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Henderson JT, Webber EM, Weyrich M, et al. Screening for Breast Cancer: A Comparative Effectiveness Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2024 Apr. (Evidence Synthesis, No. 231.)
Literature Search
We reviewed 10,379 abstracts and assessed 420 full-text articles for inclusion (Appendix B Figure 1). Overall, we identified 20 studies (reported in 45 articles79,80,126–168) that met our inclusion criteria. Lists of included and excluded studies (with reasons for exclusion) are available in Appendix C and Appendix D. No RCTs were excluded from this review due to poor quality; however, 15 nonrandomized studies of interventions (NRSIs) were excluded for poor quality, primarily due to confounding based on imbalances in baseline characteristics (without proper statistical adjustment), selection into study groups, and the absence of information on participant characteristic by study arm.
The numbers of studies and outcomes reported for each KQ are described in Table 3. Details on study design, population, and methodologies are provided in Table 4, Table 5, and Appendix E Table 1. The age to begin screening was not addressed in any of the included studies; the age to stop screening was addressed in one NRSI.136 The effects of different screening intervals (i.e., annual, biennial, triennial) were addressed in five studies, one RCT,126 and four NRSIs.140,153,154,159 Eleven of the included studies, four RCTs,129,139,143,160 and seven NRSIs79,132,140,144,147,162,168 compared outcomes for screening with DBT versus DM. One RCT164 and one NRSI135 evaluated the effects of an invitation to supplemental screening with MRI for participants with dense breasts after receiving a negative screening mammography. One RCT158 and one NRSI152 addressed the use of supplemental ultrasound screening. No studies of interventions involving personalized screening based on predicted risk met the eligibility criteria for this review.
Health outcomes (KQ1) associated with different screening programs were reported in only two fair-quality NRSIs that addressed the age to stop screening136 or screening interval159 (Table 4). For invasive cancer detection (KQ2), two studies addressed the effect of screening frequency on the characteristics of detected cancers, including one fair-quality RCT of multiple rounds of screening126 and one fair-quality cases-only analysis from the BCSC.154 Five studies of DBT compared with DM, three RCTs129,143,160 (two good- and one fair-quality), and two NRSIs144,168 reported screening outcomes from more than one round of screening and were included for KQ2. These studies reported characteristics of cancers detected at each round, necessary to assess whether screening resulted in stage shift toward less advanced cases with better prognosis. All 20 studies were included to examine potential harms of different screening approaches (KQ3).
Overall, the demographic characteristics of study participants were minimally described (Table 5). Most studies included participants in their 40s to 60s, with one study focusing on screening after age 70 years.136 Only seven of the 20 studies reported racial and/or ethnic characteristics. For six studies, participants were primarily White (73% to 92%), with <1 to 11 percent identified as Black, 2 to 11 percent as Asian, and 5 to 7 percent as Hispanic.132,136,147,152,154,168 An included electronic health record–based study included primarily Hispanic/Latina participants (76%) along with 10 percent Black and 10 percent White participants.153
KQ1. What Is the Comparative Effectiveness of Different Mammography-Based Screening Strategies on Breast Cancer Morbidity and Mortality?
Summary of Results
We did not identify any RCTs designed to test the comparative effectiveness of ages to start or stop screening, screening interval, or screening modality that reported morbidity, mortality, or quality of life outcomes. Two NRSIs reported mortality outcomes (breast cancer mortality, all-cause mortality)—one comparing mortality based on different ages to stop screening and another comparing annual to triennial screening intervals. One fair-quality observational study (N = 1,058,013) was conducted in the United States using a random sample from Medicare claims data to estimate the effect of women stopping screening at age 70 compared with those who continued annual screening after age 70. Individuals included in the study had a high probability of living for 10 more years at the start of the study. The data were analyzed using statistical methods that have been developed to emulate per-protocol trials of screening. Continued screening between the ages of 70 and 74 was associated with a 22 percent decrease in the risk of breast cancer mortality compared with a cessation of screening after age 70. The difference in absolute rates was small (1 fewer death per 1,000 women screened) and the confidence interval for the rate difference included null. The analysis found no difference in the hazard ratio or absolute rates of breast cancer mortality with continued versus discontinued screening from ages 75 to 84. The second NRSI was a fair-quality study (N = 14,765) conducted in Finland during the years 1985 to 1995 that assigned participants ages 40 to 49 years of age to annual or triennial screening invitations using birth year. The study reported similar mortality from incident breast cancer and for all-cause mortality between the two study groups.
Detailed Results by Screening Intervention
Age to Start or Stop Screening
Study and Population Characteristics
One fair-quality NRSI study by García-Albéniz et al. used U.S. Medicare data from 1999–2008 and National Death index data to conduct an emulated trial evaluating the effect of stopping annual mammogram screening at the age of 70 versus continuing annual screening beyond this age (Table 4).136 Annual screening was the most frequent pattern in the data for this time frame. An emulated trial uses statistical techniques to structure and adjust observational data in a way that can approximate a target (per-protocol) randomized trial.169 The study was conducted using a 20 percent random sample of enrollees ages 70 to 84 years in Medicare parts A and B (N = 1,058,013) between 1999 and 2008 (Medicare Advantage enrollees, who comprised 13%–21% of Medicare beneficiaries, were not included). Data on demographic characteristics, chronic conditions, preventive care, screening mammograms, breast cancer symptoms and signs, and breast cancer incidence and treatments were analyzed along with cause of death information obtained from the National Death Index from the National Center for Health Statistics.
A Medicare-specific comorbidity score was computed to exclude individuals that did not have a high probability of living an additional 10 years. Participants could not have a prior breast cancer diagnosis or have breast symptoms or a mammogram in the previous nine months. The trial was emulated for two age groups, those ages 70 to 74 (N = 1,235,459) and those ages 75 to 84 (N = 1,403,735). At each year of age, individuals were randomly assigned to the stop screening or continue screening strategy and the data were analyzed according to whether they had adhered to their assignment, resulting in 15 per protocol trial emulations (for each year of ages 70 to 84). Participants were followed until death, Medicare disenrollment, or the year 2008, whichever came first. A discrete hazard model was approximated using a pooled logistic regression model, and observations were cloned for analytic reasons and censored when they deviated from the randomly assigned screening strategy. Sensitivity analyses were used to evaluate the robustness of findings for a range of assumptions. The baseline characteristics for the sample were described for these two groups and showed that a majority of the sampled eligible participants in these Medicare plans were White (>90%), with 5 percent of participants reported as Black, and 3 percent as “other” (no additional information provided) (Table 5). The older age group (75 to 84) had more frequent visits to the emergency room and more chronic conditions. These factors and other baseline characteristics were adjusted for in all analyses to account for possible differences that could affect assignment and adherence to the screening strategy (stop at age 70 or continue).
Outcomes
In the García-Albéniz NRSI,136 1,058,013 individuals contributed data to an average of 2.5 age-specific emulated trials. Therefore, after pooling all ages (70 to 84 years), 2,639,194 individuals contributed 4,656,465 person-years to the continued screening strategy and 7,170,142 person-years to the stop screening strategy. In the continued screening group, there were 1,533 breast cancer deaths and in the stop screening strategy there were 1,304 breast cancer deaths.
For women ages 70 to 74, the estimated 8-year risk of breast cancer mortality with continued annual screening was 2.7 per 1,000 women (95% CI, 1.8 to 3.7); it was 3.7 per 1,000 women (95% CI, 2.7 to 5.0) with discontinuation after age 70 (risk difference, −1.0 [95% CI, −2.3 to 0.1]). Despite this small, statistically nonsignificant risk difference in mortality risk for the age group, the adjusted hazard ratio (aHR) suggested a 22 percent lower hazard of 8-year breast cancer mortality with continued screening among those ages 70 to 74 (aHR, 0.78 [95% CI, 0.63 to 0.95]). For women ages 75 to 84, the 8-year estimated risk of breast cancer mortality was 3.8 per 1,000 women (95% CI, 2.7 to 5.1) with continued screening and 3.7 per 1,000 women (95% CI, 3.0 to 4.6) (risk difference, 0.07 [95% CI, −0.93 to 1.3]) with discontinuation, with an estimated hazard ratio of 1.00 (95% CI, 0.83 to 1.19). These study results are the fully adjusted effect estimates that account for baseline demographics, chronic conditions, and health care use, as well as time-varying factors including screening history, use of health care resources, and comorbidities. Without adjustment for factors that would contribute to adherence to the continue or stop screening strategy, the risk differences are larger and more favorable for those who continued annual screening, especially in the 70 to 74 years age group. Overall, the adjusted findings did not show a statistical difference in the 8-year risk of breast mortality for women screened beyond age 75 compared with women who discontinued screening.
KQ1a. Does Comparative Effectiveness Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
The included study for KQ1 on age to stop screening did not present comparisons that tested or stratified mortality by participant characteristics or risk markers.
Screening Interval
Study and Population Characteristics
One fair-quality NRSI159 conducted in Turku, Finland from 1987 to 2007 compared rates of mortality associated with annual or triennial screening from ages 40 to 49 (Table 4). Over 10 years (1985–1995) the study sent invitations to all female residents of the screening catchment area starting at age 40 as part of the national screening program (N =14,765). Study group assignment was determined based on birth year (even year birth annual, odd year birth triennial). All individuals invited to screening were followed for 10 years to assess incident cancer and an additional three years (to age 52) to assess mortality from breast cancers presenting from ages 40 to 49 as well as all-cause mortality. No data were reported on the demographics of participants, such as race, breast density, or presence of underlying risk factors (Table 5). Two-view, double read mammography was conducted by eight radiologists at a single screening center serving the city of Turku. The attendance rate for those invited to screening was 85 percent (not reported by study arm).
The intention-to-treat analysis was designed to test the effect of invitations to more or less frequent screening (2.8 versus 9.2 on average per person over the 10-year period). Data for the study outcomes were obtained through linkage with the Finnish Cancer Registry, the national Statistics Finland mortality registry, and the Turku clinical breast cancer database. All diagnoses and outcomes were cross-checked across the data sources, and medical chart review was conducted to resolve discrepancies. The analysis used person-years calculated from ages 40 to 49 for breast cancer incidence outcomes and from ages 40 to 52 for mortality outcomes to compute rates per 100,000 person-years. During the study, breast cancer incidence between ages 40 and 49 was similar for those invited to annual screening (141.1 per 100,000 person-years) and those invited to triennial screening (144.0 per 100,000 person-years). Unadjusted Poisson regression was used to estimate the relative rate of incidence and mortality.
Outcomes
The 14,765 people invited to screening for this study contributed 100,738 person-years to the triennial screening invitation group and 88,780 person-years to the annual screening invitation group for estimation of mortality outcomes.159 Mortality from incident breast cancer diagnoses occurring from ages 40 to 49 (with followup to age 52) was similar between groups, with 20.3 deaths per 100,000 person-years with annual screening invitations and 17.9 deaths per 100,000 person-years with triennial screening invitations (relative risk [RR], 1.14 [95% CI, 0.59 to 1.27]).
All-cause mortality (including mortality from prevalent and incident breast cancer diagnoses) was higher in the intention-to-treat analysis for invitation to annual screening (230.9 per 100,000 person-years) compared with invitation to triennial screening (192.6 per 100,000 person-years) and there was a trend suggesting an estimated 20 percent increased risk due to the relative risk and a confidence interval on the margin of null (RR, 1.20 [95% CI, 0.99 to 1.46]). An explanation or mechanism for the higher mortality rate related to more frequent screening could not be identified by the study authors. Deaths from other cancers and deaths from “other natural causes” (not defined) were higher in the annual screening invitation group, whereas deaths from violent causes (accidents, intoxication, murder, suicide) were higher in the triennial invitation group.
KQ1a. Does Comparative Effectiveness Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
The included study for KQ1 on screening intervals did not present comparisons that tested or stratified mortality by participant characteristics or risk markers.
Digital Breast Tomosynthesis
No comparative studies reporting morbidity or mortality outcomes for screening with DBT compared with DM were identified.
Magnetic Resonance Imaging
No eligible comparative studies of MRI screening that reported mortality or morbidity health outcomes were identified.
Ultrasound
No eligible comparative studies of ultrasound screening that reported mortality or morbidity health outcomes were identified.
Personalized Screening Programs Using Risk Assessment
No eligible comparative studies of personalized screening that reported mortality or morbidity health outcomes were identified.
KQ2. What Is the Comparative Effectiveness of Different Mammography-Based Screening Strategies on the Incidence and Progression to Advanced Breast Cancer?
Summary of Results
There were no eligible comparative effectiveness studies of the age to start or stop screening that reported the outcome of cancer incidence and progression to advanced cancer across multiple screening rounds.
One older fair-quality RCT (n = 76,022) conducted between 1989 and 1996 randomized individuals to annual or triennial screening.126 The number of screen-detected cancers was higher in the annual screening study arm (RR, 1.64 [95% CI, 1.28 to 2.09]). The total number of cancers diagnosed either clinically or with screening was similar after three years of screening (one triennial incidence screen, three annual incidence screens). Cancers occurring in the annual screening group (including clinically diagnosed cancers) did not differ by prognostic features such as tumor size, node positivity status, or histologic grade compared with those in the triennial screening group. The study did not report mortality outcomes, so it was not possible to ascertain whether the increase in the proportion of cancers detected by screening would influence health outcomes. Estimated effects based on prognostic indices did not predict statistically significant differences in mortality based on the tumor characteristics. Given the timing of the study, applicability is limited due to developments in screening technology, prognostics, and treatment effectiveness.
A fair-quality NRSI used BCSC data (N = 15,440) to compare the tumor characteristics of cancers detected following annual versus biennial screening intervals.154 The reported tumor characteristics were presented in adjusted analyses stratified by age and menopausal status categories. The detection of stage IIB or higher cancers and cancers with less favorable characteristics did not differ by age when comparing annual to biennial screening intervals. For premenopausal individuals, however, a biennial interval preceding diagnosis was associated with having a higher stage tumor (IIB or higher) (RR, 1.28 [95% CI, 1.01 to 1.63]; p=0.04) and tumors with less favorable prognostic characteristics (RR, 1.11 [95% CI, 1.00 to 1.22]; p=0.047). For postmenopausal individuals with and without use of hormone therapy, there was no difference between cancers that were preceded by annual or biennial screening. The study did not conduct formal tests for interaction in the subgroup comparisons.
Results from three RCTs (N = 130,196)129,143,160 and two NRSIs (N = 597,267)144,168 comparing DBT with DM screening reported invasive cancer detection and the characteristics of detected cancers from at least two rounds of screening (study participants were screened with a common modality at the second round). While cancer mortality results are not yet available from the trials, stage shift in the tumor characteristics across screening rounds could offer indirect evidence of potential screening benefit. Two RCTs129,160 and one NRSI144 used DM for all participants at the second screening round and one RCT143 used DBT for all participants at the second screening round. An additional NRSI reported DBT screening outcomes over multiple rounds compared with individuals receiving only DM.168 The three trials showed higher invasive cancer detection at the first round of screening in the DBT arm (pooled RR, 1.41 [95% CI, 1.20 to 1.64]; I2=7.6%; 3 trials; n = 129,492). Results were consistent with these in one NRSI, and not the other. At the second screening round in the RCTs (where all study participants were screened with a common modality), invasive cancer detection was similar for the group assigned to DBT at round one compared with the group assigned DM at round one (pooled RR, 0.87 [95% CI, 0.73 to 1.05]; I2=0%; 3 trials; n = 105,244). Results in the NRSI were not entirely consistent with the trial results; one reported fewer cancers at the second round for those originally screened with DBT144 and another reported no differences in detection by modality at round one or two, but a small difference at round three.168
The three trials and two NRSIs reported tumor characteristics that inform staging such as tumor diameter, histologic grade, or node status. No statistically significant differences in these or other individual tumor prognostic characteristics that were reported at followup rounds of screening were found, but statistical power was limited for comparisons of less common tumor types. None of the three RCTs reported statistically significant differences in cancer stage (stage II or higher) at the second screening round. Other outcomes reflecting potential tumor progression, such as tumor size, nodal status, and grade, also were not statistically different at round two in the trials, including when quantitative pooling was supported. The NRSI reporting findings from two or more rounds of screening with DBT versus DM found no statistically significant difference in screen-detected advanced cancer (−0.06 per 1,000 [95% CI, −0.14 to 0.03]).168 Taken together, these results do not provide evidence that DBT screening generates stage shift or prevents progression to advanced cancer. Limited results stratified by age and breast density reported in the RETomo and To-Be RCTs did not suggest differences in invasive cancer detection at a second round of screening for people who had been screened with DBT at the first screening round, but tests for interaction were not conducted and estimates were imprecise.
We did not identify any studies that reported data from more than a single screening round that could be used to compare shifts in cancer stage to assess the effectiveness of age to start or stop screening, the use of supplemental screening modalities, or personalized screening programs using risk assessment.
Detailed Results by Screening Strategy
Age to Start or Stop Screening
No eligible studies were identified that reported the cancer stage at detection across multiple screening rounds to provide evidence of a beneficial stage shift with screening when commenced earlier or continued to later ages.
Screening Interval
Study and Population Characteristics
Two studies addressed the effect of screening frequency on the characteristics of detected cancers. The fair-quality UKCCCR RCT was conducted as part of the U.K. National Breast Screening Program during the years 1989 to 1996 that randomized people ages 50 to 62 to annual (N = 37,530) or triennial (N = 38,492) breast cancer screening (Table 4).126 No characteristics other than participant age were reported (Table 5). The cumulative incidence of invasive cancer (including screen-detected and invasive cancers) was reported for all participants who attended a prevalence screening visit. The study was designed to compare the incidence of cancer in an annually screened group (three screens after the prevalence screen) and in a triennially screened group (one screen after the prevalence screen). The randomization scheme for the trial was conducted by month of birth for the first two years of the trial but thereafter used a computerized randomization scheme implemented through the national screening program. Cancer outcomes were obtained through searches of the pathology reports and databases maintained by hospitals involved in the U.K. National Breast Screening Program. Reports from pathologists on the prognostic factors for each cancer were obtained and reviewed by two consultants. Size, node status, and histological grade were also used to code prognostic indices for the cancers (e.g., Nottingham Prognostic Index). The analysis of cancer prognostic characteristics included both screen-detected and interval cancers. The study also reported the tumor diameter, lymph node positivity, and histologic grade for all of the cancers diagnosed during the study, including interval and screen-detected cancers.
A fair-quality BCSC NRSI by Miglioretti et al. used data on cancers detected in the BCSC registries from 1996 to 2012 (Table 4).154 The study compared the interval of screening relative to the characteristics of screen-detected and interval cancers. Individuals were included in the analysis if their cancer was preceded by at least two screening mammograms either 11 to 14 months apart (annual interval) or 23 to 26 months apart (biennial interval). The characteristics of women with cancers preceded by an annual screening interval (n = 12,070) and those preceded by a biennial interval (n = 3,370) differed on some reported factors; those with an annual interval preceding a cancer diagnosis were less likely to be ages 40 to 49 (14% versus 18%) or 70 to 85 (29% versus 27%), and more likely to have a first-degree family history of breast cancer (23% versus 18%). The groups did not differ in race and ethnicity composition, and over three-quarters of the study population was non-Hispanic White (78%), with the remaining participants reported as Black (5%), Asian (5%), Hispanic (5%), AI/AN (<1%), and 7% reported as “other” or unknown (Table 5). This study did not report overall effects of the screening interval on cancer detection by stage, but provided detailed results on the stage at detection stratified by age and menopausal status that are reported as KQ2a results below.
Outcomes
Screen-Detected Invasive Cancer and Prognostic Characteristics by Round
In the UKCCCR, there were more invasive screen-detected cancers detected in the annual screening arm (4.42 per 1,000 people screened, representing 71% of overall cancers) compared with the triennial screening arm (2.70 per 1,000 people screened, representing 50% of overall cancers) (RR, 1.64 [95% CI, 1.28 to 2.09]) (Table 6). After three years of screening (three incidence screens in the annual arm, one incidence screen in the triennial arm) a similar number of cancers (screen-detected and interval cancers) had been diagnosed in the annual screening arm (6.26 per 1,000 screened) and the triennial screening arm (5.40 per 1,000 screened) (RR, 1.16 [95% CI, 0.96 to 1.40]). In comparisons of all cancers that occurred over the course of the study, including interval and screen-detected, there were no statistically significant differences in tumor size, nodal status, histological grade, or the prognosis (Table 6). Mortality data from the study have not been reported, but based on estimates from the prognostic indices, the authors concluded that annual screening confers lead time bias (estimated to be ~6 months) but did not result in downstaging of screen-detected cancers that would influence breast cancer survival or risk of death.
KQ2a. Does Comparative Effectiveness Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
The Miglioretti BCSC NRSI reported the tumor characteristics and a prognostic characteristic variable for cancers diagnosed among individuals with an annual or biennial screening interval preceding their diagnosis, stratified by age (40 to 49, 50 to 59, 60 to 69, 70 to 85) and by menopausal status.154 The adjusted analysis presented in the study compared those with a biennial versus an annual interval preceding their diagnosis. Screen-detected and interval cancers (12 months followup for annual screened, 24 months followup for biennial screened) were included in the comparisons (Table 7). The relative risk of being diagnosed with a stage IIB or higher cancer was not statistically different for biennially compared with annually screened women in any of the age categories. The composite variable indicating less favorable prognostic characteristics (stage IIB+, tumor size >15 mm, or node-positive) also was not statistically different for any age group comparing those biennially versus annually screened before their diagnosis. Analyses comparing stage (IIB or higher) and less favorable prognostic tumor characteristics stratified by menopausal status showed statistically significant effects of the screening interval. The risk of a stage IIB or higher diagnosis was higher for premenopausal women screened biennially compared with annually (RR, 1.28 [95% CI, 1.01 to 1.63]; p=0.04). Similarly, a marginally significant increased risk of having a tumor with less favorable prognostic characteristics was seen for premenopausal women when they had been screened biennially versus annually prior to their diagnosis (RR, 1.11 [95% CI, 1.00 to 1.22]; p=0.047). For postmenopausal individuals (with and without hormone therapy use), tumor stage and prognosis were statistically similar when preceded by annual or biennial screening. The study did not conduct formal tests for interaction in the subgroup comparisons and did not adjust for multiple comparisons.
Digital Breast Tomosynthesis
Study and Population Characteristics
We included three RCTs129,143,160 and two NRSIs144,168 that reported cancer detection across more than one round of screening and could therefore be used to assess invasive cancer detection and stage shift across screening rounds as an intermediate outcome to compare the effectiveness of DBT with DM screening (Table 4). Overall, population characteristics were sparsely reported for the trials (Table 5).
The fair-quality Proteus Donna RCT conducted in Italy reported screening results from two rounds of screening with randomization to DBT/DM (n = 30,844) or DM (n = 43,022) for the first round of screening and DM screening for all participants at the second round of screening.129 Participants in the national screening program from ages 46 to 49 were offered annual screening if they opted to participate in the screening program, and routine screening in the program was offered biennially for women ages 50 to 68. Recruitment began in December 2014 and the trial was completed in December 2017. The mean age of participants was 57 years; information on breast density was not reported. Independent double reading was used with participants recalled based on the recommendation of either radiologist.
A good-quality RCT conducted in northern Italy reported on the characteristics of cancers detected at two consecutive rounds of screening. The Reggio Emilio Tomosynthesis study (RETomo) prospectively randomized women to undergo DBT/DM (n = 13,356) or DM (n = 13,521) at baseline followed by DM screening for all eligible participants one or two years later.160 Women ages 45 to 49 were offered annual screening and those ages 50 to 69 were offered biennial screening. Followup is ongoing, and to date results have been reported over two rounds of screening, with an additional nine months of followup to obtain the final diagnosis for cancers detected at the second screening round. Participants were women ages 45 to 69 who had participated in the regional screening program but had never received a DBT examination. Just over one-third (38%) of participants were ages 45 to 49 at the first screening round in both study arms and the mean age was 55. Breast density category distributions were similar, with 9 percent of women classified as having very dense breasts. In both study arms, two radiologists independently read the images and a third reader made the final judgment in cases of disagreement (usual screening program practice). Followup evaluations and final diagnosis results were obtained from screening program and cancer registry databases.
The To-Be study is a good-quality RCT conducted in Norway that randomized participants to DBT/sDM screening (n = 14,380) or DM screening (n = 14,369) and followed them for two years, or until the next screening episode.143 The second screening round consisted of DBT/sDM for all participants. Therefore, outcomes at the second screening round with DBT/sDM were compared between those originally screened with DBT/sDM (n = 11,201) and those originally screened with DM (n = 11,105). The study was conducted within the population-based BreastScreen Norway program, which offers all women ages 50 to 69 biennial mammogram screening. The mean age of study participants was 60 years, with 7 percent of women classified as having very dense breasts. In this program, independent dual reading with consensus is standard and prior mammograms, if available, are used to assist image reading. The first round of screening was conducted in January 2016 through December 2017 and the second screening in January 2018 through January 2020.
A fair-quality NRSI using a concurrent geographical comparison cohort design was conducted within the BreastScreen national screening program in Norway. The Oslo-Vestfold-Vestre Viken (OVVV) cohort was used to compare cancer screening outcomes from one round of screening with DBT/sDM (n = 37,185) or DM (n = 61,742) and a second round of DM for all attending the consecutive round of screening (n = 72,017).144 Individuals screened in Oslo received DBT at the baseline screening round and DM in the consecutive round, and in Vestfold and Vestre Viken DM screening was provided at both rounds. Those ages 50 to 69 years presenting to be screened in Oslo, Vestfold, and Vestre Viken from February 2014 to December 2015 were included in the cohort. In this program, biennial screening is provided, so the second screening visit (for those not diagnosed at baseline) occurred two years later. Those participating in BreastScreen were assigned to the baseline screening modality based solely on their county of residence and were not given an option to select the screening type. The mean age of study participants was 59; data on breast density were not reported. In the BreastScreen Norway program, independent double reading of mammography images with random pairs of breast radiologists are used to determine the mammography result.
A fair-quality NRSI by Sprague et al. used retrospective cohort data from 58 clinical sites from five BCSC registries (Carolina, Chicago, New Hampshire, San Francisco, Vermont) to compare DBT with DM-only screenings conducted within 30 months of a prior screening mammogram.168 All women ages 40 to 79 obtaining such DBT and DM screenings from the years 2011 to 2020 were included (n = 504,843). Thus, all included mammograms were subsequent screenings, and participants could contribute data from multiple consecutive screening rounds. Because all study participants were selected based on having a prior screening history, all screening results reported in the study represent subsequent screening visits, including those designated “round one.” Examinations were also excluded if supplemental screening with ultrasound (within 3 months) or MRI (within 12 months) was conducted. The screening modality was coded as DM only if there was no known prior history of DBT screening. Followup on screening outcomes was obtained using databases including SEER, BCSC, and state/regional tumor registries and examinations with less than one year of followup data for cancer diagnosis were excluded. Advanced statistical analyses were conducted to account for the clustered data structure (women within radiologists within facilities) and differences in breast cancer risk characteristics across modality and screening round. Adjustment for age, breast density, race or ethnicity, time since last mammogram, BCSC 5-year invasive cancer risk, benign breast disease history, first-degree family history of breast cancer, and examination year was conducted for all study estimates. The analytic sample included 1,531,608 examinations after exclusions for diagnostic evaluations and other factors. Screening using DBT was more common among non-Hispanic White women with a family history of breast cancer and individuals with an annual screening frequency. Overall, women receiving DBT examinations were at higher 5-year invasive breast cancer risk and those with multiple rounds of DBT screening were more likely to be at high risk than those with just one subsequent DBT screening round.
Outcomes
Screen-Detected Invasive Cancer and Prognostic Characteristics by Screening Round
Three trials randomized participants to DBT or DM at a first round of screening, followed by a second round of screening with either DM for everyone (Proteus Donna, RETomo) or DBT for everyone (To-Be). One NRSI with a concurrent geographic comparison design compared people receiving DBT/sDM or DM at a first screening round and DM for everyone in the second round (OVVV). A second NRSI used BCSC data to compare individuals screened with DBT versus those receiving DM over at least two screening rounds. The 2D image accompanying DBT (DM or sDM) was not reported (Table 8).
The three RCTs reported increased detection of invasive cancer with DBT at the first round of screening (pooled RR, 1.41 [95% CI, 1.20 to 1.64]; I2=7.6%; 3 trials; n = 129,492) and effects in the opposite direction, but not statistically different at second round screening (pooled RR, 0.87 [95% CI, 0.73 to 1.05]; I2=0%; 3 trials; n = 105,064) (Figure 3).129,143,160 Information on the characteristics of cancers detected at each screening round can help with indirect inferences about whether the additional or earlier cancer detection at the first round of screening would affect health outcomes. Two RCTs conducted in Italy reported detection of cancers stage II or higher and the same variable was obtained via author communication from the To-Be study. There was no difference within any of the studies in the detection of stage II or higher cancers at either round of screening, and results were inconsistent at round two, with one trial nearing statistical significance for more stage II+ cancers and the other two trials in the direction of reduced stage II+ cancer in the DBT arm.
In the Proteus Donna trial, the DBT study arm detected more invasive cancers during the first round of screening (7.3 versus 5.0 per 1,000 screened; RR, 1.46 [95% CI, 1.21 to 1.77]) and at the second round the detection of invasive cancers was not statistically different between arms (RR, 0.85 [95% CI, 0.64 to 1.13]).129 For the RETomo trial, detection of invasive cancer was higher for the DBT/DM study arm at round one (RR, 1.60 [95% CI, 1.16 to 2.22]) with a rate of 6.3 versus 3.9 per 1,000 screened.160 Detection at second round screening (all DM) did not differ by study arm (RR, 0.90 [95% CI, 0.62 to 1.30]) (Figure 3). There were no statistical differences in the characteristics of screen-detected cancers at either screening round, including cancers detected at stage II or higher, tumor size, histologic grade, or node status (Table 8, Figures 4–7).
The To-Be RCT randomized people to DBT/sDM or DM in the first round of screening followed by DBT/sDM for all at the second round of screening.143 There was not a statistically significant difference between study arms in the detection of invasive cancer at the first round of screening using DBT or DM (5.6 versus 4.9 per 1,000 screened, respectively; RR, 1.13 [95% CI, 0.82 to 1.55]) or the subsequent screening round using DBT for all participants (6.9 versus 7.8 per 1,000 screened, respectively; RR, 0.88 [95% CI, 0.65 to 1.19]). No statistical differences in tumor stage, tumor size, histologic grade, or nodal status were seen for cancers detected in the DBT/sDM arm compared with the DM arm (Table 8, Figures 4–7).
The OVVV NRSI reported on a single round of screening with DBT/sDM followed by DM at the subsequent round of screening two years later compared with a concurrently screened group from another region that was screened with DM at both rounds. More invasive cancers were detected at the first round of screening for those in the DBT/sDM screened region (7.6 versus 5.3 per 1,000 screened; RR, 1.43 [95% CI, 1.22 to 1.67]). During the second round of screening, where all received DM, the incidence of screen-detected invasive cancer was lower in the arm that received DBT/sDM at the first round (3.2 versus 4.5 per 1,000 screened; RR, 0.71 [95% CI, 0.55 to 0.92]) compared with those who received DM at both screens. The study did not report cancer stage but reported some characteristics of the screen-detected invasive cancers. No statistical differences were identified between cancers detected by either arm, including tumor diameter, histologic grade, and node status (Table 8).
The BCSC NRSI by Sprague et al. reported screening outcomes by round, with round one reflecting a screening examination occurring within 30 months of a prior examination and round two providing screening results from an additional screening round with either DBT or DM, and so on. In adjusted analyses, the invasive cancer detection at round one with DBT was 4.8 per 1,000 (95% CI, 4.4 to 5.2) and with DM was 4.4 per 1,000 (95% CI, 3.8 to 5.2), and no statistical difference was observed (absolute difference, 0.4 per 1,000 [95% CI, −0.4 to 1.2]). In adjusted analyses, the invasive cancer detection at rounds one and two with DBT was not statistically different from DM (absolute difference, 0.4 per 1,000 [95% CI, −0.4 to 1.2] and 0.4 per 1,000 [95% CI, −0.2 to 0.9], respectively). At round three, invasive cancer detection with DBT was 3.9 per 1,000 (95% CI, 3.6 to 4.4) and with DM was 3.4 (95% CI, 3.1 to 3.8), and the difference was 0.6 per 1,000 more invasive cancers detected with DBT (95% CI, 0.2 to 1.1). The detection of advanced cancer was not statistically different for DBT compared with DM at round one (0.21 versus 0.26 per 1,000; difference of −0.5 per 1,000 [95% CI, −0.19 to 0.09]) or for rounds two and above (0.13 versus 0.20 per 1,000; difference of −0.6 per 1,000 [95% CI, −0.14 to 0.03]).
The number of examinations was highest at the first round (DBT, 207,280; DM, 355,944) and comparisons of less common outcomes combined examinations from rounds two and higher (DBT, 316,205; DM, 652,179). Characteristics of the two study groups diverged considerably at round three compared with round one in terms of the race and ethnicity composition of the women screened as well as the timing of screening and breast cancer risk (non-Hispanic White and more frequently screened women more heavily represented in later rounds). There were also differences in the composition of the screened population for both groups at higher rounds compared to the first round (e.g., higher BCSC 5-year risk at round three).
KQ2a. Does Comparative Effectiveness Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
None of the included studies were designed to enroll populations to support comparisons in the screening outcomes of DBT and DM by race, ethnicity, or family history.
Age- and breast density–stratified analysis of cancers detected at the second round of screening was reported in the RETomo RCT. As in the overall population, DBT resulted in a higher invasive cancer detection at the first round of screening for women ages 50 to 69 (RR, 1.60 [95% CI, 1.10 to 2.30]) and for women with nondense breasts (RR, 1.80 [95% CI, 1.10 to 3.00]), but at the next round of screening when all were screened with DM, there was not a statistically significant difference in invasive cancer detection. For women ages 45 to 49 and women with dense breasts, there was no statistical difference in the detection of invasive cancers at either round of screening (Table 9). No test for interaction was conducted for either the age- or density-stratified analyses and no information on the characteristics of the screen-detected tumors was provided.
Density-stratified results were presented in the To-Be RCT. No statistical difference was seen for detection of invasive cancer using DBT or DM for any breast density subgroup at both round one and two of screening (Table 9).
Magnetic Resonance Imaging
No eligible studies were identified that reported on cancer detection and characteristics over multiple rounds of screening comparing usual care mammography with mammography plus supplemental MRI screening.
Ultrasound
No eligible studies were identified that reported on cancer detection and characteristics over multiple rounds of screening comparing usual care mammography with mammography plus supplemental ultrasound screening.
Personalized Screening Programs Using Risk Assessment
No eligible studies were identified that reported on cancer detection and characteristics over multiple rounds of screening comparing usual care mammography personalized screening programs using risk assessment.
KQ3. What Are the Comparative Harms of Different Breast Mammography-Based Cancer Screening Strategies?
Summary of Results
One NRSI with an emulated trial design used Medicare data to estimate the effects of screening beyond age 70 compared to stopping at ages 70 or 75.136 No difference was found in 8-year breast cancer mortality for screening beyond age 75 compared with stopping at that age. Cancers diagnosed in the stop screening strategy were more likely to receive aggressive treatment.
One RCT126 and four NRSIs140,153,154,159 reported potential harms of screening with respect to the screening interval. One RCT reported approximately 1 fewer interval cancer per 1,000 with annual screening compared with triennial screening. Data related to interval cancer risks were limited in the four NRSIs for comparisons of different screening periods.140,153,154,159 False-positive recall was more likely to occur with annual screening compared with longer intervals between screenings. The probability of false-positive recall and biopsy over 10 years of screening was higher with annual screening. The highest cumulative false-positive estimates occurred among young people with dense breasts screened annually.
Three large RCTs found no statistically significant difference in the rates of interval cancers following screening with DBT compared with DM (pooled RR, 0.87 [95% CI, 0.64 to 1.17]; I2=0%; 3 trials; n = 130,196) (Figure 10).129,143,160 Data on interval cancers from six NRSIs were mixed, and interpretation was limited by differences in study design. The effects of DBT screening on recall, false-positive recalls, and biopsy rates varied between trials and by screening round, with no or small statistical differences between study groups, not consistently favoring DBT or DM. The cumulative rates of false-positive recall and false-positive biopsy were slightly lower with DBT compared with DM screening, regardless of screening interval (cumulative probability over 10 years: 50% versus 56% for annual screening, 36% versus 38% with biennial screening). No statistically significant differences were seen in the trials related to DCIS detection or adverse events. Rates of radiation were approximately two times higher when DBT was performed in addition to DM; however, these increases were not present in two studies using DBT to generate synthetic DM images (DBT/sDM). Data on subgroups were limited, with all but one of the studies providing stratified results only, without tests for interaction.
One RCT reported on the effects of an invitation to screening MRI for women ages 50 to 75 with extremely dense breasts following a negative mammogram.164 The risk of invasive interval cancer was reduced by approximately half (RR, 0.47 [95% CI, 0.29 to 0.77]) after the first invitation and prior to the next screening round (2 years). MRI resulted in additional recall, false-positive recall, and biopsy (95, 80, and 63 per 1,000 screened, respectively) that did not occur for the DM-only group. An NRSI analysis of U.S. insurance claims data found that health care use related to conditions that were not breast-related (a measure of possible incidental findings) was higher following screening with MRI compared with receiving mammography screening only.135
One RCT of women ages 40 to 49158 and one NRSI of BCSC data152 reported outcomes related to the potential harms of supplemental ultrasound screening. In the analyses comparing event rates presented in our review, there was not a statistically significant difference in interval cancer rates between study groups in either study. In the trial, additional recalls (48 per 1,000 screened) were experienced by those screened with ultrasound. In the BCSC analysis, referral to biopsy and false-positive biopsy results were twice as high for the group screened with ultrasound.
No eligible studies were identified that reported on the potential harms of personalized screening programs using risk assessment.
Detailed Results by Screening Intervention
Age to Start or Stop Screening
Study and Population Characteristics
One fair-quality NRSI (N = 1,058,013) analyzed data to emulate a trial of discontinuation of mammography screening between the ages of 70 and 84 compared with continued annual screening (described in detail for KQ1 above) (Table 4).136 Additional details on study design are available in Appendix E.
Outcomes
Overdiagnosis and Overtreatment
Overall, the 8-year cumulative risk of a breast cancer diagnosis was higher for the continued annual screening strategy after age 70 (5.5% overall; 5.3% ages 70 to 74, 5.8% ages 75 to 84) compared with the stop screening strategy (3.9% overall; same proportion for both age groups) (Table 10). Lumpectomy and radiotherapy were more common for cancers diagnosed in the continued annual screening strategy compared with those who stopped screening after age 70, whereas mastectomy and chemotherapy were more common for cancers diagnosed in those who discontinued screening after age 70 (Table 10). Overall, because fewer cancers were diagnosed under the stop screening strategy (ages 70 to 84), there was a lower risk of undergoing followup and treatment. For those ages 75 to 84, additional diagnoses did not contribute to a difference in the risk of breast cancer mortality.
KQ3a. Do Comparative Harms Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
No studies of ages to start or stop screening presented data that would allow for testing of effect differences or stratification of results by different population characteristics or risk markers.
Screening Interval
Study and Population Characteristics
Three of the studies included to address potential harms of different screening intervals have been described previously in KQs 1 and 2.126,154,159 Two additional studies examined the potential cumulative harms across multiple rounds of screening (Table 4). One analysis of 2005 to 2018 data from the BCSC estimates the cumulative probability of a false-positive result after 10 years of screening with DM or DBT.140 The second additional study was the Know Your Risk: Assessment at Screening (KYRAS) study that calculated the cumulative risk of false-positive screens over a median of 8.9 years at Columbia University Medical Center.153
Demographic characteristics were not commonly reported in the studies of screening interval (Table 5). The BCSC study population reported by Miglioretti was primarily White (78%), with the remaining participants reported as Black (5%), Asian (5%), Hispanic (5%), AI/AN (<1%), and 7% reported as “other” or unknown. In the KYRAS study, the population was majority Hispanic (76%), with the remaining reported as White (10%), Black (10%), or other (4%) including Asian, Pacific Islander, Native American, or Alaska Native. Twenty-four percent of the non-Hispanic White women were of Ashkenazi Jewish descent. Additional details on study design are available in Appendix G.
Outcomes
Interval Cancers
Three studies presented data on interval cancers by participant screening interval with mixed findings (Table 11). The UKCCCR RCT reported the rate of interval cancers was significantly lower in the annual invitation group (1.84 per 1,000 women initially screened) than in the triennial invitation group (2.70 per 1,000 women initially screened) (RR, 0.68 [95% CI, 0.50 to 0.92]). The Parvinen et al. quasi-randomized study found that similar numbers of cases were reported in the annual screening and triennial screening groups, and a statistical test for the difference was null (p=0.22). The Miglioretti et al. BCSC NRSI found that 22.2 percent of cancers diagnosed following an annual screening interval were interval cancers compared with 27.2 percent of cancers proceeded by a biennial interval. However, the study did not provide adjusted comparisons, limiting the ability to draw inferences about differences in the interval cancer rate associated with biennial and annual screening from this study.
False-Positive Recall
Based on two studies, false-positive recall was more likely to occur with annual screening compared with longer intervals. A NRSI of BCSC data by Ho estimated the 10-year cumulative probability of at least one false-positive recall was 49.6 percent for those screened annually and 35.7 percent for those screened biennially (proportion difference, −13.9% [95% CI, −14.9% to −12.8%]). The difference in cumulative false-positive recall between annual and biennial screening was larger for DM (−18.2 [95% CI, −18.6 to −17.7]) (Figure 8, Appendix F Tables 3 and 4). In the KYRAS study, individuals screened with DM annually had 2.18 times the odds of having a false-positive result compared with those who screened biennially (odds ratio, 2.18 [95% CI, 1.70 to 2.80]) after controlling for total years of followup, age, race and ethnicity, BMI, breast density, and breast cancer risk status (Appendix F Table 4).
False-Positive Biopsy
The comparative NRSI from Ho used data from the BCSC and found biennial screening compared with annual screening led to a 5 percent lower 10-year cumulative false-positive biopsy rate whether the screening was conducted with DBT or DM (Figure 9, Appendix F Tables 3 and 4). For individuals screened with DBT, the estimated cumulative probability of at least one false-positive biopsy recommendation was 11.2% for those screened annually and 6.6% for those screened biennially (proportion difference, −4.6% [95% CI, −5.2 % to −3.9%]). For individuals screened with DM, the difference was similar (proportion difference, −5.0% [95% CI, −5.4% to −4.7%]).
KQ3a. Do Comparative Harms Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
The Ho et al. BCSC NRSI reported 10-year cumulative false-positive and biopsy rates by age and breast density category. Annual screening was associated with higher cumulative false-positive recall and biopsy for most age and density groups (Figures 8 and 9). There was not a strong association between age and cumulative false-positive biopsy regardless of the screening interval among those with the lowest breast density (Figures 8 and 9, Appendix F Tables 5 and 6).
Digital Breast Tomosynthesis
Study and Population Characteristics
We identified 10 eligible studies, four RCTs (three good-quality, one fair-quality),129,139,143,160 and seven fair-quality NRSIs79,132,140,144,147,162,168 that reported on potential harms of screening associated with the use of DBT (plus DM or sDM) compared to DM-only screening (Tables 4 and 5). Four large trials were conducted with individuals participating in organized screening programs in Germany, Italy, and Norway. Three of these trials were previously discussed in KQ2.129,143,160 One additional RCT was identified that addresses the potential harms of screening with DBT compared with DM. The TOmosynthesis plus SYnthesised MAmmography Study (TOSYMA) is a good-quality RCT conducted in Germany that assigned 99,634 women ages 50 to 69 to DBT/sDM (DBT with synthetic two-view imaging) versus DM alone between July 5, 2018, and December 30, 2020. Available results from the trial report on performance at a single round of screening and for this review was included only for rare or uncommonly reported harms (adverse events, radiation exposure).139 The seven NRSIs included for KQ3 were conducted using data from populations screened with DBT and DM in the United States,132,140,147,162,168 Sweden,79 and Norway144 (Tables 4 and 5). Additional details on study design and results are available in Appendix G.
Outcomes
Interval Cancers
Three trials reported interval cancers following screening with DBT or DM (Table 12).129,143,160 The three RCTs did not show statistically significant differences in the risk of interval cancer following screening with DBT or DM (pooled RR, 0.87 [95% CI, 0.64 to 1.17]; I2=0%; 3 trials; n = 130,196) (Figure 10). Six observational studies used data from medical systems, registries, and cancer screening and surveillance programs to compare interval cancers occurring after screening with DBT or DM (Table 12). Four of the NRSIs found no significant difference in the rate of interval cancers diagnosed following screening with DBT or DM (including data from the BCSC, PROSPR consortium, and the OVVV comparative cohort study),132,144,147,168 while one found a slight increased risk with DBT screening162 and one found an unadjusted decreased risk with DBT screening.79 These studies differed in the timeline of followup and method of identifying interval cancers (Appendix E Table 1), highlighting the variability in interval cancer definitions and data used to assess the outcome across the included NRSIs and the need for more standardization of definitions and study protocols.
Recall
The same three RCTs and two NRSIs included for KQ2 reporting data across multiple rounds of screening were also included to assess screening recall rates and false-positive recalls (Tables 13 and 14). In the trials, results for recall and false-positive recall were mixed across the first round of screening, and statistical heterogeneity was high, so a pooled effect is not presented. The studies varied in their approaches to screening at round two: two RCTs used DM screening for both study groups (Proteus Donna, RETomo) and one used DBT for both study groups (To-Be) at round two. Results for round two were more consistent and did not suggest a difference in recall rates or false-positive recalls between study groups when combined using meta-analysis (Figures 11 and 12).
The fair-quality BSCS NRSI by Sprague et al. reported lower recall and lower false-positive recall at round one and round two screening with DBT compared with DM (Tables 13 and 14). The difference in false-positive recall at round one was 34 fewer per 1,000 examinations with DBT versus DM (95% CI, 22 to 47 fewer) and at round two was 18 per 1,000 fewer with DBT (95% CI, 7 to 30 fewer). False-positive recall was not statistically lower with DBT versus DM among those included for round three comparisons (−11 per 1,000 [95% CI, 23 fewer to 2 additional]).
The fair-quality NRSI OVVV study did not report statistically significant difference in recall rates between the DBT and DM arms at round one (Tables 13 and 14). At round two, when both groups received DM, false-positive recall rates were lower in the group previously screened with DBT compared with the DM group (20 versus 25 per 1,000).
Biopsy and Surgical Followup
Two of the included RCTs reported on the rate of referral to biopsy143,160 and two reported on referral to surgery following screening129,160 (Table 13). At round one, when the trials compared screening with DBT and DM, there were mixed results, with one trial finding a significantly higher rate of referral to biopsy with DBT and another trial finding no difference in referral to biopsy or false-positive biopsy rates. Two trials found that the referral to surgery was higher among those screened with DBT. The RETomo RCT reported higher referrals to surgical followup, including open biopsy, following DBT screening (8.7 versus 5.0 per 1,000; RR, 1.70 [95% CI, 1.3 to 2.30]). Findings from the Proteus Donna RCT were similarly higher for surgical referrals following DBT/DM (9.9 versus 6.4 per 1,000; RR, 1.54 [95% CI, 1.31 to 1.82]).
The trials screened both study groups with an identical modality at the second round, and effects should be interpreted as findings from screening following previous round of screening with DBT or DM. Overall, no significant difference between arms was found for rates of biopsy at round two. The Proteus Donna trial129 found a lower risk of surgical referrals among those originally screened with DBT (4.3 versus 5.7 per 1,000; RR, 0.76 [95% CI, 0.59 to 0.97]); however, this finding was not confirmed by RETomo, where screening was with DM in both study groups at round two (5.3 versus 6.4 per 1,000; RR, 0.83 [95% CI, 0.60 to 1.10]).
One fair-quality BCSC NRSI by Sprague et al.168 reported slightly lower biopsy and false-positive biopsy at round one with DBT compared with DM (Tables 13 and 14). The difference in false-positive biopsy at round one was 3 fewer per 1,000 screening examinations with DBT (95% CI, 2 to 5 fewer). False-positive biopsy rates were similar for DBT and DM for those included for two or more screening rounds.
Cumulative False-Positive Recall and Biopsy
The comparative BCSC NRSI from Ho et al. reported the estimated cumulative probability of having at least one false-positive recall and biopsy over 10 years of screening with DBT or DM on an annual or biennial basis (Figures 8 and 9, Appendix F Tables 3 and 4). Probabilities were mostly lower with DBT screening compared with DM screening, regardless of the screening interval, but the difference was greater with annual screening. With annual screening, the 10-year cumulative probability of a false-positive recall was 49.6% with DBT and 56.3% with DM (difference, −6.7% [95% CI, −7.4 to −6.1]). The 10-year cumulative probability of a false-positive biopsy was 11.2% with DBT and 11.7% with DM (difference, −0.5 [95% CI, −1.0 to −0.1]). With biennial screening, the 10-year cumulative probability was 35.7% for DBT and 38.1% for DM (difference, −2.4% [95% CI, −3.4 to −1.5]) and the 10-year cumulative probability of a false-positive biopsy was 6.6% for DBT and 6.7% for DM (difference, −0.1% [95% CI, −0.5 to 0.4]).
Overdetection and Overtreatment
In the three RCTs, rates of DCIS detected at each screening round and between study arms were similar, ranging from 0.7 to 1.3 per 1,000 screened at the first screening round and from 0.6 to 1.3 per 1,000 screened at the second screening round, with no statistical differences between the DBT and DM screened groups (Table 15). Meta-analysis was used to generate combined estimates that also did not show statistically significant differences at round one (pooled RR, 1.33 [95% CI, 0.92 to 1.93]; I2=0%; 3 RCTs; n = 130,196) or round 2 (pooled RR, 0.75 [95% CI, 0.49 to 1.14]; I2=0%; 3 RCTs; n = 130,196) (Figure 14). The OVVV NRSI reported higher DCIS detection at the first screening round in the DBT group compared with the DM group (1.8 versus 0.8 per 1,000 screened; RR, 2.16 [95% CI, 1.49 to 3.12]).
Adverse Events
The TOSYMA RCT reported on adverse events from a single round of screening using DBT/sDM compared with DM only.139 The study randomized 49,804 individuals to DBT/sDM and 49,830 to DM. Six adverse events were reported in each study arm, with none categorized as serious.
Radiation Exposure
Five studies (four RCTs, one NRSI) reported the median, mean, or relative radiation dose by study arms from a single screening round (Table 16). In three of these studies, participants underwent a DBT and DM screening (in one or two compressions) and in two studies, participants underwent DBT with a synthetic reconstruction of a 2D DM image.139,143 Studies using DBT/DM screening reported radiation exposure approximately two times higher in the intervention group compared with the DM-only control group.79,129,160 Differences between study groups in radiation exposure were smaller in studies using DBT/sDM. The TOSYMA RCT reported median glandular radiation dose in the DBT/sDM group was 1.86 mGy (interquartile range, 1.48 to 2.45) and in the DM group was 1.36 mGy (interquartile range, 1.02 to 1.85).139 In the To-Be RCT, which also used DBT/sDM, the mean radiation dose was 2.96 mGy compared with 2.95 mGy in the DM group.128
KQ3a. Do Comparative Harms Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
None of the included studies were designed to enroll populations to support comparisons in the screening outcomes of DBT and DM by race, ethnicity, or family history. Two RCTs143,160 and four NRSIs79,140,147,162 that compared DBT-based screening strategies with DM-only screening strategies presented results stratified by age and/or breast density. Most studies did not report interaction tests and were not designed to test these subgroup comparisons, making it difficult to draw conclusions about differences by age and/or breast density.
Age
The RETomo RCT reported the effects of DBT/sDM versus DM on recall, biopsy, and surgical procedures stratified by age category (45 to 49 versus 50 to 69) (Tables 17 and 18). Overall, these stratified results suggest some risk of increased biopsy or surgery with DBT screening at the first round for all, followed by lower rates at the next round for those ages 45 to 49. One trial160 and two NRSIs79,162 reported no significant findings related to the relationship between age and interval cancer outcomes (Table 19). Two of these studies did not report interaction tests, making it difficult to draw conclusions about differences by age group.
Breast Density
The To-Be trial reported recall and biopsy stratified by Volpara density grade categories (VDG1–VDG4). There was lower recall at the first screening round for those screened with DBT who had lower density breasts (VDG1 and VDG2) but not for those with higher density breasts (VDG3 and VDG4) (Table 17). Two trials143,160 and one analysis of BCSC data147 found no statistically significant differences in the incidence of interval cancer for the breast density–stratified comparisons (Table 19).
The To-Be RCT reported mean radiation doses for the study groups, stratified by breast density in a figure. The study reported that there were no statistically significant differences in radiation dose for DBT/sDM compared with DM for any of the density categories.
Age and Breast Density Subgroups
The Ho et al. BCSC NRSI presented 10-year cumulative false-positive recall and biopsy probabilities stratified by breast density and age, comparing DBT to DM screening. Overall, the study reported lower false-positive recall with DBT screening. In stratified analyses, however, there was not a statistical difference in cumulative false-positive recall or biopsy among those with extremely dense breasts in any age group (Figure 13).
Magnetic Resonance Imaging
Study and Population Characteristics
The Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial is a good-quality RCT conducted in The Netherlands that enrolled participants from December 2011 to November 2015 (N = 40,373) (Table 4). The aim of the study was to determine whether an invitation to supplemental MRI screening after a negative mammogram for those ages 50 to 75 with extremely dense breast tissue would reduce the incidence of interval cancer. The baseline characteristics of the study groups were balanced on the reported characteristics (Table 5). Among those invited to MRI screening, 59 percent underwent the MRI examination (n = 4,783). While this study included two rounds of screening with MRI, findings from the second round of screening in the mammography-only arm have not been published. Therefore, this study was not eligible for inclusion in KQ2, but it is included for interval cancers and potential harms of supplemental MRI imaging.
A fair-quality NRSI compared commercially insured women ages 40 to 64 in the MarketScan database who had received at least one bilateral screening breast MRI (n = 9,208) or mammogram (n = 9,208) between January 2017 and June 2018 (Tables 4 and 5). Propensity score matching was used to compare cascade events (mammary and extramammary) in the six months following the MRI or mammogram that were potentially attributable to having a breast MRI. Additional details on study design and results are available in Appendix G.
Outcomes
Interval Cancers
In the DENSE RCT, the intention-to-treat analysis based on invitation to MRI screening found a rate of invasive interval cancers for the DM+MRI of 2.2 per 1,000 invited to screening compared with 4.7 per 1,000 screened for the DM-only control group (RR, 0.47 [95% CI, 0.29 to 0.77]) (Table 12).
Adverse Events
In the DENSE RCT, eight adverse events (including five classified as serious adverse events) occurred during or immediately after the MRI screening. Adverse events included two vasovagal reactions and three allergic reactions to the contrast agent (serious adverse events) as well as two reports of extravasation (leaking) of the contrast agents and one shoulder subluxation. Twenty-seven individuals (0.6% of MRI arm) reported a serious adverse event within 30 days of the MRI.
Downstream Consequences of Supplemental Imaging, Including Incidental Findings
In the first round of the DENSE trial, the rate of recall among those who underwent additional imaging with MRI was 94.9 per 1,000 screens and the false-positive rate was 79.8 per 1,000 screened. The rate of biopsy for those undergoing supplemental MRI was 62.7 per 1,000 screened (Table 20). Among the cancers diagnosed by MRI, over 90 percent were classified as DCIS (stage 0) or stage 1 cancer. Without information for two rounds of screening from both arms of the study, there is not sufficient information to weigh the relative benefit versus harms of these diagnoses and downstream imaging consequences.
In the U.S. insurance claims NRSI, individuals who had an MRI compared to those receiving only a mammogram were more likely in the subsequent six months to have additional cascade events (adjusted difference between groups, 19.6 per 1,000 screened [95% CI, 8.6 to 30.7]) and were mostly comprised of additional health care visits. (Table 20).
KQ3a. Do Comparative Harms Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
No studies of supplemental MRI screening presented data that would allow for testing of effect differences or stratification of results by different population characteristics or risk markers.
Ultrasound
Study and Population Characteristics
The Japan Strategic Anti-cancer Randomized Trial (J-START) is a fair-quality RCT that randomly assigned asymptomatic women ages 40 to 49 in 23 prefectures in Japan to breast cancer screening with mammography plus handheld ultrasound (DM/US) (n = 36,859) or mammography only (DM) (n = 36,139) over two rounds of annual screening during 2007 to 2011 (Table 4).158 The two study groups were balanced across a range of characteristics (Table 5). The authors note that 58 percent of women were classified as having dense breasts. Only one round of screening has been reported; therefore, this study was not eligible for inclusion in KQ2, but it is discussed here for interval cancers and potential harms related to supplemental ultrasound imaging.
An NRSI by Lee et al. reported results of an analysis using data from two BCSC registries to compare screening outcomes for individuals receiving ultrasonography on the same day as a screening mammogram (DM/US) (n = 3,386, contributing 6,081 screens) compared with those who received only a mammogram (DM) (n = 15,176, contributing 30,062 screens) (Tables 4 and 5, see Appendix E for detailed methods).152 The majority of individuals included in the study were White (accounting for 80% of the screening examinations) and represent a higher-risk population, with a significant proportion of examinations among those with a first-degree family history of breast cancer or previous breast biopsy. Additional details on study design and results are available in Appendix G.
Outcomes
Interval Cancers
The interval cancer rates reported were not statistically significantly different in the J-START RCT when comparing the DM with ultrasound versus DM-only groups (RR, 0.58 [95% CI, 0.31 to 1.08]). The published results from the trial were population-average effects that included DCIS and statistical adjustments for the clustered data structure. The result presented is a calculated individual-level intervention effect for invasive interval cancer without adjustment for clustering based on the reported event rates. Adjustment for clustering would result in a greater imprecision since it would statistically compensate for the correlated variances with wider confidence intervals. In the NRSI using BCSC data, the confidence interval was wide and not statistically significant (adjusted relative risk [aRR], 0.67 [95% CI, 0.33 to 1.37]) (Table 12).
Downstream Consequences of Supplemental Imaging
The rate of recall based only on ultrasound was 49.7 per 1,000 in the ultrasound arm, and 48.0 per 1,000 had a false-positive recall (Table 20). Of those cancers identified only by ultrasound, 76.2 percent were classified as stage 0 or 1 cancer. Without information for two rounds of screening from both arms of the study, there is not sufficient information to weigh the relative benefit versus harms of these diagnoses and downstream imaging consequences. In the BCSC analysis, the rates of referral to biopsy and false-positive biopsy recommendations were twice as high and short interval followup were three times as high for the group screened with ultrasound (Table 20).
KQ3a. Do Comparative Harms Differ by Population Characteristics and Risk Markers (e.g., Age, Breast Density, Race and Ethnicity, Family History)?
A secondary analysis of J-START reported results for trial participants from a single screening center in one Japanese prefecture (Miyagi) to compare interval cancer rates for DM/US and DM screening among women ages 40 to 49.138 Analyses stratified by breast density did not show a statistically significant difference in interval cancer rates for any density category (Table 19). The rates of recall based only on ultrasound were 69.7 per 1,000 (95% CI, 63.3 to 76.6) among those with dense breasts and 39.4 per 1,000 (95% CI, 33.5 to 46.0) among those without dense breasts.
Personalized Screening Programs Using Risk Assessment
No eligible studies were identified that reported on the potential harms of screening comparing usual care mammography personalized screening programs using risk assessment.
Figures
Figure 3Pooled Analysis of Screen-Detected Invasive Cancers Diagnosed in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 4Proportion of Screen-Detected Invasive Cancers Diagnosed at Stage II or Higher in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 5Proportion of Screen-Detected Invasive Cancers Diagnosed with Tumor Size >20 mm in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; mm=millimeters; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 6Proportion of Screen-Detected Invasive Cancers Diagnosed as Grade 3 in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 7Proportion of Screen-Detected Invasive Cancers Diagnosed as Node Positive in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 8Cumulative Probability of False-Positive Recall in One NRSI* Using BCSC Data Comparing Annual Versus Biennial Screening with Digital Breast Tomosynthesis or Digital Mammography
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; DBT=digital breast tomosynthesis; DM=digital mammography; NRSI=nonrandomized study of intervention
- *
Based on data from Ho et al. (2022)140
Figure 9Cumulative Probability of False-Positive Biopsy in One NRSI* Using BCSC Data Comparing Annual Versus Biennial Screening with Digital Breast Tomosynthesis or Digital Mammography
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; DBT=digital breast tomosynthesis; DM=digital mammography; NRSI=nonrandomized study of intervention
- *
Based on data from Ho et al. (2022)140
Figure 10Pooled Analysis of Interval Cancers Diagnosed in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 11Pooled Analysis of Recall Rates Reported in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 12Pooled Analysis of False-Positive Recalls Reported in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Figure 13Cumulative Probability of False-Positive Recall or Biopsy in One NRSI* Using BCSC Data Comparing Annual Versus Biennial Screening with Digital Breast Tomosynthesis or Digital Mammography, Among Women With Extremely Dense Breasts
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; DBT=digital breast tomosynthesis; DM=digital mammography; NRSI=nonrandomized study of intervention
- *
Based on data from Ho et al. (2022)140
Figure 14Pooled Analysis of DCIS Diagnosed in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography
Abbreviations: CG=control group; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen
Tables
Table 3Health Outcomes and Harms Reported by Included Trials and Nonrandomized Studies, by Intervention Category (k = 19*)
| Intervention Category | Number of Included Studies | Population | Health Outcomes (KQ1) (# of included studies) | Intermediate Outcomes (KQ2) (# of included studies) | Harms (KQ3) (# of included studies) |
|---|---|---|---|---|---|
| Age to Stop |
1 NRSI=1136 | General screening population | Breast cancer mortality (1) |
Overtreatment (1) Overdiagnosis (1) | |
| Frequency |
5 RCT=1126 | General screening populations starting screening at ages 40 or 50 |
Breast cancer mortality (1) All-cause mortality (1) |
Screen-detected invasive cancers (2) Tumor characteristics (2) |
Interval cancers (2) Cumulative false-positive rates (1) False-positive recalls (1) False-positive biopsy recommendations (1) |
| Digital Breast Tomosynthesis |
10 | General screening populations starting screening at ages 40 years, 45 years, and 50 years |
Screen-detected cancers (5) Tumor characteristics (4) |
Interval cancers (false-negative and new cancers combined) (8) False-negative cancers (1) Recall rates (5) Biopsies (3) False-positive recalls (4) False-positive biopsy recommendations (2) Overtreatment (1) Adverse events (1) | |
| Supplemental MRI |
2 RCT=1164 NRSI=1135 | NRSI in general screening population (ages 40 to 64 years); RCT among individuals with negative mammography and extremely dense breasts |
Interval cancers (1) Adverse events (1) Incidental findings/overtreatment (1) | ||
| Supplemental Ultrasound |
2 RCT=1158 NRSI=1152 | NRSI in general screening populations; RCT among individuals ages 40 to 49 years |
Interval cancers (2) Recall rates (1) Biopsies (1) |
- *
One study (Ho et al., 2022) is reflected in both the interval and DBT intervention categories.
Abbreviations: DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; k=number of included studies; MRI=magnetic resonance imaging; NRSI=nonrandomized study of intervention; US=ultrasound
Table 4Study Characteristics of Included Trials and Nonrandomized Studies of Screening Approaches and Modalities
| Intervention Category | Study Design |
Author, Year Study/Trial Name Quality | Country | N Screened (Round 1) | Brief Population Description | Study Years | Screening Intervention | Screening Control |
|---|---|---|---|---|---|---|---|---|
| Age to Stop | NRSI |
Garcia-Albeniz, 2020136 Fair | US | 1,058,013 | Women ages 70 to 84, enrolled in Medicare Parts A and B between 1999 and 2008, with a high probability of living 10 additional years (based on calculated Medicare-specific comorbidity score <1) | 2000 to 2008 | Continuing annual DM beyond 70 years of age | Stopping annual DM at 70 years of age |
| Screening Frequency | RCT |
Blamey, 2002126 UKCCCR Fair | UK | 76,022 | Women ages 50 to 62 attending a population-based screening program | 1989 to 1996 | Annual DM | Triennial DM |
| NRSI |
Ho, 2022140 BCSC Fair | US | 903,495 | Women ages 40 to 79 years | 2005 to 2018 | Annual DBT/sDM or DM | Biennial DBT/sDM or DM | |
|
McGuinness, 2018153 KYRAS Fair | US | 2,019 | Women age 18 years or older attending screening at one academic medical center | 2014 to 2015 | Annual DM | Biennial DM | ||
|
Miglioretti, 2015154 BCSC Fair | US | 15,440 | Women ages 40 to 85 years diagnosed with a screen-detected or interval invasive breast cancer or DCIS and at least two screening mammography examinations 11-14 or 23-26 months apart before diagnosis | 1996 to 2012 | Annual DM | Biennial DM | ||
|
Parvinen, 2011159 Fair | Finland | 14765 | Women ages 40 to 49 years attending a population-based screening program | 1987 to 2007 | Annual DM | Triennial DM | ||
| Digital Breast Tomosynthesis (DBT) | RCT |
Armaroli, 2022129 Proteus Donna Fair | Italy | 73,866 | Women ages 46 to 68 years attending a population-based screening program | 2004 to 2017 | DBT/DM (round 1), DM (round 2) | DM |
|
Heindel, 2022139 TOSYMA Good | Germany | 99,634 | Women ages 50 to 69 years attending a population-based screening program | 2018 to 2020 | DBT/sDM | DM | ||
|
Pattacini, 2022160 RETomo Good | Italy | 26,877 | Women ages 45 to 69 years attending screening in one of three clinics equipped with DBT who had already participated in at least one round of the Reggio Emilia screening program | 2014 to 2017 | DBT/DM (round 1), DM (round 2) | Annual DM (age 45-49), biennial DM (age 50-69) | ||
|
Hofvind, 2021143 To-Be Good | Norway | 28,749 | Women ages 50 to 69 years attending a population-based screening program | 2016 to 2020 | DBT/sDM | DM (round 1), DBT/sDM (round 2) | ||
| NRSI |
Sprague, 2023 BCSC Fair | US | 504,863 | Women ages 40 to 79 years with no personal history of breast cancer or mastectomy who had a previous mammogram within the past 30 months | 2011 to 2020 | DBT | DM | |
|
Ho, 2022140 BCSC-2022a Fair | US | 903,495 | Women ages 40 to 79 years | 2005 to 2018 | DBT | DM | ||
|
Kerlikowske, 2022147 BCSC-2022b Fair | US | 504,427 | Women ages 40 to 79 years with no history of breast cancer or mastectomy who had a screening mammogram and/or DBT | 2011 to 2018 | DBT | DM | ||
|
Johnson, 202179 MBTST Fair | Sweden | 40,107 | Women enrolled in a breast cancer screening trial and population-based match controls | 2010 to 2015 | DBT/DM | DM | ||
|
Richman, 2021162 Fair | US | 4,580,698 | Women ages 40 to 64 years with at least one screening mammogram between January 1, 2015, and December 31, 2017 | 2015 to 2017 | DBT/DM | DM | ||
|
Hovda, 2020144 OVVV Fair | Norway | 92,404 | Women ages 50 to 69 years participating in population-based screening program | 2014 to 2017 | DBT/sDM (round 1), DM (round 2) | DM | ||
|
Conant, 2016132 PROSPR Fair | US | 103,401 | Women ages 40 to 74 years attending screening at academic medical centers participating in the BCSC registry | 2011 to 2014 | DBT/DM | DM | ||
| Supplemental MRI | RCT |
Veenhuizen, 2021164 DENSE Good | The Netherlands | 40,373 | Women ages 50 to 75 years with negative mammography results (BI-RADS radiographic score of 1 or 2) and extremely dense breast tissue | 2011 to 2015 | DM plus MRI | DM |
| NRSI |
Ganguli, 2022135 Fair | US | 18,416 | Women ages 40 to 64 years who had a bilateral breast MRI or bilateral screening mammogram claim | 2016 to 2018 | MRI | DM | |
| Supplemental Ultrasound | RCT |
Ohuchi, 2016158 J-START Fair | Japan | 72,717 | Women ages 40 to 49 years | 2007 to 2011 | DM plus US | DM |
| NRSI |
Lee, 2019152 BCSC Fair | US | 18,562 | Women undergoing screening at eligible BCSC sites | 2000 to 2013 | DM plus US | DM |
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; BI-RADS=Breast Imaging Reporting and Data System; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; DENSE=Dense Tissue and Early Breast Neoplasm Screening; J-START= Japan Strategic Anti-cancer Randomized Trial; MBTST=Malmo Breast Tomosynthesis Screening Trial; MRI=magnetic resonance imaging; RETomo=Reggio Emilia Tomosynthesis Trial; sDM=synthetic mammography; PROSPR=Population-based Research Optimizing Screening through Personalized Regimens; To-Be=Tomosynthesis Trial in Bergen; TOSYMA=TOmosynthesis plus SYnthesized MAmmography study; OVVV=Oslo-Vestfold-Vestre Viken; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial; US=ultrasound
Table 5Population Characteristics of Included Trials and Nonrandomized Studies, by Intervention Category
| Intervention Category | Study Design |
Author, Year Study/Trial Name | Age (years) | Study-Described Race/Ethnicity | Breast Density* | First-Degree Family History of Breast Cancer | Hormonal Status |
|---|---|---|---|---|---|---|---|
| Age to Stop | NRSI | Garcia-Albeniz, 2020136 |
70 to 74: 47% ≥75: 53% |
White: 92% Black: 5% Other: 3% | NR | NR | NR |
| Interval | RCT |
Blamey, 2002126 UKCCCR | 50 to 62 (range) | NR | NR | NR | NR |
| NRSI |
Ho, 2022140 BCSC-2022a | NR | NR | NR | NR | NR | |
|
McGuinness, 2018153 KYRAS | 59 (median) |
White: 10% Black: 10% Hispanic: 76% Other: 4% |
BI-RADS A, B: 70% BI-RADS C, D: 30% | NR | NR | ||
|
Miglioretti, 2015154 BCSC | 40 to 85 (range) |
White: 78% Black: 5% Asian: 5% AI/AN: <1% Hispanic: 5% Other: 1% Unknown: 6% | NR | 22%† |
Premenopausal: 13% Menopausal: 64% Current HRT use: 22% | ||
| Parvinen, 2011159 | 40 to 49: 100% | NR | NR | NR | NR | ||
| Digital Breast Tomosynthesis (DBT) | RCT |
Armaroli, 2022129 Proteus Donna | 57 (mean [SD, 6]) | NR | NR | NR | NR |
|
Heindel, 2022139 TOSYMA |
50 to 59: 62% 60 to 69: 38% | NR | NR | NR | NR | ||
|
Pattacini, 2022160 RETomo | 55 (mean) | NR |
BI-RADS A: 8% BI-RADS B: 38% BI-RADS C: 35% BI-RADS D: 9% NR: 9% | NR | NR | ||
|
Hofvind, 2021143 To-Be | 60 (mean) | NR |
Volpara grade 1: 25% Volpara grade 2: 43% Volpara grade 3: 24% Volpara grade 4: 7% NR: 7% | NR | NR | ||
|
Sprague, 2023 BCSC | 59 (mean) |
White: 72% Black: 13% Asian: 7% Hispanic: 6% Other: 2% |
BI-RADS A: 10% BI-RADS B: 42% BI-RADS C: 37% BI-RADS D: 8% NR: 3% | 17% | NR | ||
| NRSI |
Ho, 2022140 BCSC-2022a | 40 to 79 (range) | NR | NR | NR | NR | |
|
Kerlikowske, 2022147 BCSC-2022b |
40 to 49: 23% 50 to 59: 33% 60 to 69: 29% 70 to 79: 15% |
White: 73% Black: 11% Asian: 9% Hispanic: 5% Other: 2% |
BI-RADS A: 11% BI-RADS B: 45% BI-RADS C: 37% BI-RADS D: 7% | 19† |
Premenopausal: 28% Postmenopausal or surgical menopause: 72% | ||
|
Johnson, 202179 MBTST | 56 (mean) | NR | NR | NR | NR | ||
| Richman, 2021162 |
40 to 49: 31% 50 to 59: 47% 60 to 69: 22% | NR | NR | 7%‡ | NR | ||
|
Hovda, 2020144 OVVV | 59 (mean) | NR | NR | NR | NR | ||
|
Conant, 2016132 PROSPR |
40 to 49: 28% 50 to 59: 36% 60 to 74: 36% |
White: 79% Black: 10% Asian: 2% AI/AN: <1% Hispanic: 6% Other: 3% |
BI-RADS A: 14% BI-RADS B: 45% BI-RADS C: 29% BI-RADS D: 4% NR: 8% | NR | NR | ||
| Supplemental MRI | RCT |
Veenhuizen, 2021164 DENSE | 54 (median; IQR, 51-61) | NR | Volpara grade 4: 100% | NR | NR |
| NRSI | Ganguli, 2022135 | 51 (mean) | NR | 17%§ | 50%║ | NR | |
| Supplemental Ultrasound | RCT |
Ohuchi, 2016158 J-START | 44 (mean) | NR | Dense breasts (BI-RADS 3 or 4): 58% | 5%† |
Premenopausal: 76% Menopausal: 24% |
| NRSI |
Lee, 2019152 BCSC |
<40: 4% 40 to 49: 42% 50 to 59: 35% 60 to 69: 14% ≥70: 40% |
White: 80% Black: 0.4% Asian: 11% Hispanic: 7% Other: 2% |
BI-RADS A: 2% BI-RADS B: 29% BI-RADS C: 57% BI-RADS D: 8% NR: 4% | 31%† |
Premenopausal: 38% Menopausal: 41% |
- *
Breast density defined using the BI-RADS system (which uses visual assessent to categorize breast density as (A) almost entirely fatty; (B) scattered areas of fibroglandular density; (C) heterogeneously dense; and (D) extremely dense) or the Volpara system (which uses a quantitative measure of volumetric breast density and assigns density to one of four categories, Volpara density grade [VDG] 1 to 4, which are analogous to BI-RADS A to D).
- †
First-degree family history of breast cancer.
- ‡
Family history of breast cancer.
- §
Breast density definition based on ICD-10-CM diagnosis code (R92.2 – inconclusive mammogram), which indicates dense breast findings.
- ║
Family history of breast cancer or genetic susceptibility.
Abbreviations: AI/AN=American Indian/Alaskan Native; BCSC=Breast Cancer Surveillance Consortium; BI-RADS=Breast Imaging Reporting and Data System; DENSE=Dense Tissue and Early Breast Neoplasm Screening; HRT=hormone replacement therapy; IQR=interquartile range; J-START= Japan Strategic Anti-cancer Randomized Trial; MBTST=Malmo Breast Tomosynthesis Screening Trial; NRSI=nonrandomized study of intervention; RCT=randomized controlled trial; RETomo=Reggio Emilia Tomosynthesis Trial; SD=standard deviation; sDM=synthetic mammography; PROSPR=Population-based Research Optimizing Screening through Personalized Regimens; To-Be=Tomosynthesis Trial in Bergen; TOSYMA=TOmosynthesis plus SYnthesized MAmmography study; OVVV=Oslo-Vestfold-Vestre Viken; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial
Table 6Characteristics of Screen-Detected Invasive Cancers Diagnosed Following an Annual Versus Triennial Screening Frequency
|
Author, Year Study/Trial Name | Population | Followup | Frequency | Invasive Cancer Detection (rate per 1,000) | ≥Stage II (rate per 1,000) | Tumor Diameter, mm (SD) | Tumor >20 mm (rate per 1,000) | Lymph Node Positive (rate per 1,000) | Histologic Grade 3 (rate per 1,000) | Poor Prognostic Index |
|---|---|---|---|---|---|---|---|---|---|---|
|
Blamey, 2002126 UKCCCR | Women ages 50 to 62 attending a population-based screening program | Cumulative cancer incidence (3 years) | Annual DM | 166/37,530 (4.4) | NR | NR | 63 (1.7)* | 63 (1.7)* | 96 (2.6)* | 20 (0.5)*† |
| Triennial DM | 104/38,492 (2.7) | NR | NR | 69 (1.8)* | 61 (1.6)* | 86 (2.2)* | 22 (0.6)*† |
- *
Includes both screen-detected invasive cancers and interval cancers but excludes cancers with missing information.
- †
Nottingham Prognostic Index score.
Abbreviations: DM=digital mammography; mm=millimeter; NR=not reported; SD=standard deviation; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial
Table 7Characteristics of Cancers Diagnosed Following an Annual Versus Biennial Screening Frequency, by Population Subgroup
|
Author, Year Study/ Trial Name | Comparison (IG vs. CG) | Outcome Definition | Subgroup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI)* |
|---|---|---|---|---|---|---|
|
Miglioretti, 2015154 BCSC | Annual DM preceding diagnosis vs. biennial DM preceding diagnosis† | Stage IIB or higher | 40-49 years | 246/1,155 (213.0) | 103/425 (242.4) | RR: 1.17 (95% CI, 0.93 to 1.46) |
| 50-59 years | 499/2,532 (197.1) | 129/680 (189.8) | RR: 0.98 (95% CI, 0.80 to 1.21) | |||
| 60-69 years | 429/2,616 (164.0) | 98/666 (147.2) | RR: 0.99 (95% CI, 0.79 to 1.24) | |||
| 70-85 years | 341/2,506 (136.1) | 95/782 (121.5) | RR: 0.98 (95% CI, 0.76 to 1.27) | |||
| Premenopausal | 217/1,095 (198.2) | 89/346 (257.2) | RR: 1.28 (95% CI, 1.01 to 1.63) | |||
| Postmenopausal without HRT use | 588/3,720 (158.1) | 141/1,071 (131.7) | RR: 0.95 (95% CI, 0.79 to 1.15) | |||
| Postmenopausal with HRT use | 355/1,982 (169.0) | 96/547 (175.5) | RR: 1.14 (95% CI, 0.89 to 1.47) | |||
| Less favorable characteristic (stage IIB or higher, tumor size greater than 15 mm, or positive node status) | 40-49 years | 692/1,171 (591.0) | 268/425 (630.6) | RR: 1.04 (95% CI, 0.94 to 1.14) | ||
| 50-59 years | 1,374/2,545 (539.9) | 368/685 (537.2) | RR: 1.03 (95% CI, 0.94 to 1.12) | |||
| 60-69 years | 1,277/2,627 (486.1) | 329/662 (497.0) | RR: 1.07 (95% CI, 0.97 to 1.19) | |||
| 70-85 years | 1,102/2,505 (439.9) | 345/774 (445.7) | RR: 1.05 (95% CI, 0.94 to 1.18) | |||
| Premenopausal | 660/1,105 (597.3) | 229/349 (656.2) | RR: 1.11 (95% CI, 1.00 to 1.22)‡ | |||
| Postmenopausal without HRT use | 1,737/3,735 (465.1) | 494/1,062 (465.2) | RR: 1.03 (95% CI, 0.95 to 1.12) | |||
| Postmenopausal with HRT use | 1,005/1,995 (503.8) | 278/547 (508.2) | RR: 1.12 (95% CI, 1.00 to 1.25)§ |
- *
Adjusted for race and ethnicity, first-degree family history of breast cancer, and Breast Cancer Surveillance Consortium registry using log-binomial regression unless otherwise specified.
- †
Annual cancers diagnosed within 12 months of screening examination performed 11 to 14 months after prior mammogram; biennial cancers diagnosed within 24 months of screening examination performed 23 to 26 months after prior mammogram.
- ‡
p=0.047.
- §
p=0.05.
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; DM=digital mammography; HRT=hormone replacement therapy; mm=millimeter
Table 8Characteristics of Screen-Detected Invasive Cancers Diagnosed in Studies Comparing Digital Breast Tomosynthesis and Digital Mammography
|
Author, Year Study/Trial Name Study Design | Population | Followup | Modality (previous round modality) | Invasive Cancer Detection (rate per 1,000) | ≥Stage II or IIB (rate per 1,000) | Tumor Diameter, mm (SD) | Tumor >20 mm (rate per 1,000) | Lymph Node Positive (rate per 1,000) | Histologic Grade 3 (rate per 1,000) | Poor Prognostic Index |
|---|---|---|---|---|---|---|---|---|---|---|
|
Armaroli, 2022129 Proteus Donna RCT | Women ages 46 to 68 years | First Round | DBT/DM | 224/30,844 (7.3) | 38 (1.2) | NR | 25 (0.8)* | 35 (1.1) | 17 (0.6) | NR |
| DM | 214/43,022 (5.0) | 53 (1.2) | NR | 31 (0.7)* | 42 (1.0) | 22 (0.5) | NR | |||
| Second Round | DM (DBT/DM) | 81/23,760 (3.4) | 17 (0.7) | NR | 10 (0.4)* | 14 (0.6) | 12 (0.5) | NR | ||
| DM | 135/33,534 (4.0) | 37 (1.1) | NR | 19 (0.6)* | 28 (0.8) | 14 (0.4) | NR | |||
|
Pattacini, 2022160 RETomo RCT | Women ages 45 to 69 years | First Round | DBT/DM | 84/13,356 (6.3) | 21 (1.6)† | NR | 8 (0.6) | 17 (1.3) | 12 (0.9) | NR |
| DM | 52/13,521 (3.8) | 17 (1.3)‡ | NR | 12 (0.9) | 9 (0.7) | 14 (1.0) | NR | |||
| Second Round | DM (DBT/DM) | 53/12,733 (4.2) | 15 (1.2)§ | NR | 9 (0.7) | 15 (1.2) | 11 (0.9) | NR | ||
| DM | 60/12,911 (4.6) | 6 (0.5)║ | NR | 4 (0.3) | 8 (0.6) | 13 (1.0) | NR | |||
|
Hofvind, 2021143 To-Be RCT | Women ages 50 to 69 years | First Round | DBT/sDM | 80/14,380 (5.6) | 22 (1.5)¶ | 16.0 (8.4) | 17 (1.2) | 14 (1.0) | 16 (1.1) | NR |
| DM | 71/14,369 (4.9) | 19 (1.3)¶ | 14.5 (8.8) | 13 (0.9) | 18 (1.3) | 10 (0.7) | NR | |||
| Second Round | DBT/sDM | 77/11,201 (6.9) | 16 (1.4)¶ | 15.2 (9.3) | 14 (1.2)¶ | 7 (0.6) | 13 (1.2) | NR | ||
| DBT/sDM (DM) | 87/11,105 (7.8) | 24 (2.2)¶ | 15.8 (8.6) | 21 (1.9)¶ | 15 (1.4) | 14 (1.3) | NR | |||
|
Sprague, 2023168 BCSC NRSI | Women ages 40 to 79 years | First Round | DBT | NR (4.8) | NR (0.21) | NR | NR | NR | NR | NR |
| DM | NR (4.4) | NR (0.26) | NR | NR | NR | NR | NR | |||
| Second Round+# | DBT | NR (4.1) | NR (0.13) | NR | NR | NR | NR | NR | ||
| DM | NR (3.7) | NR (0.20) | NR | NR | NR | NR | NR | |||
|
Hovda, 2020144 OVVV NRSI | Women ages 50 to 69 years | First Round | DBT/sDM | 283/37,815 (7.6) | NR | NR | 38 (1.0) | 36 (1.0) | 28 (0.8) | NR |
| DM | 329/61,742 (5.3) | NR | NR | 57 (0.9) | 45 (0.7) | 56 (0.9) | NR | |||
| Second Round | DM (DBT/sDM) | 84/26,474 (3.2) | NR | 15.4 (13.0) | NR | 16 (0.6) | 19 (0.7) | NR | ||
| DM | 203/45,543 (4.5) | NR | 14.3 (8.2) | NR | 30 (0.7) | 30 (0.7) | NR |
Note: Unless otherwise indicated, data are number of patients. Rates are per 1,000 women screened.
- *
Tumor diameter >10 mm.
- †
Stage III or higher: 3 (0.2).
- ‡
Stage III or higher: 2 (0.1).
- §
Stage III or higher: 2 (0.2).
- ║
Stage III or higher: 4 (0.3).
- ¶
Provided through author communication.
- #
Second round and higher was defined as individuals previously screened at least twice consecutively with the same modality (DM or DBT-based).
Abbreviations: DBT=digital breast tomosynthesis; DM=digital mammography; mm=millimeter; NR=not reported; RETomo=Reggio Emilia Tomosynthesis Trial; SD=standard deviation; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken
Table 9Incidence of Screen-Detected Invasive Cancers Diagnosed in Trials Comparing Digital Breast Tomosynthesis and Digital Mammography, by Population Subgroup
|
Author, Year Study/Trial Name | Followup | Subgroup | Modality (previous round modality) | Invasive Cancer Detection* | Effect (95% CI) |
|---|---|---|---|---|---|
|
Pattacini, 2022160 RETomo | First Round | Ages 45 to 49 years | DBT/DM | 19/5,053 (3.8) | RR=1.9 (95% CI, 0.89 to 4.1) |
| DM | 10/5,103 (2.0 | ||||
| Ages 50 to 69 years | DBT/DM | 65/8,303 (7.8) | RR=1.6 (95% CI, 1.1 to 2.3) | ||
| DM | 42/8,418 (5.0) | ||||
| Nondense breasts (BI-RADS A or B) | DBT/DM | 39/6,261 (6.2) | RR=1.8 (95% CI, 1.1 to 3.0) | ||
| DM | 22/6,286 (3.5) | ||||
| Dense breasts (BI-RADS C or D) | DBT/DM | 40/5,970 (6.7) | RR=1.5 (95% CI, 0.94 to 2.5) | ||
| DM | 26/5,978 (4.3) | ||||
| Second Round | Ages 45 to 49 years | DBT/DM | 7/4,813 (1.5) | RR=0.50 (95% CI, 0.20 to 1.2) | |
| DM | 14/4,855 (2.9) | ||||
| Ages 50 to 69 years | DBT/DM | 46/7,920 (5.8) | RR=1.0 (95% CI, 0.68 to 1.5) | ||
| DM | 46/8,056 (5.7) | ||||
| Nondense breasts (BI-RADS A or B) | DBT/DM | 31/5,970 (5.2) | RR=0.97 (95% CI, 0.60 to 1.6) | ||
| DM | 32/6,002 (5.3) | ||||
| Dense breasts (BI-RADS C or D) | DBT/DM | 16/5,686 (2.8) | RR=0.64 (95% CI, 0.34 to 1.2) | ||
| DM | 25/5,706 (4.4) | ||||
|
Hofvind, 2021143 To-Be | First Round | VDG1 Density | DBT/sDM | 17/3,929 (4.3) | RR=1.07 (95% CI, 0.52 to 2.20) |
| DM | 13/3,212 (4.0) | ||||
| VDG2 Density | DBT/sDM | 38/6,216 (6.1) | RR=1.16 (95% CI, 0.73 to 1.85) | ||
| DM | 33/6,280 (5.3) | ||||
| VDG3 Density | DBT/sDM | 20/3,152 (6.3) | RR=1.10 (95% CI, 0.60 to 2.03) | ||
| DM | 21/3,655 (5.7) | ||||
| VDG4 Density | DBT/sDM | 5/962 (5.2) | RR=1.97 (95% CI, 0.47 to 8.21) | ||
| DM | 3/1,136 (2.6) | ||||
| Second Round | VDG1 Density | DBT/sDM | 18/3,214 (5.6) | RR=1.04 (95% CI, 0.53 to 2.03) | |
| DBT/sDM (DM) | 16/2,960 (5.4) | ||||
| VDG2 Density | DBT/sDM | 29/4,353 (6.7) | RR=0.94 (95% CI, 0.57 to 1.56) | ||
| DBT/sDM (DM) | 31/4,395 (7.1) | ||||
| VDG3 Density | DBT/sDM | 23/2,656 (8.7) | RR=0.82 (95% CI, 0.47 to 1.41) | ||
| DBT/sDM (DM) | 29/2,736 (10.6) | ||||
| VDG4 Density | DBT/sDM | 7/900 (7.8) | RR=0.66 (95% CI, 0.26 to 1.70) | ||
| DBT/sDM (DM) | 11/934 (11.8) |
- *
Rate per 1,000 women screened.
Abbreviations: BI-RADS=Breast Imaging Reporting and Data Systems; DBT=digital breast tomosynthesis; DM=digital mammography; mm=millimeter; RETomo=Reggio Emilia Tomosynthesis Trial; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; VDG=Volpara Density Grade
Table 10Overdiagnosis and Overtreatment in Studies of Age to Stop Screening in an Emulated Trial, by Population Subgroup
|
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Population | Outcome Category | Outcome Definition | IG Proportion (95% CI) | CG Proportion (95% CI) |
|---|---|---|---|---|---|---|
| Garcia-Albeniz, 2020136 | Continued screening after age 70 vs. cessation of screening | Women ages 70 to 74 years with a life expectancy of at least 10 years | Incidence | 8-year cumulative risk of breast cancer diagnosis | 5.3 (NR) | 3.9 (NR) |
| Treatments received by women diagnosed with breast cancer* | Lumpectomy | 52.6 (51.8–53.4) | 36.5 (35.2–38.0) | |||
| Simple mastectomy | 11.3 (10.8–11.8) | 10.4 (9.5–11.3) | ||||
| Radical mastectomy | 13.9 (13.4–14.5) | 18.2 (17.0–19.4) | ||||
| Radiotherapy | 51.0 (50.3–51.8) | 39.9 (38.6–41.3) | ||||
| Chemotherapy | 15.2 (14.7–15.8) | 21.1 (20.0–22.1) | ||||
| Continued screening after age 75 vs. cessation of screening | Women ages 75 to 84 years with a life expectancy of at least 10 years | Incidence | 8-year cumulative risk of breast cancer diagnosis | 5.8 (NR) | 3.9 (NR) | |
| Treatments received by women diagnosed with breast cancer* | Lumpectomy | 48.8 (47.9–49.5) | 32.6 (31.5–33.8) | |||
| Simple mastectomy | 10.8 (10.3–11.2) | 10.1 (9.4–10.9) | ||||
| Radical mastectomy | 14.2 (13.7–14.6) | 17.0 (16.0–17.9) | ||||
| Radiotherapy | 41.2 (40.4–41.9) | 31.9 (30.7–33.1) | ||||
| Chemotherapy | 8.6 (8.3–9.1) | 11.5 (10.6–12.3) |
- *
Percentages are standardized to the age group–specific distribution of age; comorbidity score; new diagnosis of Alzheimer disease, acute myocardial infarction, chronic heart failure, chronic kidney disease, chronic obstructive pulmonary disease, hip fracture, stroke, or cancer (lung, endometrial, or colorectal); and institutionalization in a long-term care center.
Abbreviations: CG=control group; CI=confidence interval; IG=intervention group; NR=not reported
Table 11Interval Cancer Rates in Studies Comparing Breast Cancer Screening Frequencies
| Study Design |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Population | Outcome Definition | Histologic Type | IG n/N (rate per 1,000 screened), or IG Proportion (95% CI) | CG n/N (rate per 1,000 screened), or CG Proportion (95% CI) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|
| RCT |
Blamey, 2002126 UKCCCR | Annual DM vs. Triennial DM | Women ages 50 to 62 |
Interval cancers Annual screening group: detected in the three intervals between screening visits during the three years of followup. Triennial screening group: detected before the consecutive screen following the baseline screen | Invasive | 69/37,530 (1.8) | 104/38,492 (2.7) | RR: 0.68 (95% CI, 0.50 to 0.92)* |
| NRSI | Parvinen, 2011159 | Annual DM vs. Triennial DM | Women ages 40 to 49 | Interval cancers occurring after a negative mammogram and between two subsequent screening visits | Invasive | NR | NR | P=0.22 |
| Miglioretti, 2015154 | Annual DM vs. Biennial DM | Women ages 40 to 85 diagnosed with an incident invasive breast cancer or DCIS | Proportion of cancers detected that were diagnosed clinically as interval cancers. Defined as occurring within 12 months following an annual screening interval and within 24 months following a biennial screening interval | Invasive or DCIS | 22.2% (21.5% to 23.0%) | 27.2% (25.7% to 28.8%) | NR |
- *
Relative risk calculated from Ns.
Abbreviations: DCIS=ductal carcinoma in situ; DM=digital mammography; NRSI=nonrandomized study of intervention; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial
Table 12Rates of Interval Cancers (Invasive Cancer and DCIS) in Studies Comparing Breast Cancer Screening Modalities, per 1,000 Screened*
| Modality | Study Design |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Age | Followup Following Screening | Histologic Type | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
| DBT | RCT |
Armaroli, 2022129 Proteus Donna | DBT/DM (round 1), DM (round 2) vs. DM* | 46 to 68 | Median, 25 months (range, 0 to 36 months) | Invasive | 38/30,588 (1.2) | 58/42,774 (1.4) | RR: 0.92 (95% CI, 0.59 to 1.40) |
| DCIS | 4/30,588 (0.1) | 5/42,774 (0.1) | RR: 1.12 (95% CI, 0.22 to 5.20) | ||||||
|
Pattacini, 2022160 RETomo | DBT/DM vs. DM | 45 to 70 | 12-months (ages 40 to 49 years) or 24-months (ages 50 to 69 years) | Invasive | 19/12,845 (1.5) | 20/12,999 (1.5) | RR: 0.96 (95% CI, 0.51 to 1.80) | ||
| Interval cancers (DCIS only) at 12-months followup (women ages 40 to 49 years) or 24-months followup (women ages 50 to 69 years) among women with negative findings at previous screening | DCIS | 2/12,845 (0.2) | 2/12,999 (0.2) | RR: 1.0 (95% CI, 0.14 to 7.20) | |||||
|
Hofvind, 2021143 To-Be | DBT/sDM vs. DM | 50 to 69 | 24-months† | Invasive | 20/14,380 (1.4) | 28/14,369 (1.9) | RR: 0.71 (95% CI, 0.40 to 1.27)‡ | ||
| Interval cancers (DCIS only) at 24-months followup among women with negative findings at previous screening or 6- to 24-months followup among women with a false-positive result at previous screening | DCIS | 0/14,380 | 1/14,369 (0.07) | p=0.32 | |||||
| NRSI |
Sprague, 2023168 BCSC | DBT/sDM vs. DM | 40 to 79 | Within 12 months of screening round 1 | Invasive | NR (0.69) | NR (0.71) | RD: −0.02 (95% CI, −0.26 to 0.24)§ | |
| Advanced (pathologic prognostic stage II, III, or IV) | NR (0.20) | NR (0.18) | RD: 0.03 (95% CI, −0.06 to 0.14)§ | ||||||
| Invasive and DCIS | NR (0.79) | NR (0.79) | RD: 0.00 (95% CI, −0.24 to 0.30)§ | ||||||
| Within 12 months of screening rounds ≥2 | Invasive | NR (0.57) | NR (0.56) | RD: 0.01 (95% CI, −0.16 to 0.20)§ | |||||
| Advanced (pathologic prognostic stage II, III, or IV) | NR (0.15) | NR (0.12) | RD: 0.03 (95% CI, −0.05 to 0.15)§ | ||||||
| Invasive and DCIS | NR (0.66) | NR (0.62) | RD: −0.04 (95% CI, −0.19 to 0.31)§ | ||||||
|
Kerlikowske, 2022147 BCSC-2022b | DBT/sDM vs. DM | 40 to 79 | 12-months | Invasive | NR (0.57)║ | NR (0.61)║ | Adj rate difference: −0.04 (95% CI, −0.14 to 0.06)║ | ||
|
Johnson, 202179 MBTST¶ | DBT/DM vs. DM | 40 to 74 | 18-months (ages 40 to 54 years) or 24-months (ages 55 to 74 years) | Invasive and DCIS | 21/13,369 (1.6) | 76/26,738 (2.8) | OR: 0.6 (95% CI, 0.3 to 0.9) | ||
| DBT/DM vs. DM | 40 to 74 | Interval cancers diagnosed after a negative DM screening but before the next scheduled screening round at 18-months (ages 40 to 54 years), or within 24 months of screening for women who have reached the upper age limit (ages 55 to 74 years) | Invasive | 19/13,369 (1.4) | 72/26,738 (2.7) | RR: 0.53 (95% CI, 0.32 to 0.87) | |||
| DCIS | 2/13,369 (0.1) | 4/26,738 (0.1) | RR: 1.0 (95% CI, 0.18 to 5.46) | ||||||
| Richman, 2021162 | DBT/DM vs. DM | 40 to 64 | 12-months# | Invasive | NR (0.52)** | NR (0.45)** | Adj proportion difference: 0.07 (99% CI, 0.01 to 0.12)** | ||
|
Hovda, 2020144 OVVV | DBT/sDM (round 1), DM (round 2) vs. DM | 50 to 69 | 6- to 24-months followup among women with a false-positive result at baseline screening | Invasive and DCIS | 68/34,641 (2.0) | 88/57,763 (1.5) | Adj RR: 1.30 (95% CI, 0.95 to 1.78) | ||
|
Hovda, 2020 OVVV | DBT/sDM (round 1), DM (round 2) vs. DM | 50 to 69 | 24-months | Invasive | 63/34,641 (1.8) | 83/57,763 (1.4) | RR: 1.27 (95% CI, 0.91 to 1.76)║ | ||
| DCIS | 5/34,641 (0.1) | 5/57,763 (0.1) | RR: 1.67 (95% CI, 0.48 to 5.76) | ||||||
|
Conant, 2016132 PROSPR | DBT/DM vs. DM | 40 to 74 | 12 months | Invasive and DCIS | 68/11,3061 (0.6) | 12/25,268 (0.5) | Adj OR: 0.55 (95% CI, 0.13 to 2.26) | ||
| Suppl. MRI | RCT |
DENSE | DM plus MRI vs. DM | 50 to 75†† | 24 months‡‡ | Invasive | 18/8,061 (2.2) | 152/32,312 (4.7) | RR: 0.47 (95% CI, 0.29 to 0.77)‡ |
| DCIS | 2/8,061 (0.2)§§ | 9/32,312 (0.3)§§ | RR: 0.89 (95% CI, 0.19 to 4.12)‡, §§ | ||||||
| Suppl. US | RCT |
Ohuchi, 2016158 J-START | DM plus US vs. DM | 40 to 49 | 12 months║║ | Invasive | 16/36,752 (0.4)§§ | 27/35,965 (0.8)§§ | RR: 0.58 (95% CI, 0.31 to 1.08)‡, §§ |
| DCIS and LCIS | 2/36,752 (0.1)§§ | 8/35,965 (0.2)§§ | RR: 0.24 (95% CI: 0.05 to 1.15)‡, §§ | ||||||
| NRSI |
Lee, 2019152 BCSC | DM plus US vs. DM | NR | 12 months¶¶ | Invasive and DCIS | 9/6,081 (1.5)§§ | 56/30,062 (1.9)§§ | Adj RR: 0.67 (95% CI, 0.33 to 1.37)§§, ## |
Note: Unless otherwise noted, rates are per 1,000 women screened.
- *
Screening interval varied by age group (annual 45-49, biennial 50-69).
- †
6- to 24-months followup among women with a false-positive result at previous screening.
- ‡
Relative risk calculated from Ns.
- §
Adjusted for age, breast density, race and ethnicity, time since last mammogram, BCSC 5-year invasive breast cancer risk, benign biopsy history, family history of breast cancer, and examination year.
- ║
Adjusted for at examination, BCSC registry, facility academic or not, calendar year, race and ethnicity, breast density, first-degree family history of breast cancer, time since last mammogram, and the most severe prior benign biopsy result. Rates are per 1,000 screening examinations.
- ¶
This study is a nonrandomized study based on MBTST participants compared with a contemporary age-matched population cohort. Data are presented per 1,000 mammograms.
- #
Excluded cancers within 5 months of screening.
- **
This mammogram-level, multivariate logistic regression analysis was adjusted for use of screening ultrasound, age, time period of index mammogram, time since last mammogram, metro location, hospital referral region, and family history of breast cancer. The analysis cluster-robust standard errors at the person level to account for the correlation of mammogram. Rates are per 1,000 screening examinations.
- ††
With extremely dense breasts.
- ‡‡
Before the next scheduled mammogram if less than 24-month interval.
- §§
Rates are per 1,000 screening examinations.
- ║║
Limited to individuals with screening results of no findings or benign findings at round 1.
- ¶¶
Before next scheduled mammograph if less than 12-month interval.
- ##
Adjusted for site, age, menopausal status, first-degree family history of breast cancer, year of examination, prior benign breast biopsy result, and correlation among women within the same matched set using generalized estimated equations.
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; BI-RADS=Breast Imaging Reporting and Data System; CI=confidence interval; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; DENSE=Dense Tissue and Early Breast Neoplasm Screening; J-START= Japan Strategic Anti-cancer Randomized Trial; LCIS=lobular carcinoma in situ; MBTST=Malmo Breast Tomosynthesis Screening Trial; MRI=magnetic resonance imaging; NRSI=nonrandomized study of intervention; PROSPR=Population-based Research to Optimize the Screening Process through Personalized Regimens; RD=risk difference; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; TOSYMA=TOmosynthesis plus SYnthesized MAmmography study; OVVV=Oslo-Vestfold-Vestre Viken; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial; US=ultrasound; VDG=Volpara Density Grade
Table 13Followup of Abnormal Screening in Studies Comparing Digital Breast Tomosynthesis and Digital Mammography
| Outcome | Study Design |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Age | Followup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|
| Recalled for further assessment | RCT |
Armaroli, 2022129 Proteus Donna* | DBT/DM (round 1), DM (round 2) vs. DM | 46 to 68 | First Round | 1,995/30,844 (63.4) | 2,191/43,022 (50.9) | RR: 1.24 (95% CI, 1.17 to 1.32) |
| Second Round | 1,000/23,760 (42.1) | 1,456/33,534 (43.4) | RR: 0.97 (95% CI, 0.89 to 1.05) | |||||
| Pattacini, 2022160 |
RETomo† DBT/DM (round 1), DM (round 2) vs. DM | 45 to 69 | First Round | 511/13,356 (38.3) | 522/13,521 (38.6) | RR: 0.99 (95% CI, 0.88 to 1.10) | ||
| Second Round | 464/12,733 (36.4) | 506/12,911 (39.2) | RR: 0.93 (95% CI, 0.82 to 1.10) | |||||
|
Hofvind, 2021143 To-Be† | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | 50 to 69 | First Round | 444/14,380 (30.9) | 571/14,369 (39.7) | RR: 0.78 (95% CI, 0.69 to 0.88)‡ | ||
| Second Round | 440/11,201 (39.3) | 441/11,105 (39.7) | RR: 0.99 (95% CI, 0.87 to 1.13)‡ | |||||
| NRSI |
Spague, 2023168 BCSC | DBT vs. DM | 40 to 79 | First Round§ | NR (75) | NR (109) | Proportion difference: −33 (95% CI, −46 to −21)║ | |
| Second Round¶ | NR (69) | NR (86) | Proportion difference: −18 (95% CI, −29 to −7)║ | |||||
| ≥Third round# | NR (61) | NR (73) | Proportion difference: −12 (95% CI, −24 to −1)║ | |||||
|
Hovda, 2020144 OVVV† | DBT/sDM (round 1), DM (round 2) vs. DM | 50 to 69 | First Round | 1,253/37,185 (33.7) | 2,037/61,742 (33.0) | RR: 1.02 (95% CI, 0.95 to 1.09)‡ | ||
| Second Round | 621/26,474 (23.5) | 1,408/45,543 (30.9) | RR: 0.76 (95% CI, 0.69 to 0.83)‡ | |||||
| Percutaneous needle biopsy | RCT |
Pattacini, 2022160 RETomo | DBT/DM (round 1), DM (round 2) vs. DM | 45 to 69 | First Round | 159/13,356 (11.9) | 110/13,521 (8.1) | RR: 1.50 (95% CI, 1.10 to 1.90) |
| Second Round | 78/12,733 (6.1) | 104/12,911 (8.1) | RR: 0.76 (95% CI, 0.57 to 1.00) | |||||
| Biopsy** | RCT |
Hofvind, 2021143 To-Be | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | 50 to 69 | First Round | 252/14,380 (17.5) | 271/14,369 (18.9) | RR: 0.93 (95% CI, 0.78 to 1.10)‡ |
| Second Round | 248/11,201 (22.1) | 258/11,105 (23.2) | RR: 0.95 (95% CI, 0.80 to 1.13)‡ | |||||
| NRSI |
Sprague, 2023168 BCSC | DBT vs. DM | 40 to 79 | First Round | NR (15) | NR (18) | Proportion difference: −3 (95% CI, −5 to −1) | |
| Second Round | NR (13) | NR (14) | Proportion difference: 0 (95% CI, −3 to 2) | |||||
| ≥Third round | NR (12) | NR (13) | Proportion difference: 0 (95% CI, −2 to 3) | |||||
| Surgical referrals | RCT |
Armaroli, 2022129 Proteus Donna | DBT/DM (round 1), DM (round 2) vs. DM | 46 to 68 | First Round | 305/30,844 (9.9) | 276/43,022 (6.4) | RR: 1.54 (95% CI, 1.31 to 1.82)‡ |
| Second Round | 103/23,760 (4.3) | 191/33,534 (5.7) | RR: 0.76 (95% CI, 0.59 to 0.97)‡ | |||||
| Surgical procedures (including open biopsy) | RCT |
Pattacini, 2022160 RETomo | DBT/DM vs. DM | 45 to 69 | First Round | 116/13,356 (8.7) | 68/13,521 (5.0) | RR: 1.70 (95% CI, 1.30 to 2.30) |
| Second Round | 68/12,733 (5.3) | 83/12,911 (6.4) | RR: 0.83 (95% CI, 0.60 to 1.10) |
- *
Recalled for an assessment after double reading based on positive or suspicious screening result by either radiologist (without consensus or arbitration).
- †
Recalled for an assessment (after double reading and arbitration) based on positive or suspicious screening results.
- ‡
Relative risk calculated from Ns.
- §
First round was defined as individuals screened with the same modality received at a previous round (DM only or DBT-based screening).
- ║
Adjusted for age, breast density, race and ethnicity, time since last mammogram, Breast Cancer Surveillance Consortium 5-year invasive breast cancer risk, benign biopsy history, family history of breast cancer, and examination year.
- ¶
Second round was defined as individuals previously screened twice consecutively with the same modality (DM or DBT-based).
- #
Third round and higher was defined as individuals previously screened at least three times consecutively with the same modality (DM or DBT-based).
- **
Type of biopsy not defined.
Abbreviations: CG=control group; CI=confidence interval; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; NRSI=nonrandomized study of intervention; RCT=randomized controlled trial; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken
Table 14False Positives in Studies Comparing Digital Breast Tomosynthesis and Digital Mammography
| Outcome | Study Design |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Age | Followup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|
| False-positive recall† | RCT |
Armaroli, 2022129 Proteus Donna‡ | DBT/DM vs. DM (round 1), DM vs. DM‡ (round 2) | 46 to 68 | First Round | 1,699/30,844 (55.1) | 1,943/43,022 (45.2) | RR: 1.22 (95% CI, 1.14 to 1.30)* |
| Second Round | 900/23,760 (37.9) | 1,286/33,534 (38.3) | RR: 0.99 (95% CI, 0.91 to 1.08)* | |||||
|
Pattacini, 2022160 RETomo§ | DBT/DM (round 1), DM (round 2) vs. DM | 45 to 69 | First Round | 410/13,356 (30.7) | 461/13,521 (34.1) | RR: 0.90 (95% CI, 0.79 to 1.00)* | ||
| Second Round | 403/12,733 (31.7) | 430/12,911 (33.3) | RR: 0.95 (95% CI, 0.83 to 1.09)* | |||||
|
Hofvind, 2021143 To-Be§ | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | 50 to 69 | First Round | 349/14,380 (24.3) | 484/14,369 (33.7) | RR: 0.72 (95% CI, 0.63 to 0.83)* | ||
| Second Round | 349/11,201 (31.2) | 340/11,105 (30.6) | RR: 1.02 (95% CI, 0.88 to 1.18)* | |||||
| NRSI |
Sprague, in press BCSC-in press | DBT vs. DM | 40 to 79 | First Round | NR (66) | NR (101) | Proportion difference: −34 (95% CI, −47 to −22)§ | |
| Second Round | NR (60) | NR (78) | Proportion difference: −18 (95% CI, −30 to −7)§ | |||||
| ≥Third round | NR (55) | NR (66) | Proportion difference: −11 (95% CI, −23 to 2)§ | |||||
|
Hovda, 2020144 OVVV|| | DBT/sDM vs. DM (round 1), DM vs. DM (round 2) | 50 to 69 | First Round | 905/37,185 (24.3) | 1,658/61,742 (26.9) | RR: 0.91 (95% CI, 0.84 to 0.98)* | ||
| Second Round | 518/26,474 (19.6) | 1,154/45,543 (25.3) | RR: 0.77 (95% CI, 0.70 to 0.86)* | |||||
| False-positive biopsy¶ | RCT |
Hofvind, 2021143 To-Be | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | 50 to 69 | First Round | 157/14,380 (10.9) | 184/14,369 (12.8) | RR: 0.85 (95% CI, 0.69 to 1.05)* |
| Second Round | 157/11,201 (14.0) | 157/11,105 (14.1) | RR: 0.99 (95% CI, 0.80 to 1.24)* | |||||
| NRSI |
Sprague, 2023 BCSC | DBT vs. DM | 40 to 79 | First Round | NR (10) | NR (13) | Proportion difference: −3 (95% CI, −5 to −2) | |
| Second Round | NR (8) | NR (10) | Proportion difference: −2 (95% CI, −4 to 0) | |||||
| ≥Third round | NR (8) | NR (8) | Proportion difference: −1 (95% CI, −3 to 1) |
- *
Relative risk calculated from Ns.
- †
Recalled for assessment without a finding of invasive cancer or DCIS.
- ‡
Recalled for an assessment after double reading based on positive or suspicious screening result by either radiologist (without consensus or arbitration).
- §
Adjusted for age, breast density, race and ethnicity, time since last mammogram, Breast Cancer Screening Consortium 5-year invasive breast cancer risk, benign biopsy history, family history of breast cancer, and examination year.
- ||
Recalled for an assessment (after double reading and arbitration) based on positive or suspicious screening results.
- ¶
Underwent biopsy without a finding of invasive cancer or DCIS.
Abbreviations: CG=control group; CI=confidence interval; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; NRSI=nonrandomized study of intervention; RCT=randomized controlled trial; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken
Table 15Screen-Detected DCIS Diagnosed in Studies Comparing Digital Breast Tomosynthesis and Digital Mammography
| Study Design |
Author, Year Study/Trial Name | Followup | Modality (previous round modality) | Invasive Cancer Detection* | Effect (95% CI) |
|---|---|---|---|---|---|
| RCT |
Armaroli, 2022129 Proteus Donna | First Round | DBT/DM | 32/30,844 (1.04) | RR=1.39 (95% CI, 0.83 to 2.35) |
| DM | 32/43,022 (0.74) | ||||
| Second Round | DM (DBT/DM) | 17/23,760 (0.72) | RR=0.75 (95% CI, 0.39 to 1.39) | ||
| DM | 32/33,534 (0.95) | ||||
|
Pattacini, 2022160 RETomo | First Round | DBT/DM | 17/13,356 (1.27) | RR=1.91 (95% CI, 0.85 to 4.30) | |
| DM | 9/13,521 (0.67) | ||||
| Second Round | DBT/DM | 8/12,733 (0.63) | RR=0.51 (95% CI, 0.22 to 1.20) | ||
| DM | 16/12,911 (1.24) | ||||
|
Hofvind, 2021143 To-Be | First Round | DBT/sDM | 15/14,380 (1.04) | RR=0.94 (95% CI, 0.46 to 1.89) | |
| DM | 16/14,369 (1.11) | ||||
| Second Round | DBT/sDM | 14/11,201 (1.25) | RR=0.99 (95% CI, 0.47 to 2.08) | ||
| DBT/sDM (DM) | 14/11,105 (1.26) | ||||
| NRSI |
Hovda, 2020144 OVVV | First Round | DBT/sDM | 65/37,185 (1.75) | RR=2.16 (95% CI, 1.49 to 3.12) |
| DM | 50/61,742 (0.81) | ||||
| Second Round | DM (DBT/sDM) | 19/26,474 (0.72) | RR=0.64 (95% CI, 0.38 to 1.09) | ||
| DM | 51/45,543 (1.12) |
- *
Rate per 1,000 women screened.
Abbreviations: CI=confidence inerval; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; mm=millimeter; NR=not reported; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken
Table 16Radiation Exposure in Studies Comparing Digital Breast Tomosynthesis and Digital Mammography
| Study Design |
Author, Year Study/Trial Name | Modality (previous round modality) | Mean (SD) or Median (IQR) Glandular Dose |
|---|---|---|---|
| RCT |
Armaroli, 2022129 Proteus Donna | DBT/DM vs. DM (round 1); DM vs. DM (round 2) | Combined DBT and DM was approximately 2.5 times higher than that of a standard DM alone* |
|
Heindal, 2022139 TOSYMA | DBT/sDM | 1.86 mGy (IQR, 1.48 to 2.45 mGy) | |
| DM | 1.36 mGy (IQR, 1.02 to 1.85 mGy) | ||
|
Pattacini, 2022160 RETomo | DBT/DM | 6.40 mGy (IQR, 5.68 to 7.36 mGy) | |
| DM | 4.84 mGy (IQR, 4.24 to 5.72 mGy) | ||
|
Hofvind, 2021143 To-Be† | DBT/sDM | 2.96 mGy (SD, NR) | |
| DM (round 1), DBT/sDM (round 2) | 2.95 mGy (SD, NR)‡ | ||
| NRSI |
Johnson, 202179 MBTST | DBT/DM | 2.3 mGy (SD, 0.7 mGy) |
| DM | 2.7 mGy (SD, 0.8 mGy) |
- *
Radiation dose description as reported by the study.
- †
Study also noted that radiation dose did not differ with mammographic density, or within the density groups.
- ‡
Test for mean difference between groups p=0.43.
Abbreviations: DBT=digital breast tomosynthesis; DM=digital mammography; IQR=interquartile range; MBTST=Malmo Breast Tomosynthesis Screening Trial; mGy=milligray; NR=not reported; RETomo=Reggio Emilia Tomosynthesis Trial; sDM=synthetic 2-view mammography; SD=standard deviation; To-Be=Tomosynthesis Trial in Bergen; TOSYMA=TOmosynthesis plus SYnthesized MAmmography study
Table 17Followup of Abnormal Screening in Randomized Trials Comparing Digital Breast Tomosynthesis and Digital Mammography, by Population Subgroup
| Outcome |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Followup | Subgroup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|
| Recalled for further assessment |
Pattacini, 2022160 RETomo† | DBT/DM (round 1), DM (round 2) vs. DM | Round 1 | Ages 45 to 49 | 200/5,053 (39.6) | 206/5,103 (40.4) | RR: 0.98 (95% CI, 0.81 to 1.20) |
| Ages 50 to 69 | 311/8,303 (37.5) | 316/8,418 (37.5) | RR: 1.00 (95% CI, 0.86 to 1.20) | ||||
| Round 2 | Ages 45 to 49 | 163/4,813 (33.9) | 195/4,855 (40.2) | RR: 0.84 (95% CI, 0.69 to 1.00) | |||
| Ages 50 to 69 | 301/7,920 (38.0) | 311/8,056 (38.6) | RR: 0.98 (95% CI, 0.84 to 1.10) | ||||
|
Hofvind, 2021143 To-Be† | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | Round 1 | VDG1 | 83/3,929 (21.1) | 106/3,212 (33.0) | RR: 0.64 (95% CI, 0.48 to 0.85)* | |
| VDG2 | 199/6,216 (32.0) | 270/6,280 (43.0) | RR: 0.74 (95% CI, 0.62 to 0.89)* | ||||
| VDG3 | 129/3,152 (40.9) | 146/3,655 (39.9) | RR: 1.02 (95% CI, 0.81 to 1.29)* | ||||
| VDG4 | 30/9,62 (31.2) | 45/1,136 (39.6) | RR: 0.79 (95% CI, 0.50 to 1.24)* | ||||
| Round 2 | VDG1 | 74/3,214 (23.0) | 79/2,960 (26.7) | RR: 0.86 (95% CI, 0.63 to 1.18)* | |||
| VDG2 | 168/4,353 (38.6) | 177/4,395 (40.3) | RR: 0.96 (95% CI, 0.78 to 1.18)* | ||||
| VDG3 | 141/2,656 (53.1) | 139/2,736 (50.8) | RR: 1.04 (95% CI, 0.83 to 1.31)* | ||||
| VDG4 | 53/900 (58.9) | 44/934 (47.1) | RR: 1.25 (95% CI, 0.85 to 1.84)* | ||||
| Percutaneous biopsy |
Pattacini, 2022160 RETomo | DBT/DM (round 1), DM (round 2) vs. DM | Round 1 | Ages 45 to 49 | 47/5,053 (9.3) | 31/5,103 (6.1) | RR: 1.50 (95% CI, 0.97 to 2.40) |
| Ages 50 to 69 | 112/8,303 (13.5) | 79/8,418 (9.4) | RR: 1.40 (95% CI, 1.10 to 1.90) | ||||
| Round 2 | Ages 45 to 49 | 15/4,813 (3.1) | 30/4,855 (6.2) | RR: 0.50 (95% CI, 0.27 to 0.94) | |||
| Ages 50 to 69 | 63/7,920 (8.0) | 74/8,056 (9.2) | RR: 0.87 (95% CI, 0.62 to 1.20) | ||||
| Biopsy |
Hofvind, 2021143 To-Be | DBT/sDM vs. DM (round 1), DBT/sDM (round 2) | Round 1 | VDG1 | 47/3,929 (12.0) | 45/3,212 (14.0) | RR: 0.85 (95% CI, 0.57 to 1.28)* |
| VDG2 | 106/6,216 (17.1) | 132/6,280 (21.0) | RR: 0.81 (95% CI, 0.63 to 1.05)* | ||||
| VDG3 | 79/3,152 (25.1) | 69/3,655 (18.9) | RR: 1.33 (95% CI, 0.96 to 1.83)* | ||||
| VDG4 | 19/962 (19.8) | 25/1,136 (22.0) | RR: 0.90 (95% CI, 0.50 to 1.62)* | ||||
| Round 2 | VDG1 | 49/3,214 (15.2) | 52/2,960 (17.6) | RR: 0.87 (95% CI, 0.59 to 1.28)* | |||
| VDG2 | 89/4,353 (20.4) | 96/4,395 (21.8) | RR: 0.94 (95% CI, 0.70 to 1.25)* | ||||
| VDG3 | 79/2,656 (29.7) | 84/2,736 (30.7) | RR: 0.97 (95% CI, 0.72 to 1.31)* | ||||
| VDG4 | 29/900 (32.2) | 25/934 (26.8) | RR: 1.20 (95% CI, 0.71 to 2.04)* | ||||
| Surgical procedures (including open biopsy) |
Pattacini, 2022160 RETomo | DBT/DM (round 1), DM (round 2) vs. DM | Round 1 | Ages 45 to 49 | 29/5,053 (5.7) | 14/5,103 (2.7) | RR: 2.10 (95% CI, 1.10 to 4.00) |
| Ages 50 to 69 | 87/8,303 (10.5) | 54/8,418 (6.4) | RR: 1.60 (95% CI, 1.20 to 2.30) | ||||
| Round 2 | Ages 45 to 49 | 11/4,813 (2.3) | 22/4,855 (4.5) | RR: 0.50 (95% CI, 0.24 to 1.00) | |||
| Ages 50 to 69 | 57/7,920 (7.2) | 61/8,056 (7.6) | RR: 0.95 (95% CI, 0.66 to 1.40) |
- *
Relative risk calculated from Ns.
- †
Recalled for an assessment (after double reading and arbitration) based on positive or suspicious screening results.
Abbreviations: CG=control group; CI=confidence interval; DBT=digital breast tomosynthesis; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken; VDG=Volpara Density Grade
Table 18False Positives in Randomized Trials Comparing Digital Breast Tomosynthesis and Digital Mammography, by Population Subgroup
| Outcome |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Followup | Subgroup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|
| False-positive recall† |
Pattacini, 2022160 RETomo | DBT/DM vs. DM | Round 1 | Ages 45 to 49 | 179/5,053 (35.4) | 194/5,103 (38.0) | RR: 0.93 (95% CI, 0.76 to 1.10)* |
| Ages 50 to 69 | 231/8,303 (27.8) | 267/8,418 (31.7) | RR: 0.88 (95% CI, 0.74 to 1.00)* | ||||
| Round 2 | Ages 45 to 49 | 154/4,813 (32.0) | 177/4,855 (36.5) | RR: 0.88 (95% CI, 0.71 to 1.09)* | |||
| Ages 50 to 69 | 249/7,920 (31.4) | 253/8,056 (31.4) | RR: 1.00 (95% CI, 0.84 to 1.19)* | ||||
|
Hofvind, 2021143 To-Be | DBT/sDM vs. DM | Round 1 | VDG1 | 65/3,929 (16.5) | 91/3,212 (28.3) | RR: 0.58 (95% CI, 0.43 to 0.80)* | |
| VDG2 | 151/6,216 (24.3) | 231/6,280 (36.8) | RR: 0.66 (95% CI, 0.54 to 0.81)* | ||||
| VDG3 | 106/3,152 (33.6) | 121/3,655 (33.1) | RR: 1.02 (95% CI, 0.79 to 1.31)* | ||||
| VDG4 | 24/962 (24.9) | 38/1,136 (33.5) | RR: 0.75 (95% CI, 0.45 to 1.23)* | ||||
| Round 2 | VDG1 | 55/3,214 (17.1) | 62/2,960 (20.9) | RR: 0.81 (95% CI, 0.57 to 1.17)* | |||
| VDG2 | 132/4,353 (30.3) | 142/4,395 (32.3) | RR: 0.94 (95% CI, 0.74 to 1.19)* | ||||
| VDG3 | 114/2,656 (42.9) | 105/2,736 (38.4) | RR: 1.12 (95% CI, 0.86 to 1.45)* | ||||
| VDG4 | 44/900 (48.9) | 29/934 (31.0) | RR: 1.57 (95% CI, 0.99 to 2.49)* | ||||
| False-positive biopsy‡ |
Hofvind, 2021143 To-Be | DBT/sDM vs. DM | Round 1 | VDG1 | 21/3,929 (5.3) | 30/3,212 (9.3) | RR: 0.57 (95% CI, 0.33 to 1.00)* |
| VDG2 | 59/6,216 (9.5) | 93/6,280 (14.8) | RR: 0.64 (95% CI, 0.46 to 0.89)* | ||||
| VDG3 | 68/3,152 (21.6) | 44/3,655 (12.0) | RR: 1.79 (95% CI, 1.23 to 2.61)* | ||||
| VDG4 | 17/962 (17.7) | 18/1,136 (15.8) | RR: 1.12 (95% CI, 0.58 to 2.15)* | ||||
| Round 2 | VDG1 | 30/3,214 (9.3) | 35/2960 (11.8) | RR: 0.79 (95% CI, 0.49 to 1.28)* | |||
| VDG2 | 53/4,353 (12.2) | 61/4,395 (13.9) | RR: 0.88 (95% CI, 0.61 to 1.26)* | ||||
| VDG3 | 52/2,656 (19.6) | 50/2,736 (18.3) | RR: 1.07 (95% CI, 0.72 to 1.57)* | ||||
| VDG4 | 20/900 (22.2) | 10/934 (10.7) | RR: 2.08 (95% CI, 0.98 to 4.41)* |
- *
Relative risk calculated from Ns.
- †
Recalled for assessment without a finding of invasive cancer or DCIS.
- ‡
Underwent biopsy without a finding of invasive cancer or DCIS.
Abbreviations: CG=control group; CI=confidence interval; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; IG=intervention group; RETomo=Reggio Emilia Tomosynthesis Trial; RR=relative risk; sDM=synthetic 2-view mammography; To-Be=Tomosynthesis Trial in Bergen; OVVV=Oslo-Vestfold-Vestre Viken; VDG=Volpara Density Grade
Table 19Rates of Interval Cancers (Invasive Cancers and DCIS) in Studies Comparing Breast Cancer Screening Modalities, by Population Subgroup
| Modality | Study Design |
Author, Year Study/Trial Name | Comparison (IG vs. CG) | Timepoint | Histologic Type | Subgroup | IG n/N (rate per 1,000 screened) | CG n/N (rate per 1,000 screened) | Effect (95% CI) |
|---|---|---|---|---|---|---|---|---|---|
| DBT | RCT |
Pattacini, 2022160 RETomo | DBT/DM vs. DM | 12-months (ages 40 to 49 years) or 24-months (ages 50 to 69 years) | Invasive | Ages 45 to 49 | 3/4,853 (0.6) | 7/4,897 (1.4) | RR: 0.43 (95% CI, 0.11 to 1.70) |
| Ages 50 to 69 | 16/7,992 (2.0) | 13/8,102 (1.6) | RR: 1.20 (95% CI, 0.60 to 2.60) | ||||||
| DCIS | Ages 45 to 49 | 0/4,853 | 1/4,897 (0.2) | - | |||||
| Ages 50 to 69 | 2/7,992 (0.3) | 1/8,102 (0.1) | RR: 2.0 (95% CI, 0.18 to 22.0) | ||||||
| Invasive | Nondense breasts (BI-RADS A, B)* | 6/6,051 (1.0) | 4/6,094 (0.7) | RR: 1.50 (95% CI, 0.43 to 5.30) | |||||
| Dense breasts (BI-RADS C, D)* | 13/5,704 (2.3) | 15/5,691 (2.6) | RR: 0.86 (0.41 to 1.80) | ||||||
| DCIS | Nondense breasts (BI-RADS A, B)* | 1/6,051 (0.2) | 2/6,094 (0.3) | RR: 0.50 (95% CI, 0.05 to 5.60) | |||||
| Dense breasts (BI-RADS C, D)* | 1/5,704 (0.2) | 0/5,691 | - | ||||||
|
Hofvind, 2021143 To-Be | DBT/sDM vs. DM | 24-months† | Invasive | VDG1 Density‡ | 2/3,930 (0.5) | 0/3,212 | - | ||
| VDG2 Density‡ | 6/6,215 (1.0) | 7/6,279 (1.1) | RR: 0.87 (95% CI, 0.29 to 2.58)§ | ||||||
| VDG3 Density‡ | 8/3,146 (2.5) | 16/3,654 (4.4) | RR: 0.58 (95% CI, 0.25 to 1.36)§ | ||||||
| VDG4 Density‡ | 4/967 (4.1) | 5/1,136 (4.4) | RR: 0.94 (95% CI, 0.25 to 3.49)§ | ||||||
| DCIS | VDG1 Density‡ | 0/3,930 | 0/3,212 | - | |||||
| VDG2 Density‡ | 0/6,215 | 0/6,279 | - | ||||||
| VDG3 Density‡ | 0/3,146 | 1/3,654 (0.3) | - | ||||||
| VDG4 Density‡ | 0/967 | 0/1,136 | - | ||||||
|
Johnson, 202179 MBTST|| | DBT/DM vs. DM | 18-months (ages 40 to 54 years) or 24-months (ages 55 to 74 years) | Invasive and DCIS | Ages 40 to 54 | 8/6,289 (1.3) | 33/12,541 (2.6) | OR=0.5 (95% CI, 0.2 to 1.1)¶ | ||
| Ages 55 to 74 | 13/7,080 (1.8) | 43/14,197 (3.0) | OR=0.6 (95% CI, 0.3 to 1.1)¶ | ||||||
| NRSI |
Kerlikowske, 2022 BCSC-2022b | DBT/sDM vs. DM | 12-months | Invasive | BI-RADS A* | NR (0.12) | NR (0.24) | Adj. rate difference: −0.12 (95% CI, −0.31 to 0.07) | |
| BI-RADS B* | NR (0.31) | NR (0.39) | Adj. rate difference: −0.08 (95% CI, −0.24 to 0.07) | ||||||
| BI-RADS C* | NR (0.99) | NR (0.87) | Adj. rate difference: 0.11 (95% CI, −0.11 to 0.34) | ||||||
| BI-RADS D* | NR (0.87) | NR (1.21) | Adj. rate difference: −0.34 (95% CI, −0.76 to 0.07) | ||||||
| Richman, 2021162 | DBT/DM vs. DM | 12-months** | Invasive | Ages 40 to 44 | NR (0.6)†† | NR (0.5)†† | Adj. proportion difference: 0.04 (99% CI, −0.13 to 0.21)‡‡ | ||
| Ages 45 to 49 | NR (0.6)†† | NR (0.5)†† | Adj. proportion difference: 0.03 (99% CI, −0.12 to 0.17)‡‡ | ||||||
| Ages 50 to 54 | NR (0.7)†† | NR (0.5)** | Adj. proportion difference: 0.18 (99% CI, 0.04 to 0.32)‡‡ | ||||||
| Ages 55 to 59 | NR (0.5)†† | NR (0.5)†† | Adj. proportion difference: 0.02 (99% CI, −0.09 to 0.13)‡‡ | ||||||
| Ages 60 to 64 | NR (0.6)†† | NR (0.5)†† | Adj. proportion difference: 0.08 (99% CI, −0.05 to 0.22)‡‡ | ||||||
| Suppl. US | RCT |
J-START | DM plus US vs. DM | 12-months | Invasive and DCIS | Nondense breasts (BI-RADS A, B)* | 2/3,908 (0.5) | 9/3,915 (2.3) | RR: 0.22 (95% CI, 0.05 to 1.03)§ |
| Dense breasts (BI-RADS C, D)* | 3/5,797 (0.5) | 10/5,593 (1.8) | RR: 0.29 (95% CI, 0.08 to 1.05)§ |
- *
BI-RADS uses visual assessment to categorize breast density as (A) almost entirely fatty; (B) scattered areas of fibroglandular density; (C) heterogeneously dense; and (D) extremely dense.
- †
6- to 24-months followup among women with a false-positive result at previous screening.
- ‡
The Volpara system uses a quantitative measure of volumetric breast density and assigns density to one of four categories (Volpara density grade [VDG] 1 to 4), which are analogous to BI-RADS A to D.
- §
Relative risk calculated from Ns.
- ||
This study is a nonrandomized study based on MBTST participants compared with a contemporary age-matched population cohort.
- ¶
Age-adjusted odds ratio.
- **
Excluded cancers diagnosed within 5 months of screening.
- ††
Models adjusted for use of screening ultrasound, time period of index mammogram, time since last mammogram, metro location, hospital referral region, and family history of breast cancer. Rates and risk differences reported in table are adjusted per 100,000 from original study reported rates of a per 1,000 mammogram scale.
- ‡‡
Interaction between screening type and all age group from multivariable logistic regression model was p=0.54.
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; BI-RADS=Breast Imaging Reporting and Data System; CI=confidence interval; DBT=digital breast tomosynthesis; DCIS=ductal carcinoma in situ; DM=digital mammography; DENSE=Dense Tissue and Early Breast Neoplasm Screening; J-START= Japan Strategic Anti-cancer Randomized Trial; MBTST=Malmo Breast Tomosynthesis Screening Trial; MRI=magnetic resonance imaging; RETomo=Reggio Emilia Tomosynthesis Trial; NRSI=nonrandomized study of intervention; RR=relative risk; sDM=synthetic mammography; PROSPR=Population-based Research Optimizing Screening through Personalized Regimens; To-Be=Tomosynthesis Trial in Bergen; TOSYMA=Tomosynthesis plus Synthesized Mammography study; OVVV=Oslo-Vestfold-Vestre Viken; UKCCR=United Kingdom Coordinating Committee on Cancer Research trial; US=ultrasound; VDG=Volpara Density Grade
Table 20Downstream Consequences of Supplemental Screening With MRI or Ultrasound
| Modality |
Author, Year Study/Trial Name Study Design | Comparison | Population | Outcome | Followup | IG n/N (rate per 1,000 screened) | Details |
|---|---|---|---|---|---|---|---|
| Suppl. MRI |
Veenhuizen, 202127 DENSE RCT | DM+MRI vs. DM | Women ages 50 to 75 years with negative mammography results (BI-RADS radiographic score of 1 or 2) and extremely dense breast tissue | Serious adverse event | 0-days | 5/4,783 (1.0) | 2 vasovagal reactions, 3 allergic reactions to contrast agent |
| 30-days | 27/4,783 (5.6) | Events reported regardless of relatedness to screening MRI: 27 serious adverse events (required emergency department visit or unplanned hospital admission: 5 nervous system disorders, 2 gastrointestinal disorders, 2 skin/subcutaneous tissue disorders, 2 cardiovascular disorders, 7 musculoskeletal disorders, 3 ear/nose/throat/eye disorders, 1 general disorder, 1 respiratory disorder, 1 urologic disorder, 1 reproductive system and breast disorder/complaint, 2 medical procedures [complications during/after biopsy procedure]) | |||||
| Adverse event | 0-days | 3/4,783 (0.6) | 2 extravasation of contrast agent, 1 subluxation shoulder | ||||
| 30-days | 1,233/4,783 (257.8) | Events reported regardless of relatedness to screening MRI. Most common listed were nervous system disorder, gastrointestinal disorder, psychosocial/psychiatric disorder, musculoskeletal disorder, respiratory disorder | |||||
| Recall | 0-days | 454/4,783 (94.9) | |||||
| False-positive recall | 0-days | 375/4,700 (80.0) | |||||
| Biopsy | 0-days | 300/4,783 (62.7) | |||||
|
Ganguli, 2022135 NRSI | MRI vs. DM | Women ages 40 to 64 years who had a bilateral breast MRI or bilateral screening mammogram claim | Laboratory tests due to extramammary findings | 6-months | NR/9,208 (12) | Rate difference: 3.2 (95% CI, −2.2 to 8.5) | |
| Imaging tests due to extramammary findings | 6-months | NR/9,208 (3) | Rate difference: 0.5 (95% CI, −2.7 to 1.8) | ||||
| Procedures following extramammary findings | 6-months | NR/9,208 (1) | Rate difference: 1.0 (95% CI, −0.1 to 2.0) | ||||
| New diagnoses following extramammary findings | 6-months | NR/9,208 (0.5) | Rate difference: 0.3 (95% CI, −0.5 to 1.1) | ||||
| All extramammary cascade events | 6-months | NR/9,208 (31) | Rate difference: 19.6 (95% CI, 8.6 to 30.7) | ||||
| Suppl. US |
Ohuchi, 2016158 J-START RCT | DM+US vs. DM | Women ages 40 to 49 years | Recall rate for positive ultrasound only | First round | 1,826/36,752 (49.7) | |
| False-positive recall for positive ultrasound only | First round | 1,765/36,752 (48.0) | |||||
| Women ages 40 to 49 years with nondense breasts | Recall rate for positive ultrasound only | First round | 154/3,908 (39.4) | ||||
| Women ages 40 to 49 years with dense breasts | Recall rate for positive ultrasound only | First round | 404/5,797 (69.7) | ||||
|
Lee, 2019152 BCSC NRSI | DM+US vs. DM | Women undergoing screening at eligible BCSC sites | Biopsy | First round | NR (57) | RR=2.05 (95% CI, 1.79 to 2.34) | |
| False-positive biopsy recommendation | First round | NR (52) | RR=2.23 (95% CI, 1.93 to 2.58) | ||||
| Short-interval imaging followup | First round | NR (0.4) | RR=3.1 (95% CI, 2.6 to 3.7) |
Abbreviations: BCSC=Breast Cancer Surveillance Consortium; DM=digital mammography; DENSE=Dense Tissue and Early Breast Neoplasm Screening; J-START=Japan Strategic Anti-cancer Randomized Trial; MRI=magnetic resonance imaging; NR=not reported; NRSI=nonrandomized study of intervention; US=ultrasound