for each mammographic tumor sign or their combinations as detection rates (DR) per 10,000 women examined. Subsequently, the DR differences between the two study arms were calculated.

Results

Stage I breast cancer was found in 255 women in the DBT+SM group (DR 51.6 per 10,000) and in 149 women in the DM arm (30.0/10,000). The most common individual mammographic tumor sign leading to the diagnosis in both study arms was masses (DBT+SM: 20.2 per 10,000 vs. DM: 16.1 per 10,000; difference +4.1 per 10,000), less frequently, it was based on the morphology of microcalcification (DBT+SM: 6.1/10,000 vs. DM: 3.0/10,000; difference +3.1/10,000) or the morphology of architectural distortion (6.1 vs. 2.4/10,000; difference +3.7/10,000). For all tumor signs considered above, DR was higher with DBT+SM than with DM, the largest DR difference between the two study arms was achieved with the combination of mammographic tumor signs: it was 12.4/10,000 higher with DBT+SM (18.0/10,000) than with DM (5.6/10,000). In both study arms, asymmetries and densities were rare as tumor signs for stage I ([Table 1], [Fig. 1], [Fig. 2]).

Table 1 Frequencies of mammographic tumor signs of stage I breast cancer with corresponding detection rates of the randomized controlled screening study TOSYMA.

Mammographic tumor signs*	DM No. of stage I breast cancer (DR per 10,000)	DBT+ SM No. of stage I breast cancer (DR per 10,000)	Difference No. of DBT+SM – DM	Difference in detection rate DBT+SM – DM per 10,000
DM: Digital mammography. DBT+SM: Digital breast-tomosynthesis plus synthetic mammography *Mammographic tumor signs based on the ACR BI-RADS Atlas, Breast Imaging Reporting and Data System [19]. Examinations included in the DM arm: 49,669 Examinations included in the DBT+SM arm: 49,462 DR: Detection rate per 10,000 examinations
Mass	80 (16.1)	100 (20.2)	20	+4.1
Combination	28 (5.6)	89 (18.0)	61	+12.4
Microcalcification	15 (3.0)	30 (6.1)	15	+3.1
Architectural distortion	12 (2.4)	30 (6.1)	18	+3.7
Asymmetry	3 (0.6)	0 (0)	−3	−0.6
Density	9 (1.8)	2 (0.4)	−7	−1.4
No data	2 (0.4)	4 (0.8)
Total	149 (30.0)	255 (51.6)	106	+21.6

Fig. 1 Part of a single layer of a screening examination with digital breast tomosynthesis of a right cranio-caudal view of the lateral quadrants. Marked with a circle is an architectural distortion measuring 15 mm, which has centrally amorphous microcalcifications. Histology: Invasive breast carcinoma, pT1b (8mm), pN0, cM0.

Fig. 2 Part of the magnification view right cranio-caudal of the lateral quadrants, which was obtained as part of the assessment. Amorphous microcalcifications are marked with a circle, morphologically depicted comparable to the single layer in Figure 1. Magnifying mammography does not reveal the architectural distortion shown by digital breast tomosynthesis. Histology: Invasive breast carcinoma, pT1b (8mm), pN0, cM0.

In both study arms, fewer stage I grade 1 carcinomas (DBT+SM) were detected: 18.0/10,000 vs. DM: 8.7/10,000; difference +9.3/10,000) compared to grade 2 or 3 (DBT+SM: 33.6/10,000 vs. DM: 21.3/10,000; difference: +12.3/10,000) ([Table 2], [Table 3]).

Table 2 Frequencies of mammographic tumor signs of stage I breast cancer histological grade 1 with corresponding detection rates of the randomized controlled screening study TOSYMA.

Mammographic tumor signs*	DM No. of stage I breast cancer Grade 1 (DR per 10,000)	DBT+ SM No. of stage I breast cancer Grade 1 (DR per 10,000)	Difference No. DBT+SM – DM	Difference in detection rate DBT+SM – DM per 10,000
DM: Digital mammography DBT+SM: Digital breast-tomosynthesis plus synthetic mammography *Mammographic tumor signs based on the ACR BI-RADS Atlas, Breast Imaging Reporting and Data System [19]. Examinations included in the DM arm: 49,669 Examinations included in the DBT+SM arm: 49,462 DR: Detection rate per 10,000 examinations
Mass	25 (5.0)	32 (6.5)	7	+1.5
Combination	9 (1.8)	39 (7.9)	30	+6.1
Microcalcification	2 (0.4)	6 (1.2)	4	+0.8
Architectural distortion	4 (0.8)	12 (2.4)	8	+1.6
Asymmetry	1 (0.2)	0 (0)	−1	−0.2
Density	2 (0.4)	0 (0)	−2	−0.4
No data	0 (0)	0 (0)
Total	43 (8.7)	89 (18.0)	46	+9.3

Table 3 Frequencies of mammographic tumor signs of stage I breast cancer histological grade 2 or 3 with corresponding detection rates of the randomized controlled screening study TOSYMA.

Mammographic tumor signs*	DM No. of stage I breast cancer Grade 2 or 3 (DR per 10,000)	DBT+ SM No. of stage I breast cancer Grade 2 or 3 (DR per 10,000)	Difference No. DBT+SM – DM	Difference in detection rate DBT+SM – DM per 10,000
DM: Digital mammography DBT+SM: Digital breast-tomosynthesis plus synthetic mammography *Mammographic tumor signs based on the ACR BI-RADS Atlas, Breast Imaging Reporting and Data System [19]. Examinations included in the DM arm: 49,669 Examinations included in the DBT+SM arm: 49,462 DR: Detection rate per 10,000 examinations
Mass	55 (11.1)	68 (13.7)	13	+2.6
Combination	19 (3.8)	50 (10.1)	31	+6.3
Microcalcification	13 (2.6)	24 (4.9)	11	+2.3
Architectural distortion	8 (1.6)	18 (3.6)	10	+2.0
Asymmetry	2 (0.4)	0 (0)	−2	−0.4
Density	7 (1.4)	2 (0.4)	−5	−1.0
No data	2 (0.4)	4 (0.8)
Total	106 (21.3)	166 (33.6)	60	+12.3

UICC I grade 1 carcinomas were detected significantly more frequently with combinations of tumor signs using DBT+SM than with DM, the DR difference was +6.1/10,000. Among the individual tumor signs, the difference of DR DBT+SM minus DM was +1.5/10,000 for masses, +0.8/10,000 for microcalcifications, and +1.6/10,000 for architectural distortions ([Table 2]).

UICC stage I breast cancer grades 2 or 3 were detected more frequently with combinations of tumor signs with DBT+SM (DR 10.1/10,000) than with DM (3.8/10,000), corresponding to a DR difference of +6.3/10,000. Here again, masses were the leading individual tumor sign (DBT+SM: 13.7/10,000 vs. DM: 11.1/10,000); however, the DR difference DBT+SM minus DM was smaller (+2.6/10,000) compared to combinations of tumor signs. The DR differences due to microcalcifications (4.9 vs. 2.6/10,000; difference +2.3/10,000) and due to architectural distortions (3.6 vs. 1.6/10,000; difference +2.0/10,000) were of similar magnitudes ([Table 3]).

Discussion

As the first RCT, the multicenter TOSYMA study showed that in a national, population-based mammography screening program, the invasive detection rate with DBT+SM is higher than with DM [11]. A supplementary subanalysis also showed that the DBT+SM screening particularly increased the detection of stage I breast cancer at grades 2 or 3 [12]. Increased detection of breast cancers of these grades at early tumor stages may have a potentiating effect on reducing breast cancer mortality [9]. Therefore, an imaging characterization of the mammographic tumor signs leading to the detection of these carcinomas in screening with DBT+SM or DM is of particular interest.

In addition to the previously published grading-related detection rates of UICC I carcinomas [12], the present subanalysis of the TOSYMA study presents the associated mammographic tumor signs that led to diagnostic assessment after independent, qualified double reading of the screening mammography with resulting consensus conference. The documented tumor signs were based on the BIRADS Atlas, 5th edition, in accordance with study training, and referred to the level of the examination [19]. The additional characterizations from the diagnostic assessment were not included in the analysis.

Masses are the most common abnormality of breast cancer in DBT screening [20]. With DBT+SM and DM, masses were the most common tumor sign of stage I carcinomas in the TOSYMA study. Consistent with the literature, DBT achieves higher detection for breast cancers up to 20 mm than DM [21]. In the TOSYMA study, DBT+SM showed a higher detection compared to DM of +4.1/10,000 in stage I, which was more pronounced in histological grades 2 or 3 at +2.6/10,000 than in grade 1 (+1.5/10,000). The lesion-related detection rate in the DBT+SM arm of 13.7/10,000 corresponded to 41% (68 of 166) of the total stage I grade 2 or 3 breast cancers detected. By reducing masking, DBT can help to assess margins more accurately and can more clearly identify highly suspicious morphologies, such as spiculation, compared to DM [10] [20]. Although screening-detected spiculated lesions are described as having a favorable prognosis [22] [23], DBT+SM does not dominate when it comes to detecting grade 1 breast cancers, but does so instead with prognostically more significant grades [9] [22].

Microcalcifications also resulted in diagnoses of grade 2 or 3 breast cancer more frequently with DBT+SM than with DM. At the same time, the difference in detection rates after DBT+SM screening was greater for grade 2 and 3 tumors (+2.3/10,000) than for grade 1 (+0.8/10,000). In the DBT+SM arm, approx. 14% (24/166) of UICC stage I grade 2 or 3 breast cancers were detected via microcalcifications (DM approx. 12% (13/106)). The reason could be the increase in contrast of microcalcifications – despite varying technical resolution limits [10]. In line with this finding, the detection of ductal carcinoma in situ with DBT+SM versus DM did not show marked inferiority in the TOSYMA study (DBT+SM: 12/10,000; DM: 13/10,000) [11]. Breast cancers smaller than 15 mm with microcalcification have an increased breast cancer mortality risk [24]. Screening with DBT+SM could therefore slightly increase the diagnosis frequency of such breast cancers with a less favorable prognosis compared to DM. The equipment technology used does not support the need for double exposure (DBT+DM) for microcalcification imaging in screening.

Regarding the isolated architectural distortion, DBT+SM also led to a higher detection rate of grade 1 as well as grades 2 or 3 breast cancer compared to DM, but the DR differences between the study arms were very similar for both grade strata (+0.16 and +0.20/10,000, respectively). Accordingly, the architectural distortion in the diagnosis of stage I breast cancer is not strikingly typical for stage 1 breast cancer. DBT+SM may allow a somewhat clearer perception of subtle architectural distortions associated with stage I breast cancer, detecting 11% (18/166) of UICC stage I grade 2 or 3 breast cancers compared with approx. 7.5% (8/106) with DM. The number of UICC I stage 1 breast cancers detected by architectural distortions in screening was lower in both arms than in grades 2 or 3 (DBT+SM: 12 vs 18, DM: 4 vs. 8). However, a higher rate of benign findings is described for DBT compared to DM, such as radial scars, fibrosis, and sclerosing adenosis [25].

The greatest superiority of DBT+SM over DM was found in the combination of individual tumor signs (grade 1: +6.1/10,000, grade 2 or 3: +6.3/10,000). By reducing superposition effects, sensitivity could be increased by perceiving a combination of suspicious signs. For example, DBT can more accurately identify tissue thickening than DM, the combination of which with microcalcifications increases the probability of malignancy [26]. Of UICC stage I breast cancer grade 2 or 3, the combination of tumor signs with DBT+SM screening led to the detection of approx. 30% of all tumors (50/166). The perception of combined tumor signs by readers – or in the future also by the use of artificial intelligence – seems to be very important to identify as an abnormality in screening [19].

It should be emphasized that the increased tumor detection in the DBT+SM study arm is not due to an increased recall rate for diagnostic assessment (recall rates DBT+SM: 4.9% vs. DM: 5.1%), but was instead associated with a higher positive predictive value (PPV 1 DBT+SM: 17.2%, DM: 12.3%) [11].

TOSYMA is the largest randomized, controlled screening trial to date to study DBT+SM versus DM with almost 100,000 study participants. It enables additional exploratory analyses based on successful randomization. The pragmatic approach has a high degree of external validity and also demonstrates practical feasibility, particularly due to the inclusion of numerous screening units and equipment technologies. All diagnosticians were experienced and did not differ between the study arms or between the study and routine screening [15].

The study also had limitations. TOSYMA analyzed only one round of screening. So differences between study arms may be influenced by an initial prevalence screening effect with DBT+SM. In addition, there may be a learning curve in the interpretation of tomosynthesis. The comparison with previous examinations of the DBT+SM arm may have had a complicating influence on the findings, since no DBT+SM preliminary examinations were performed in the screening program [15]. Furthermore, the TOSYMA study did not include any sub-differentiations regarding mass margins, calcification morphologies, or calcification distributions. Due to the large number of possible combinations of radiological tumor signs and the resulting limited number of cases, a differentiated, comparative presentation within this stratification group was not carried out.

Clinical relevance

In DBT+SM screening, the detection rate for UICC I breast cancers is higher than in DM: this is due to single tumor signs, such as masses, microcalcifications, and architectural distortions, as well as their combinations.

The detection rates for UICC I grade 2 or 3 breast cancers are higher in both study arms than those for grade 1 cancers: the increased detection rate for grades 2 or 3 using DBT+SM is based about half on the combination of tumor signs.

A systematic evaluation of DBT+SM screening examinations has the potential to enhance intended screening effects through the increased detection of various single and, particularly, combined mammographic tumor signs.

Interessenkonflikt

S.W.: Honorare für Vorträge des Referenzzentrums Mammographie Münster; Leitungsfunktion am Referenzzentrum Mammographie Münster und der zugehörigen Referenz-Screening-Einheit; Vorstandsmitglied der AG Mammadiagnostik der Deutschen Röntgengesellschaft und der Deutschen Gesellschaft für Senologie; vor Beginn der TOSYMA-Studie wurden kostenlose Schulungsfälle von allen Herstellern für die Befunderschulung im Referenzzentrum Mammographie Münster erhalten. H.W.H. Keine relevanten Interessenkonflikte. V.W.E. Keine relevanten Interessenkonflikte. J.G. Beratungshonorare von Dr. August Wolff, Ecker + Ecker, QUIRIS Healthcare und TESARO; Honorare für Vorträge von Roche und TESARO; Mitarbeit in einem Daten- und Sicherheitsmonitoring-Gremium bzw. Beirat für die TOMAHAWK-Studie (Universitätsklinikum Schleswig-Holstein, Campus Lübeck) und Ruxo-BEAT-Studie (RWTH Aachen). W.H. Honorare für Vorträge des Referenzzentrums Mammographie Münster; Leitungsfunktion am Referenzzentrum Mammographie Münster und der zugehörigen Referenz-Screening-Einheit; vor Beginn der TOSYMA-Studie wurden kostenlose Schulungsfälle von allen Herstellern für die Befunderschulung im Referenzzentrum Mammographie Münster erhalten.

Acknowledgement

We would like to thank the German Research Foundation (Deutsche Forschungsgemeinschaft) for funding the randomized, controlled, clinical trial TOSYMA (DFG HE 1646/5-1 and HE 1646/5-2) as well as all participating women. Special thanks go to the recruiting screening units and study centers, the interdisciplinary study team of the University of Münster (Clinic for Radiology, Institute of Epidemiology and Social Medicine, Institute of Biostatistics and Clinical Research, Center for Clinical Trials Münster) and the Data and Safety Monitoring Board.

• References

• 1 IARC. Breast cancer screening: Handbook of Cancer Prevention. Lyon: International Agency for Research on Cancer; 2016
• 2 Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380: 1778-1786
• 3 Lauby-Secretan B, Scoccianti C, Loomis D. et al. Breast-cancer screening – viewpoint of the IARC Working Group. N Engl J Med 2015; 372: 2353-2358
• 4 Perry N, Broeders M, de Wolf C. et al. European guidelines for quality assurance in breast cancer screening and diagnosis. Luxembourg: Office for Official Publications of the European Communities; 2006. 4th edn.
• 5 Zielonke N, Gini A, Jansen EEL. et al. Evidence for reducing cancer-specific mortality due to screening for breast cancer in Europe: A systematic review. Eur J Cancer 2020; 127: 191-206
• 6 Saadatmand S, Bretveld R, Siesling S. et al. Influence of tumour stage at breast cancer detection on survival in modern times: population based study in 173,797 patients. BMJ 2015; 351: h4901
• 7 Schwartz AM, Henson DE, Chen D. et al. Histologic grade remains a prognostic factor for breast cancer regardless of the number of positive lymph nodes and tumor size: a study of 161 708 cases of breast cancer from the SEER Program. Arch Pathol Lab Med 2014; 138: 1048-1052
• 8 Rakha EA, El-Sayed ME, Lee AH. et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol 2008; 26: 3153-3158
• 9 Tabar L, Chen TH, Yen AM. et al. Effect of Mammography Screening on Mortality by Histological Grade. Cancer Epidemiol Biomarkers Prev 2018; 27: 154-157
• 10 Chong A, Weinstein SP, McDonald ES. et al. Digital breast tomosynthesis: concepts and clinical practice. Radiology 2019; 292: 1-14
• 11 Heindel W, Weigel S, Gerß J. et al. Digital breast tomosynthesis plus synthesised mammography versus digital screening mammography for the detection of invasive breast cancer (TOSYMA): a multicentre, open-label, randomised, controlled, superiority trial. Lancet Oncol 2022; 23: 601-611
• 12 Weigel S, Heindel W, Decker T. et al. TOSYMA Screening Trial Study Group. Digital Breast Tomosynthesis versus Digital Mammography for Detection of Early-Stage Cancers Stratified by Grade: A TOSYMA Subanalysis. Radiology 2023; 309 (03) e231533
• 13 Weigel S, Gerss J, Hense HW. et al. Digital breast tomosynthesis plus synthesised images versus standard full-field digital mammography in population-based screening (TOSYMA): protocol of a randomised controlled trial. BMJ Open 2018; 8 (05) e020475
• 14 Weigel S, Heindel W, Hense HW. et al. TOSYMA Screening Trial Study Group. Breast Density and Breast Cancer Screening with Digital Breast Tomosynthesis: A TOSYMA Trial Subanalysis. Radiology 2023; 306 (02) e221006
• 15 Weigel S, Hense HW, Weyer-Elberich V. et al. Breast cancer screening with digital breast tomosynthesis: Is independent double reading still required?. Fortschr Röntgenstr 2024; 196: 834-842
• 16 Sommer A, Weigel S, Hense HW. et al. TOSYMA Screening Trial Study Group. Radiation exposure and screening yield by digital breast tomosynthesis compared to mammography: results of the TOSYMA Trial breast density related. Eur Radiol 2024; 16
• 17 Fitzgibbons PL, Connolly JL, College of American Pathologists. Protocol for the Examination of Biopsy Specimens from Patients with Invasive Carcinoma of the Breast Cancer. 2023 Accessed August 18, 2024 at: https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates
• 18 Brierley JD, Gospodarowicz MK, Wittekind C. (Union for International Cancer Control) TNM classification of malignant tumours. Oxford: Wiley Blackwell; 2017. 8th Edition.
• 19 D’Orsi CJ, Sickles EA, Mendelson EB. et al. ACR BI-RADS Atlas: Breast Imaging Reporting and Data System. Reston: American College of Radiology; 2013. 5th Edition.
• 20 Aase HS, Danielsen AS, Hoff SR. et al. Mammographic features and screening outcome in a randomized controlled trial comparing digital breast tomosynthesis and digital mammography. Eur J Radiol 2021; 141
• 21 Gilbert FJ, Tucker L, Gillan MG. et al. The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme--a multicentre retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone. Health Technol Assess 2015; 19 (04) i-xxv
• 22 Tabar L, Chen HHT, Yan MFA. et al. Mammographic tumor features can predict long-term outcomes reliably in women with 1–14-mm invasive breast carcinoma. Cancer 2004; 101: 1745-1759
• 23 Evans AJ, Pinder SE, James JJ. et al. Is mammographic spiculation an independent, good prognostic factor in screeningdetected invasive breast cancer?. AJR 2006; 187: 1377-1380
• 24 Moshina N, Backmann HA, Skaane P. et al. Mammographic features and risk of breast cancer death among women with invasive screen-detected cancer in BreastScreen Norway 1996–2020. Eur Radiol 2024; 34: 3364-3374
• 25 Samreen N, Moy L, Lee CS. Architectural Distortion on Digital Breast Tomosynthesis: Management Algorithm and Pathological Outcome. J Breast Imaging 2020; 2 (05) 424-435
• 26 Kuwabara N, Takuwa H, Takeuchi M. et al. Can digital breast tomosynthesis improve identification of malignant calcifications?. Radiol Phys Technol 2020; 13 (03) 249-255

Publication History

Received: 02 September 2024

Accepted after revision: 17 February 2025

Article published online:
26 March 2025