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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.)

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Screening for Breast Cancer: A Comparative Effectiveness Review for the U.S. Preventive Services Task Force [Internet].

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Structured Abstract

Objective

We conducted this systematic review to support the U.S. Preventive Services Task Force (USPSTF) in updating its recommendations on breast cancer screening. Our review addresses the comparative effectiveness of breast cancer screening for improving health outcomes. The review compares different strategies regarding when to screen (e.g., age to start/stop screening, screening interval), screening modalities (e.g., digital breast tomosynthesis [DBT] versus digital mammography [DM]), supplemental screening, or screening strategies defined by breast cancer risk markers.

Data Sources

We searched MEDLINE, Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews and the reference lists of previous systematic reviews of breast cancer screening for relevant studies published through August 22, 2022.

Study Selection

We reviewed 10,379 abstracts and assessed 420 full-text articles for inclusion against prespecified inclusion criteria. Eligible studies were conducted in asymptomatic adults eligible for breast cancer screening without clinically significant genetic markers or syndromes associated with high breast cancer risk. Randomized trials and nonrandomized studies of interventions (NRSIs) with concurrent comparison groups that reported data over multiple rounds of screening were included to compare health outcomes (e.g., breast cancer mortality) and intermediate outcomes (e.g., risk of advanced cancer); study criteria were broader for identifying potential screening harms. The review was limited to studies conducted in countries with “very high” Human Development Index scores.

Data Analysis

We conducted dual independent critical appraisal of all included studies and extracted study details and outcomes from fair- or good-quality studies. We narratively synthesized results by key question and for each screening comparison. We used random-effects meta-analyses to estimate pooled effects when appropriate. We graded the overall strength of evidence as high, moderate, low, or insufficient based on criteria adapted from the Evidence-based Practice Center Program.

Results

Health outcomes (KQ1) associated with different screening programs were reported in only two fair-quality NRSIs that addressed the age to stop screening or screening interval. For invasive cancer detection (KQ2), two studies addressed the effect of screening frequency on the characteristics of detected cancers, including one fair-quality randomized controlled trial (RCT) of multiple rounds of screening and one fair quality cases-only analysis from the Breast Cancer Surveillance Consortium (BCSC). Five studies of DBT compared with DM, three RCTs (two good- and one fair-quality) and two NRSIs 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).

Age to start or stop screening. One fair-quality NRSI reported an emulated trial analysis of Medicare data (N = 1,058,013) comparing the age to stop screening with reported breast cancer mortality and all-cause mortality (KQ1). Continued screening between the ages of 70 and 74 was associated with decreased 8-year breast cancer mortality compared with a cessation of screening after age 70 (1 fewer death per 1,000 women screened), but no difference was found with continued versus discontinued screening from ages 75 to 84.

Harms (KQ3). Limited evidence on potential risks of overdiagnosis and overtreatment was reported, with more diagnosis and treatment occurring with continued screening, without a mortality benefit.

Interval of screening. A study conducted in Finland during the years 1985 to 1995 assigned participants (N = 14,765) to annual or triennial screening invitations and reported similar breast cancer mortality and all-cause mortality between the two study groups (KQ1). Intermediate cancer detection and progression outcomes (KQ2) were reported in one fair-quality RCT (n = 76,022) in the United Kingdom comparing annual or triennial screening and in one fair-quality registry study using BCSC data (N = 15,440) to compare annual with biennial screening intervals. The characteristics of tumors diagnosed among those screened with annual versus triennial intervals did not differ in the RCT, though more cancers diagnosed were screen-detected with annual screening (relative risk [RR], 1.64 [95% CI, 1.28 to 2.09]).

In the nonrandomized study, all reported results were stratified by age or hormonal status. Detection of stage IIB+ cancers and cancers with less favorable prognostic characteristics did not differ by screening interval for any reported age groups. Comparisons by menopausal status suggested that premenopausal women with a biennial interval directly preceding their breast cancer diagnosis were at increased risk of stage IIB or higher tumors (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, there was no statistical difference in tumor characteristics by the screening interval preceding diagnosis. The study did not conduct formal tests for interaction in the subgroup comparisons. Neither study reported mortality outcomes, so it is unclear whether these findings would have clinically significant effects on health outcomes.

Harms (KQ3). One RCT reported approximately one additional interval cancer per 1,000 with triennial screening compared with annual screening, and data from four nonrandomized studies were limited and inconsistent. Consistently higher cumulative false-positive rates were seen with shorter intervals between screenings. The probability of having at least one false-positive recall and biopsy over 10 years of screening was higher with annual DBT screening compared with biennial screening, with annual screening resulting in approximately 50 additional false-positive biopsies per 1,000 screened over 10 years. Cumulative false-positive estimates were highest among young women with dense breasts who were screened annually.

Mammography with digital breast tomosynthesis. No eligible studies reported breast cancer mortality or other health outcomes to compare the effectiveness of screening with DBT versus DM only (KQ1). Intermediate outcomes that compared screening with DBT versus DM were reported in three RCTs (N = 130,196) and two nonrandomized studies (N = 597,267) (KQ2). The three trials screened all participants with a single screening modality at the second screening round, with DM in two trials and DBT in the other. DBT was associated with increased detection of invasive cancer at the first screening round (pooled RR, 1.41 [95% CI, 1.20 to 1.64]; I2=8%; 3 trials; n = 129,492) and was not statistically different at the second screening round (pooled RR, 0.87 [95% CI, 0.73 to 1.05]; I2=0%; 3 trials; n = 105,064), and there was no evidence of a reduced risk of progression to advanced cancer in the second round with DBT compared with DM. The relative risk of advanced cancer (stage II+) at a subsequent screening round was not statistically significant in the three individual trials and there was also no evidence of a difference in progression to advanced cancer with DBT screening in the two NRSIs. The three trials and a nonrandomized study reported tumor diameter, histologic grade, and node status. No statistically significant differences in these or other individual tumor prognostic characteristics were reported at the first or second round of screening. Limited results stratified by age and density in two of the RCTs did not indicate 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.

Harms (KQ3). Three large RCTs reported 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) but data from six nonrandomized studies 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. In one NRSI 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). Another NRSI reported lower rates of false-positive recall and false-positive biopsy rates with DBT in two screening rounds, after which the differences were attenuated and not statistically significant. An additional adverse effect of DBT, radiation exposure, was approximately two times higher in studies where DBT was paired with DM; exposure was similar in two studies that used DBT to generate synthetic DM images (DBT/sDM).

Supplemental screening. No eligible studies reported health outcomes when comparing supplemental screening with ultrasound or magnetic resonance imaging (MRI) to usual screening with mammography only (KQ1). No studies of supplemental screening with MRI or ultrasound were included for comparisons of benefit because the trials were incomplete and reported only one screening round (KQ2).

Harms (KQ3). In an RCT among women with dense breasts randomized to supplemental screening with MRI following a negative mammogram screening result, the risk of invasive interval cancer was reduced by approximately half (RR, 0.47 [95% CI, 0.29 to 0.77]). Two studies of ultrasound screening in addition to mammogram did not find significant differences in the rates of interval cancers. Supplemental MRI screening for women with dense breasts with a negative mammography resulted in more recalls, false-positive recalls, and biopsies (95, 80, and 63 per 1,000 screened, respectively) than for those receiving DM only. With supplemental ultrasound screening, 48 per 1,000 experienced recall in a trial among women ages 40 to 49 and in a BCSC registry analysis, referral to biopsy and false-positive biopsy results were twice as high for the group screened with ultrasound compared with those receiving only mammography.

Limitations

Few published comparative effectiveness trials reported more than a single round of screening. Multiple screening rounds are necessary to identify potential intermediate effects of screening, such as stage shift, limiting conclusions about the potential health consequences of different approaches to screening. Data comparing screening outcomes for subgroups of women with different characteristics or breast cancer risk markers were limited, mainly providing stratified results only without interaction tests. Findings from older studies included in the review may not be applicable to current programs using newer screening modalities and treatment advances.

Conclusions

We did not find evidence of lower breast cancer mortality or risk of progression to advanced cancer in eligible studies comparing different breast cancer screening strategies. There were downstream consequences (e.g., more false-positive results and biopsy) with supplemental screening. Regular mammography screening is associated with reduced breast cancer mortality for women ages 50 to 69, based on trials conducted over 20 years ago, and longer-term followup from the trials has not altered these conclusions. Changes in population health, imaging technologies, and available treatments could limit the applicability of older trials. Additionally, nearly all of the trials were conducted outside of the United States and enrolled mainly White European populations. Inequities in breast cancer mortality and length of survival, especially for Black women, also warrants greater attention to health care interventions following screening, including prompt followup, diagnosis, and access to high quality treatment and support services, as well as more dedicated research to find effective treatments for triple-negative cancers. The limited early evidence from newer comparative effectiveness trials does not yet provide answers to questions about the benefits or harms of different screening strategies, but ongoing and pending trials may further the science in coming years.

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