Performance of ultrasonography screening for breast cancer: a systematic review and meta-analysis

DOI: https://doi.org/10.21203/rs.2.14015/v1

Abstract

Background To provide a global profile of supplemental ultrasonography (US) screening after mammography (MAM) screening or primary US screening for breast cancers.

Methods Electronic databases (PubMed, Scopus, Wed of Science, and Embase) were systematically searched to identify relevant studies published between January 2003 and May 2018. Only high-quality or fair-quality studies reporting any of the following performance values for supplemental or primary US screening were included: sensitivity, specificity, cancer detected rate (CDR), recall rate (RR), biopsy rate (BR), and proportions of invasive cancers (ProIC) or node-positive cancers (ProNPC) among screening-detected cancers.

Results Twenty-three studies were included, including 12 supplemental US screening studies and 11 joint screening studies in which both MAM and US were used as primary screening methods. Meta-analyses revealed that supplemental US screening could detect 96% [95% confidential intervals (CIs): 82% to 99%] of occult breast cancers missed by MAM and identify 94% (95% CIs: 88% to 97%) of healthy women, with a CDR of 2.9/1000 (95%CIs: 1.8/1000 to 3.9/1000), RR of 8.6% (95%CIs: 4.8% to 13.5%), BR of 3.9% (95%CIs: 2.5% to 5.5%), ProICof 73.9% (95%CIs: 49.0% to 93.7%), and ProNPC of 72.6% (95%CIs: 51.9% to 90.0%). Compared with primary MAM screening, primary US screening led to the recall of significantly more women with positive screening results [1.2% (95%CIs:0.4% to 1.9%), P =0.004] and detected significantly more invasive cancers [20.2% (95%CIs: 7.2% to 33.1%), P = 0.002]. However, there were no significant differences for other performance measures between the two screening methods, including sensitivity, specificity, CDR, BR, and ProNPC.

Conclusions Supplemental US screening could detect occult breast cancers missed by MAM, while primary US screening performances are comparable to those of primary MAM screening, but with a higher recall rate and a higher detection rate for invasive cancers.

Background

Cancer is a global public health issue in the world. In 2016, an estimated 17.2 million cancer cases and 8.9 million cancer deaths occurred worldwide [1]. For women, both the most commonly occuring cancer and the leading cause of cancer deaths and disability-adjusted life-years (DALYs) was breast cancer (1.7 million incident cases, 535,  000 deaths, and 14.9 million DALYs)[1]. Over the years, the burden of cancer has shifted from more developed countries to less developed countries[2]. Moreover, the burden is expected to grow worldwide due to the aging of the population and the adoption of lifestyle behaviors such as smoking, poor diet, physical inactivity, and reproductive changes (including lower parity and later age at first birth), particularly in less developed countries[2]. Therefore, broad prevention measures, such as cancer screening, are urgently needed to control this increasing burden, especially in less developed countries.

Mammography(MAM) has been used to screen for breast cancer since the 1970s and is now widely available in developed countries. However, in less developed counties, such as China, MAM is not easily accessible due to several barriers, including insufficient MAM equipment, inadequate insurance coverage for MAM, and widely dispersed populations [3]. Moreover, MAM has a low sensitivity in women with dense breasts [4], who could suffer a higher risk of breast cancer than those without dense breasts [5]. Worrisome research from Denmark and Netherlands showed that nearly one in every three or half of screening-detected breast cancers represents overdiagnosis, respectively [6, 7].

Recent data indicates that supplemental ultrasonography (US) screening could detect occult breast cancers missed by MAM, and primary US screening seems perform comparably to primary MAM screening [8–11]. However, systematic reviews of the performances of supplemental or primary US screening have been published only in limited studies. Moreover, among broad screening studies in which both MAM and US were used as primary screening methods, researchers just focused on the performance differences between joint screening and MAM screening alone. Limited studies investigated the independent performances of primary US screening. Therefore, we conducted this systematic review and meta-analysis to provide a global profile of supplemental US screening after MAM screening or primary US screening for breast cancers.

Materials And Methods

This meta-analysis was reported in line with the preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: The PRISMA-DTA Statement (Supplementary S1) [12].

Types of studies and participants

Randomized-controlled trials (RCTs), prospective or retrospective screening cohort studies reporting any of the following performance values for supplemental or primary US screening were included: sensitivity, specificity, cancer detected rate (CDR), recall rate (RR), biopsy rate (BR), and proportions of invasive cancers (ProIC) or node-positive cancers (ProNPC) among screening-detected cancers. The types of US included were hand-held ultrasonography (HHUS) and automated whole breast ultrasonography (ABUS). Diagnostic studies of patients with histopathologically proven breast cancer or women with suspicious finding after initial screening were excluded. Screening studies for second cancers among women previously diagnosed with breast cancer were also excluded.

Searching strategies

A comprehensive search was conducted according to the Cochrane handbook guidelines. The American College of Radiology (ACR) developed the Breast Imaging Reporting and Data System (BI-RADS) classification for breast ultrasonography examinations starting in 2003 [13]. Electronic databases (PubMed, Scopus, Wed of Science, and Embase) were systematically searched to identify relevant studies published in English between January 2003 and May 2018. Five groups of key words were used in the searching strategies: (1) breast neoplasm, breast cancer, breast carcinoma (2) ultrasound, ultrasonography (3) screening (4) supplemental, supplementary, adjunct, adjunctive, combined, joint, primary, single, alone (5) sensitivity, specificity, detection rate, recall rate, biopsy rate. Reference lists from retrieved articles were also reviewed. Detailed searching strategies are referred to in the supplementary S2.

Selection of studies

Two authors independently screened the titles and abstracts of all selected articles to confirm their eligibility. All selected articles were analyzed by EndNote software that allows reviewers to manage articles and detect duplicate publications. When two or more articles from the same trial were selected, the article with the larger sample size, longer duration of follow-up, or the latest results was included. Any disagreement on the selection of articles was discussed and arbitrated by a third author. Details of the selection process are provided in the supplementary S3.

Data extraction

Two authors independently extracted the following data from the qualifying studies: general information (name of first author, year of publication, and country or countries where the study was performed), design of study (sample size, mean age, percent of women with dense breasts among the whole population, type of US, screening mode), performance of US, and information for risk assessment of bias (detailed information referred to in the following section). All data was entered into STATA 14.0 software for analysis. Any disagreements on data extracted were also discussed and arbitrated by the same third author.

Risk assessment of bias in included studies

Two investigators critically appraised all included studies independently according to the pre-specified criteria, which were adjusted from the USPSTF’s design-specific criteria and the STARD checklist for reporting diagnostic accuracy studies [14, 15]. The adjusted criteria included: (1) Included population came from a representative source population (Yes: general community women or well-defined high-risk women; No: women participants in an opportunistic screening and other undefined women) (2) Sample size was greater than or equal to 1000 (Yes/No) (3) Included studies clearly described the inclusion and exclusion criteria, and women who had a personal history of breast cancer were definitely excluded before screening (Yes/No) (4) In studies in which more than one screening method was used as the primary screening method, the readers of different screening methods were masked to each other (Yes/No) (5) All participants received US screening, or the proportion of missing data for either test was less than or equal to 5% (Yes/No) (6) US findings were interpreted according to BI-RADS criteria (Yes/No) (7) Women with positive results from index screening methods were ascertained with histopathology; and women with negative results were ascertained with a minimum 12-month clinical follow-up (reference standards) (Yes/No).

According to the above mentioned criteria, high-quality studies were defined as those meeting at least six criteria for joint screening studies and five criteria for supplemental US screening studies. Fair-quality studies meet four or five criteria for joint screening studies and three or four criteria for supplemental US screening studies. Poor quality studies were defined as those meeting less than four criteria for joint screening studies and three criteria for supplemental US screening studies. Poor studies were excluded from the review.

Data synthesis and analysis

All data were extracted with pre-specified uniform tables and recalculated with uniform methods.The corresponding authors will be contacted to obtain any missing information from their studies. The recall rate was calculated as the number of women recalled for further diagnosed examinations divided by the total number of women participated the screening. If the number of women recalled for any further diagnosed examinations was not available, the number of women with a positive result of index screening modality was used instead. The biopsy rate was calculated as the number of women recalled for pathological examination divided by the total number of women participated the screening.

The variation in different screening performances attributable to heterogeneity was measured as I2. If the P value for I2 was less than 0.1, significant heterogeneity was indicated among included trials and the random-effect model was used to combine screening performances [16]. Otherwise, the fixed-effect model was used if the P value for I2 was larger than 0.1. To search for sources of heterogeneity and obtain clinically meaningful estimates, subgroup analyses were conducted according to different studies characteristics, such as sample size > 1000 (Yes/No), all women with dense breasts (Yes/No), type of US (HHUS/ABUS), and quality assessment (Yes/No), whenever possible. The package “midas” was used to combine sensitivity and specificity, to investigate whether there were potential publication biases among included studies, and to plot the summary receiver operating characteristic (SROC) curve with its 95% confidence and prediction contours [17]. The package “metaprop” was used to combine CDR, RR, BR, ProIC, and ProNPC [18]. In addition, the package “metan” was used to compare the performances between MAM and US [19].

All meta-analyses were conducted with STATA software (version 14.0). All tests were two-sided, and P values of less than 0.05 for all meta-analyses indicated statistical significance.

Results

Supplementary figure S3 shows a flowchart of the study selection procedure. The electronic searches yielded 1162 potentially relevant studies, of which 23 eligible studies were included in the final review [9–11, 20–39], including 12 supplemental US screening studies and 11 joint screening studies in which both MAM and US were used as primary screening methods.

Table 1 shows the baseline characteristics of the 23 studies. Twelve studies were conducted among women with dense breasts. Twenty studies screened women with HHUS. Twelve studies were conducted among general community women or well-defined high-risk women. Eleven studies definitely excluded women who had a personal history of breast cancer. Eight joint screening studies masked the results of primary MAM screening and primary US screening. Nineteen studies had low risk of incomplete data. Sixteen studies reported US results according to BI-RADS classification criteria. The reference standard in seventeen studies was pathologic examination combined with 12-month clinical follow-up. Finally, according to the pre-specified criteria, seven studies were of good quality, while the left 16 were of fair quality.

Screening accuracy for supplemental and primary US screening

Table 2 shows the original data of screening accuracy for supplemental and primary US screening among the included studies. Based on meta-analyses, supplemental US screening could detect 96% [95% confidential intervals (CIs): 82% to 99%; I2 = 66.3%, P < 0.01] of occult breast cancers missed by MAM and identify 94% (95% CIs: 88% to 97%; I2 = 99.8%, P < 0.01) of healthy women (Figure 1A, supplementary S4). The area under the SROC (AUC) for supplemental US screening was 99% (95CIs: 97% to 99%) (Figure 1A). No publication bias was found among these studies (P = 0.465).

Among 11 joint screening studies, primary MAM screening could detect 64% (95%CIs: 53% to 74%; I2 = 93.5%, P < 0.01) of breast cancers and identify 97% (95% CIs: 94% to 99%; I2 = 99.9%, P < 0.01) of healthy women (Figure 1B, supplementary S5), respectively. Primary US screening could detect 55% (95%CIs: 37% to 71%; I2 = 95.5%, P < 0.01) of breast cancers and identify 98% (95CIs: 94% to 99%; I2 = 100%, P < 0.01) of healthy women (Figure 1C, supplementary S6). The AUCs for primary MAM screening and primary US screening were 88% (95CIs: 85% to 91%) (Figure 1B) and 90% (95CIs: 87% to 93%) (Figure 1C), respectively. No publication bias was found for both primary MAM screening (P = 0.209) and primary US screening (P = 0.466). No significant differences were found for either sensitivity [–10.9% (95%CIs: –29.0% to 7.2%), P = 0.239; I2 = 91.8%, P < 0.001] or specificity [–0.2% (95%CIs: –0.9% to 0.4%), P = 0.510; I2 = 96.7%, P < 0.001] between primary MAM screening and primary US screening (Figure 2).

Screening efficacy for supplemental and primary US screening

Table 3 shows the original data for screening accuracy for supplemental and primary US screening reported by the included studies. Meta-analyses determined that the summary CDR for supplemental US screening was 2.9/1000 (95%CIs: 1.7/1000 to 4.5/1000; I2 = 85.2%, P < 0.001), with a RR of 8.6% (95%CIs: 4.8% to 13.5%; I2 = 99.7%, P < 0.001) and a BR of 3.9% (95%CIs: 2.5% to 5.5%; I2 = 98.4%, P < 0.001) (Figure 3).

The summary CDRs for primary MAM screening and primary US screening were 4.5/1000 (95%CIs: 3.1/1000 to 6.0/1000; I2 = 89.6%, P < 0.001) and 3.7/1000 (95%CIs: 2.4/1000 to 5.2/1000; I2 = 91.0%, P < 0.001), with summary RRs of 4.1% (95%CIs: 2.0% to 7.0%; I2 = 99.8%, P < 0.001) and 5.3% (95%CIs: 2.5% to 9.2%; I2 = 99.8%, P < 0.001), and summary BRs of 1.4% (95%CIs: 0.4% to 2.9%; I2 = 99.0%, P < 0.001) and 1.9% (95%CIs: 0.8% to 3.4%; I2 = 98.7%, P < 0.001) (Figure 4). Compared to primary MAM screening, primary US screening recalled significantly more women with positive screening results [1.2% (95%CIs: 0.4% to 1.9%), P = 0.004] (Figure 2, –1.2%, 95% CIs (–1.9% to –0.4%), P = 0.003; I2 = 96.6%, P < 0.001). No significant differences were found for either CDR [–0.6/1000 (95%CIs:–1.7/1000 to 0.6/1000, P = 0.334; I2 = 73.8%, P < 0.001] or BR [0.6% (95%CIs: –0.1% to 1.2%), P = 0.091; I2 = 92.2%, P < 0.001] between primary US screening and primary MAM screening (Figure 2).

Cancer characteristics for supplemental and primary US screening

Table 4 shows the original data for cancer characteristics for supplemental and primary US screening reported by the included studies.After meta-analyses, 73.9% (95%CIs: 49.0% to 93.7%; I2 = 66.4%, P = 0.007) of cancers detected by supplemental US screening were invasive cancers, while 72.6% (95%CIs: 51.9% to 90.0%; I2 = 0.0%, P = 0.499) of cancers were node-positive cancers (Figure 3).

Among 11 joint screening studies, 57.1% (95%CIs: 39.8% to 73.6%; I2 = 88.6%, P < 0.001) and 85.0% (95%CIs: 54.1% to 100.0%; I2 = 96.2%, P < 0.001) of cancers detected by supplemental US screening and primary MAM screening were invasive cancers, while 58.0% (95%CIs: 28.0% to 85.5%; I2 = 94.4%, P < 0.001) and 64.1% (95%CIs: 37.8% to 87.3%; I2 = 91.1 %, P < 0.001) of cancers were node-positive cancers (Figure 4). Compared to primary MAM screening, primary US screening detected significantly more invasive cancers [20.2%, 95% CIs (7.2% to 33.1%), P = 0.002; I2 = 74.2%, P < 0.001] but a similar number of node-positive cancers [–2.0%, 95% CIs (–13.5% to 9.4%), P = 0.729; I2 = 57.6%, P = 0.028] (Figure 2).

Subgroup analyses

Subgroup analyses showed very similar results to those of primary analyses (Supplementary S7 and S8). In addition to results comparable to those observed in the primary analyses, lower sensitivity, higher specificity, and higher cancer detection rate were found for supplemental US screening among women with dense breasts compared to those without dense breasts (Supplementary S7). Moreover, the differences for sensitivities, specificities, and cancer detection rates between primary MAM screening and primary US screening were smaller among women with dense breasts compared to those without dense breasts (Supplementary S8).

Discussion

The U.S. Preventive Services Task Force (USPSTF) had initially reviewed the performances and clinical outcomes of supplemental US screening in women with dense breasts or negative mammography [14]. However, only two studies were included. The authors concluded that the effects of supplemental US screening on breast cancer outcomes remain unclear due to sparse good evidence [14]. In addition, Gartlehnerhad systematically reviewed the evidence investigating the joint effectiveness of screening with MAM and US compared to MAM screening alone [40]. However, this review did not investigate the performance of primary US screening. Our studyis the first systematic review and meta-analysis to investigate the performance of primary US screening for breast cancer, and this is also an important up-to-date systematic review and meta-analysis investigating the performance of supplemental US screening.

The role of supplemental US screening was first addressed in ACRIN 6666 by Berg in 2008 [4]. Berg concluded that adding US screening to MAM screening would yield an additional 1.1 to 7.2 cancers per 1000 high-risk women [4]. Our analyses also found a similar additional 1.8 to 3.9 cancers per 1000 examinations. Moreover, after re-analysis of ACRIN 6666, Berg concluded that ultrasound could be used as the primary screening test for breast cancer [11]. However, up to now, there have been no consistent conclusions concerning whether US screening should be recommended as a screening test for women in the screening guidelines for breast cancer. For example, the National Comprehensive Cancer Network, the European Society of Breast Imaging (EUSOBI), the Japanese Breast Cancer Society, and the Chinese Anti-Cancer Association (CACA) supported that supplemental US screening should be recommended for women with dense breasts after negative mammogram [41–44], while no clear recommendations of US screening were suggested by the USPSTF, the American Cancer Society, the American College of Physicians, and the Canadian Task Force on Preventive Health Care [45–48].

Several reasons would lead to these inconsistent recommendations among current guidelines. As argued by USPSTF, sparse good evidence would be the major reason. However, as shown in our study, several high-quality studies and fair-quality studies had been conducted since 2003. Although EUSOBI supported supplemental US screening after MAM, it also addressed the concern that breast US was inappropriately suggested to be a primary screening method since primary US screening had not been shown to reduce mortality of breast cancer in the general female population. Moreover, US would lead to more biopsies and recalls than MAM [44]. In this systematic review, we did observe higher recall rates for US compared to MAM. We also observed higher biopsy rates for US compared to MAM; however, the difference was nonsignificant. This nonsignificant difference in biopsy rates between US and MAM may be due to small sample sizes, but it may also reflect no actual difference. In addition, there are several limitations of breast ultrasound that would make it inappropriate for a screening test. These include:US cannot take an image of the whole breast at once as MAM does; US cannot show microcalcifications, which would be the most common feature of tissue around a tumor; the skill level of the US operators makes a great difference in the screening results. However, as shown in our study, these concerns seemed not to cause significant differences in the sensitivity and specificity, or even in cancer detection rates and cancer characteristics (such as the proportion of node-positive cancers) between primary US screening and primary MAM screening. Moreover, lower price, larger coverage, absence of radiation effects, and lower overdiagnosis rates for US compared to MAM make US more easily accepted in China and other countries [3, 49, 50].Therefore, CACA and other societies supported supplemental US screening in their guidelines.

Lastly, the following results are significant. First, we observed significantly higher RR and ProIC for primary US screening compared with primary MAM screening. Higher recall rates would be an important barrier to promote US screening. More studies are needed to investigate the factors influencing false positive caused by US screening so as to reduce unnecessary recalls. In contrast to the higher rate of detection of microcalcified cancers by MAM, detection of more invasive cancers by US would be another potential advantage compared to MAM, since we usually cannot classify invasive cancers as overdiagnosed cancers. Second, we did not observe obvious differences in the performance of supplemental US screening between women with and without dense breasts. These results further support the position that the performance of supplemental US screening would not be easily influenced by dense breasts. However, we also did not observe significantly higher sensitivity for US compared to MAM among women with dense breasts. Small sample size could be an important factor, since only three of 11 included studies recruited women with dense breasts.

Limitations

First, due to lack of evidence for reduced mortality from breast cancer, we cannot conclude that US screening would lead to a long-term benefit. Second, in addition to breast density, no studies investigated whether other risk factors (such as obesity) influenced the differences in screening performance between US and MAM. Therefore, we cannot conclude whether these different performances between US and MAM derived from confounding effects or from the actual differences between US and MAM. Third, missing data in several important performance indexes, such as recall rate and biopsy rate, could lead to biased results. Uniform reporting guidelines for US or MAM screening studies are needed to improve comparability between different studies.

Conclusions

Current evidence suggests that supplemental US screening could detect occult breast cancers missed by MAM. The performance of primary US screening is comparable to that of primary MAM screening, the differences being higher recall rate and higher proportion of invasive cancers detected. However, more studies are needed to investigate the long-time benefits of US screening, and to investigate the influential factors of false positive caused by US screening to reduce unnecessary recall back.

Abbreviations

ABUS: automated whole breast ultrasonography; BR: biopsy rate; CDR: cancer detected rate; HHUS: hand-held ultrasonography; MAM: Mammography; ProIC: proportions of invasive cancers; ProNPC: node-positive cancers; RR: recall rate; US: ultrasonography; USPSTF: the U.S. Preventive Services Task Force; AJCC: American Joint Committee on Cancer;ACS: the American Cancer Society;IARC: the International Agency for Research on Cancer;SEER: the Surveillance, Epidemiology, and End Results;

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Yes

Availability of data and materials

The datasets analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the Natural Science Foundation of Tianjin [Grant number 18JCQNJC80300]; National Natural Science Foundation of China [Grant numbers 81502476] and the Beijing Young Talent Program [Grant number 2016000021469G189].

Authors’ contributions

Lei Yang drafted the manuscript and revising it critically for important intellectual content; Shengfeng Wang analyzed and interpretation of the data. Yubei Huang conceived and designed the study All authors contributed interpreted findings, and reviewed and approved the final version to be submitted.

Acknowledgements

Not applicable

Reference

1Fitzmaurice C, Akinyemiju TF, Al LF, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived with Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2016: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol 2018; 4: 1553–1568.

2Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.

3Fan L, Strasser-Weippl K, Li J, et al. Breast cancer in China. The Lancet Oncology 2014; 15: e279-e289.

4Berg WA, Blume JD, Cormack JB, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA 2008; 299: 2151–2163.

5Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med 2007; 356: 227–236.

6Autier P, Boniol M, Koechlin A, Pizot C, Boniol M. Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population-based study. BMJ 2017; 359: j5224.

7Jorgensen KJ, Gotzsche PC, Kalager M, Zahl PH. Breast Cancer Screening in Denmark: A Cohort Study of Tumor Size and Overdiagnosis. Ann Intern Med 2017; 166: 313–323.

8Berg WA, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA 2012; 307: 1394–1404.

9Dong H, Huang Y, Song F, et al. Improved performance of adjunctive ultrasonography after mammography screening for breast cancer among Chinese females. Clinical Breast Cancer 2017; 18: e353-e361.

10Ohuchi N, Suzuki A, Sobue T, et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet 2016; 387: 341–348.

11Berg WA, Bandos AI, Mendelson EB, et al. Ultrasound as the Primary Screening Test for Breast Cancer: Analysis from ACRIN 6666. J Natl Cancer Inst 2016; 108.

12McInnes M, Moher D, Thombs BD, et al. Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement. JAMA 2018; 319: 388–396.

13Mendelson EB, Baum JK, Berg WA, Merritt CRB, Rubin E. Breast Imaging Reporting and Data System BIRADS: Ultrasound. Reston, VA: American College of Radiology, 2003.

14Melnikow J, Fenton JJ, Whitlock EP, et al. Supplemental Screening for Breast Cancer in Women With Dense Breasts: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med 2016; 164: 268–278.

15Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. BMJ 2003; 326: 41–44.

16Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

17Dwamena BA. midas: A program for Meta-analytical Integration of Diagnostic Accuracy Studies in Stata. North American Stata Users’ Group Meetings 2007, 2007.

18Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health 2014; 72: 39.

19Ross JH, Michael JB, Jonathan JD, et al. metan: fixed- and random-effects meta-analysis. Stata Journal 2007; 8: 3–28.

20Tagliafico AS, Calabrese M, Mariscotti G, et al. Adjunct Screening with Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts: Interim Report of a Prospective Comparative Trial. J Clin Oncol 2016.

21Kim SY, Kim MJ, Moon HJ, Yoon JH, Kim EK. Application of the downgrade criteria to supplemental screening ultrasound for women with negative mammography but dense breasts. Medicine (Baltimore) 2016; 95: e5279.

22Shen S, Zhou Y, Xu Y, et al. A multi-centre randomised trial comparing ultrasound vs mammography for screening breast cancer in high-risk Chinese women. Br J Cancer 2015; 112: 998–1004.

23Moon HJ, Jung I, Park SJ, et al. Comparison of Cancer Yields and Diagnostic Performance of Screening Mammography vs. Supplemental Screening Ultrasound in 4394 Women with Average Risk for Breast Cancer. Ultraschall Med 2015; 36: 255–263.

24Hwang JY, Han BK, Ko EY, et al. Screening Ultrasound in Women with Negative Mammography: Outcome Analysis. Yonsei Med J 2015; 56: 1352–1358.

25Weigert J, Steenbergen S. The connecticut experiments second year: ultrasound in the screening of women with dense breasts. Breast J 2015; 21: 175–180.

26Girardi V, Tonegutti M, Ciatto S, Bonetti F. Breast ultrasound in 22,131 asymptomatic women with negative mammography. Breast 2013; 22: 806–809.

27Parris T, Wakefield D, Frimmer H. Real world performance of screening breast ultrasound following enactment of Connecticut Bill 458. Breast J 2013; 19: 64–70.

28Venturini E, Losio C, Panizza P, et al. Tailored breast cancer screening program with microdose mammography, US, and MR Imaging: short-term results of a pilot study in 40–49-year-old women. Radiology 2013; 268: 347–355.

29Huang Y, Kang M, Li H, et al. Combined performance of physical examination, mammography, and ultrasonography for breast cancer screening among Chinese women: a follow-up study. Curr Oncol 2012; 19: S22-S30.

30Hooley RJ, Greenberg KL, Stackhouse RM, et al. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09–41. Radiology 2012; 265: 59–69.

31Leong LC, Gogna A, Pant R, Ng FC, Sim LS. Supplementary breast ultrasound screening in Asian women with negative but dense mammograms-a pilot study. Ann Acad Med Singapore 2012; 41: 432–439.

32Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer 2011; 47: 1021–1026.

33Youk JH, Kim EK, Kim MJ, Kwak JY, Son EJ. Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. Eur Radiol 2011; 21: 667–675.

34Weinstein SP, Localio AR, Conant EF, et al. Multimodality screening of high-risk women: a prospective cohort study. J Clin Oncol 2009; 27: 6124–6128.

35Brancato B, Bonardi R, Catarzi S, et al. Negligible advantages and excess costs of routine addition of breast ultrasonography to mammography in dense breasts. Tumori 2007; 93: 562–566.

36Honjo S, Ando J, Tsukioka T, et al. Relative and combined performance of mammography and ultrasonography for breast cancer screening in the general population: a pilot study in Tochigi Prefecture, Japan. Jpn J Clin Oncol 2007; 37: 715–720.

37Wilczek B, Wilczek HE, Rasouliyan L, Leifland K. Adding 3D automated breast ultrasound to mammography screening in women with heterogeneously and extremely dense breasts: Report from a hospital-based, high-volume, single-center breast cancer screening program. Eur J Radiol 2016; 85: 1554–1563.

38Brem RF, Tabar L, Duffy SW, et al. Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight Study. Radiology 2015; 274: 663–673.

39Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol 2010; 20: 734–742.

40Gartlehner G, Thaler K, Chapman A, et al. Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk. Cochrane Database Syst Rev 2013; 4: D9632.

41Tozaki M, Kuroki Y, Kikuchi M, et al. The Japanese Breast Cancer Society clinical practice guidelines for screening and imaging diagnosis of breast cancer, 2015 edition. Breast Cancer 2016; 23: 357–366.

42National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer Screening and Diagnosis. V1 ed.2016.

43The Committee of Breast Cancer from the Chinese Anti-Cancer Association. Guidelines of Diagnosis and Treatment for Breast Cancer by the Chinese Anti-Cancer Association (2017 Edition). Journal of Chinese Oncology 2017; 27: 695–760.

44Evans A, Trimboli RM, Athanasiou A, et al. Breast ultrasound: recommendations for information to women and referring physicians by the European Society of Breast Imaging. Insights Imaging 2018; 9: 449–461.

45Siu AL. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2016; 164: 279–296.

46Wilt TJ, Harris RP, Qaseem A. Screening for cancer: advice for high-value care from the american college of physicians. Ann Intern Med 2015; 162: 718–725.

47Oeffinger KC, Fontham ET, Etzioni R, et al. Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update from the American Cancer Society. JAMA 2015; 314: 1599–1614.

48Tonelli M, Connor GS, Joffres M, et al. Recommendations on screening for breast cancer in average-risk women aged 40–74 years. CMAJ 2011; 183: 1991–2001.

49Dong H, Huang Y, Song F, et al. Improved Performance of Adjunctive Ultrasonography After Mammography Screening for Breast Cancer Among Chinese Females. Clin Breast Cancer 2017; 18: e353-e361.

50Huang Y, Dai H, Song F, et al. Preliminary effectiveness of breast cancer screening among 1.22 million Chinese females and different cancer patterns between urban and rural women. Sci Rep 2016; 6: 39459.

Tables

Table 1. Characteristics of included studies.

Author, year

Country

Age,

years

 

PerDB,

%

Type

of US

Sample

size

Screening

mode

Exclusion

of BC

Blinding

Complete

data

BIRADS

criteria

FU,

months

Quality

assessment

Supplemental US screening studies

Tagliafico, 201619

Italy

51

 

100

HHUS

3231

Community screening

Yes

-

Yes

No

<12

Fair

Kim, 201620

South Korea

NR

 

100

HHUS

3171

Opportunistic screening

Yes

-

Yes

No

12

Fair

Weigert, 201524

United States

NR

 

100

HHUS

10282

Opportunistic screening

NR

-

Yes

Yes

6

Fair

Hwang, 201523

South Korea

50

 

78

HHUS

1727

Opportunistic screening

No

-

No

Yes

12

Fair

Moon, 201522

South Korea

53

 

64

HHUS

2005

Opportunistic screening

NR

-

Yes

Yes

24

Fair

Parris, 201326

United States

52

 

100

HHUS

5519

Opportunistic screening

No

-

Yes

Yes

NR

Fair

Girardi, 201325

Italy

51

 

45

HHUS

22131

Opportunistic screening

No

-

Yes

Yes

NR

Fair

Leong, 201230

Singapore

45

 

100

HHUS

106

Community screening

No

-

Yes

No

12-24

Fair

Hooley, 201229

United States

52

 

100

HHUS

648

Opportunistic screening

No

-

Yes

Yes

>15

Fair

Corsetti, 201131

Italy

NR

 

100

HHUS

3356

Opportunistic screening

Yes

-

Yes

No

12

Fair

Youk, 201132

South Korea

48

 

100

HHUS

446

Opportunistic screening

No

-

Yes

Yes

24

Fair

Brancato, 200734

Italy

52

 

100

HHUS

5227

Opportunistic screening

NR

-

Yes

Yes

NR

Fair

Joint screening studies

Dong, 20179

China

52

 

44

HHUS

31918

Community screening

Yes

Yes

Yes

No

12

Good

Ohuchi, 201610

Japan

44

 

NR

HHUS

36752

Community screening

Yes

Yes

Yes

Yes

12

Good

Berg, 201611

United States

55

 

100

HHUS

2662

High-risk screening

Yes

Yes

Yes

Yes

>12

Good

Shen, 201521

China

46

 

NR

HHUS

4135

High-risk screening

Yes

Yes

No

Yes

12

Good

Brem, 201537

United States

53

 

100

ABUS

15318

Community screening

Yes

No

Yes

Yes

12

Good

Huang, 201228

China

46

 

48

HHUS

3028

Opportunistic screening

Yes

Yes

Yes

Yes

12

Good

Kelly, 201038

United States

53

 

68

ABUS

4419

High-risk screening

No

Yes

Yes

Yes

12

Good

Wilczek, 201636

Sweden

50

 

100

ABUS

1668

Community screening

Yes

No

Yes

No

24

Fair

Venturini, 201327

Italy

46

 

55

HHUS

1666

Community screening

Yes

No

No

Yes

6

Fair

Weinstein, 200933

United States

49

 

60

HHUS

609

High-risk screening

No

Yes

No

Yes

12

Fair

Honjo, 200735

Japan

NR

 

NR

HHUS

3453

Community screening

NR

Yes

Yes

No

≥18

Fair

PerDB, percent of women with dense breasts accounted for the whole population; US, ultrasonography; BC, breast cancer; BIRADS, Breast Imaging-Reporting and Data System; FU, follow-up; HHUS/ABUS, hand-held / automated breast ultrasonography.

 

Table 2. Screening accuracy for supplemental and primary US screening.

Author, year

Method

Case

 

Non-case

Sensitivity

(95% CI)

Specificity

(95% CI)

+

-

+

-

Supplemental US screening studies

Tagliafico, 201619

Supplemental US

23

1

 

65

3142

0.96(0.77-1.00)

0.98(0.97-0.98)

Kim, 201620

Supplemental US

9

0

 

822

2340

1.00(0.63-1.00)

0.74(0.72-0.76)

Weigert, 201524

Supplemental US

24

15

 

411

9832

0.62(0.45-0.76)

0.96(0.96-0.96)

Hwang, 201523

Supplemental US

8

1

 

92

1626

0.89(0.51-0.99)

0.95(0.93-0.96)

Moon, 201522

Supplemental US

4

0

 

619

1382

1.00(0.40-1.00)

0.69(0.67-0.71)

Parris, 201326

Supplemental US

10

0

 

175

5334

1.00(0.66-1.00)

0.97(0.96-0.97)

Girardi, 201325

Supplemental US

41

0

 

381

21709

1.00(0.89-1.00)

0.98(0.98-0.98)

Leong, 201230

Supplemental US

2

0

 

12

92

1.00(0.20-1.00)

0.88(0.80-0.94)

Hooley, 201229

Supplemental US

3

0

 

150

495

1.00(0.31-1.00)

0.77(0.73-0.80)

Corsetti, 201131

Supplemental US

32

8

 

363

6821

0.80(0.64-0.90)

0.95(0.94-0.95)

Youk, 201132

Supplemental US

10

1

 

41

394

0.91(0.57-1.00)

0.91(0.87-0.93)

Brancato, 200734

Supplemental US

2

0

 

21

5204

1.00(0.20-1.00)

1.00(0.99-1.00)

Joint screening studies

Dong, 20179

Primary MAM

84

15

 

604

31215

0.85(0.76-0.91)

0.98(0.98-0.98)

 

Primary US

61

38

 

389

31430

0.62(0.51-0.71)

0.99(0.99-0.99)

Ohuchi, 201610

Primary MAM

117

85

 

2300

33547

0.58(0.51-0.65)

0.94(0.93-0.94)

 

Primary US

143

59

 

2289

33558

0.71(0.64-0.77)

0.94(0.93-0.94)

Berg, 201611

Primary MAM

59

52

 

700

6662

0.53(0.43-0.63)

0.90(0.90-0.91)

 

Primary US

58

53

 

1012

6350

0.52(0.43-0.62)

0.86(0.85-0.87)

Shen, 201521

Primary MAM

8

6

 

3

6913

0.57(0.30-0.81)

1.00(1.00-1.00)

 

Primary US

14

0

 

6

6910

1.00(0.73-1.00)

1.00(1.00-1.00)

Brem, 201537

Primary MAM

82

30

 

2219

12987

0.73(0.64-0.81)

0.85(0.85-0.86)

 

Primary US

30

82

 

2721

12485

0.27(0.19-0.36)

0.82(0.81-0.83)

Huang, 201228

Primary MAM

28

5

 

48

2947

0.85(0.67-0.94)

0.98(0.98-0.99)

 

Primary US

24

9

 

19

2976

0.73(0.54-0.86)

0.99(0.99-1.00)

Kelly, 201038

Primary MAM

23

34

 

36

4326

0.40(0.28-0.54)

0.99(0.99-0.99)

 

Primary US

38

19

 

61

4301

0.67(0.53-0.78)

0.99(0.98-0.99)

Wilczek, 201636

Primary MAM

7

4

 

16

1641

0.64(0.32-0.88)

0.99(0.98-0.99)

 

Primary US

4

7

 

27

1630

0.36(0.12-0.68)

0.98(0.98-0.99)

Venturini, 201327

Primary MAM

12

2

 

99

1553

0.86(0.56-0.97)

0.94(0.93-0.95)

 

Primary US

2

12

 

8

813

0.14(0.03-0.44)

0.99(0.98-1.00)

Weinstein, 200933

Primary MAM

6

12

 

25

566

0.33(0.14-0.59)

0.96(0.94-0.97)

 

Primary US

3

15

 

66

483

0.17(0.04-0.42)

0.88(0.85-0.91)

Honjo, 200735

Primary MAM

7

6

 

272

3258

0.54(0.26-0.80)

0.92(0.91-0.93)

 

Primary US

6

7

 

159

3371

0.46(0.20-0.74)

0.95(0.95-0.96)

CI, confidential interval; MAM, mammography; US, ultrasonography.

 

Table 3. Screening efficacy for supplemental and primary US screening.

Author, year

Method

Cancer detected rate

 

Recall rate, %

 

Biopsy rate, %

Number

95%CI, 1/1000

Number

95%CI

Number

95%CI

Supplemental US screening studies

Tagliafico, 201619

Supplemental US

23/3231 women

7.1(4.6-10.8)

 

88/3231

2.7(2.2-3.4)

 

46/3231

1.4(1.1-1.9)

Kim, 201620

Supplemental US

9/3171 women

2.8(1.4-5.6)

 

831/3171

26.2(24.7-27.8)

 

131/3171

4.1(3.5-4.9)

Weigert, 201524

Supplemental US

24/10282 women

2.3(1.5-3.5)

 

435/10282

4.2(3.9-4.6)

 

 

 

Hwang, 201523

Supplemental US

8/1727 women

4.6(2.2-9.5)

 

100/1727

5.8(4.8-7.0)

 

37/1727

2.1(1.5-3.0)

Moon, 201522

Supplemental US

4/2005 women

2.0(0.6-5.5)

 

623/2005

31.1(29.1-33.2)

 

 

 

Parris, 201326

Supplemental US

10/5519 women

1.8(0.9-3.4)

 

185/5519

3.4(2.9-3.9)

 

185/5519

3.4(2.9-3.9)

Girardi, 201325

Supplemental US

41/22131 women

1.9(1.3-2.5)

 

422/22131

1.9(1.7-2.1)

 

422/22131

1.9(1.7-2.1)

Leong, 201230

Supplemental US

2/106 women

18.9(3.3-73.2)

 

14/106

13.2(7.7-21.5)

 

14/106

13.2(7.7-21.5)

Hooley, 201229

Supplemental US

3/648 women

4.6(1.2-14.7)

 

153/648

23.6(20.4-27.1)

 

46/648

7.1(5.3-9.4)

Corsetti, 201131

Supplemental US

32/7224 examinations

4.4(3.1-6.3)

 

395/7224

5.5(5.0-6.0)

 

395/7224

5.5(5.0-6.0)

Youk, 201132

Supplemental US

10/446 examinations

22.4(11.4-42.2)

 

51/446

11.4(8.7-14.8)

 

49/446

11.0(8.3-14.4)

Brancato, 200734

Supplemental US

2/5227 women

0.4(0.1-1.5)

 

23/5227

0.4(0.3-0.7)

 

23/5227

0.4(0.3-0.7)

Joint screening studies

Dong, 20179

Primary MAM

84/31918 women

2.6(2.1-3.3)

 

688/31918

2.2(2.0-2.3)

 

 

 

 

Primary US

61/31918 women

1.9(1.5-2.5)

 

450/31918

1.4(1.3-1.5)

 

 

 

Ohuchi, 201610

Primary MAM

117/36049 women

3.2(2.7-3.9)

 

2417/36049

6.7(6.4-7.0)

 

 

 

 

Primary US

143/36049 women

4.0(3.4-4.7)

 

2432/36049

6.7(6.5-7.0)

 

 

 

Berg, 201611

Primary MAM

59/7473 examinations

7.9(6.1-10.2)

 

453/7473

6.1(5.5-6.6)

 

97/7473

1.3(1.1-1.6)

 

Primary US

58/7473 examinations

7.8(6.0-10.1)

 

515/7473

6.9(6.3-7.5)

 

266/7473

3.6(3.2-4.0)

Shen, 201521

Primary MAM

8/6930 examinations

1.2(0.5-2.4)

 

11/6930

0.2(0.1-0.3)

 

7/6930

0.1(0.0-0.2)

 

Primary US

14/6930 examinations

2.0(1.2-3.5)

 

20/6930

0.3(0.2-0.5)

 

17/6930

0.2(0.1-0.4)

Brem, 201537

Primary MAM

82/15318 women

5.4(4.3-6.7)

 

2301/15318

15.0(14.5-15.6)

 

586/15318

3.8(3.5-4.1)

 

Primary US

30/15318 women

2.0(1.3-2.8)

 

2751/15318

18.0(17.4-18.6)

 

552/15318

3.6(3.3-3.9)

Huang, 201228

Primary MAM

28/3028 women

9.2(6.3-13.5)

 

105/3028

3.5(2.9-4.2)

 

 

 

 

Primary US

24/3028 women

7.9(5.2-12.0)

 

318/3028

10.5(9.4-11.7)

 

 

 

Kelly, 201038

Primary MAM

23/4419 women

5.2(3.4-7.9)

 

59/4419

1.3(1.0-1.7)

 

59/4419

1.3(1.0-1.7)

 

Primary US

38/4419 women

8.6(6.2-11.9)

 

99/4419

2.2(1.8-2.7)

 

99/4419

2.2(1.8-2.7)

Wilczek, 201636

Primary MAM

7/1668 women

4.2(1.8-9.0)

 

23/1668

1.4(0.9-2.1)

 

11/1668

0.7(0.3-1.2)

 

Primary US

4/1668 women

2.4(0.8-6.6)

 

31/1668

1.9(1.3-2.7)

 

12/1668

0.7(0.4-1.3)

Venturini, 201327

Primary MAM

12/1666 women

7.2(3.9-12.9)

 

76/1666

4.6(3.6-5.7)

 

14/1666

0.8(0.5-1.4)

 

Primary US

2/835 women

2.4(0.4-9.6)

 

87/835

10.4(8.5-12.7)

 

10/835

1.2(0.6-2.3)

Weinstein, 200933

Primary MAM

6/609 women

9.9(4.0-22.4)

 

31/609

5.1(3.5-7.2)

 

21/609

3.4(2.2-5.3)

 

Primary US

3/567 women

5.3(1.4-16.7)

 

39/567

6.9(5.0-9.4)

 

20/567

3.5(2.2-5.5)

Honjo, 200735

Primary MAM

7/3543 women

2.0(0.9-4.3)

 

279/3543

7.9(7.0-8.8)

 

 

 

 

Primary US

6/3543 women

1.7(0.7-3.9)

 

165/3543

4.7(4.0-5.4)

 

 

 

CI, confidential interval; MAM, mammography; US, ultrasonography.

 

Table 4. Cancer characteristics for supplemental and primary US screeningfor breast cancer

Author, year

Method

Proportions of

invasive cancers, %

 

Proportions of

node-negative cancers, %

Number

95%CI

Number

95%CI

Supplemental US screening studies

Tagliafico, 201619

Supplemental US

22/23

95.7(78.1-99.9)

 

13/21

61.9(38.4-81.9)

Kim, 201620

Supplemental US

7/9

77.8(40.0-97.2)

 

 

 

Weigert, 201524

Supplemental US

10/22

45.5(24.4-67.8)

 

 

 

Hwang, 201523

Supplemental US

7/8

87.5(47.4-99.7)

 

6/7

85.7(42.1-99.6)

Moon, 201522

Supplemental US

2/4

50.0(6.8-93.2)

 

1/2

50.0(1.3-98.7)

Leong, 201230

Supplemental US

1/2

50.0(1.3-98.7)

 

 

 

Hooley, 201229

Supplemental US

2/3

66.7(9.4-99.2)

 

2/2

100(15.8-100)

Joint screening studies

Dong, 20179

Primary MAM

14/83

16.9(9.5-26.7)

 

49/68

72.1(59.9-82.3)

 

Primary US

7/83

8.4(3.5-16.6)

 

34/68

50.0(37.6-62.4)

Ohuchi, 201610

Primary MAM

73/116

62.9(53.5-71.7)

 

54/113

47.8(38.3-57.4)

 

Primary US

111/140

79.3(71.6-85.7)

 

88/141

63.1(54.6-71.1)

Berg, 201611

Primary MAM

41/59

69.5(56.1-80.8)

 

14/41

79.7(67.2-89.0)

 

Primary US

53/58

91.4(81.0-97.1)

 

34/53

86.2(74.6-93.9)

Brem, 201537

Primary MAM

51/82

62.2(50.8-72.7)

 

46/48

4.2(0.5-14.3)

 

Primary US

28/30

93.3(77.9-99.2)

 

25/27

7.4(0.9-24.3)

Kelly, 201038

Primary MAM

17/23

73.9(51.6-89.8)

 

 

 

 

Primary US

35/38

92.1(78.6-98.3)

 

 

 

Wilczek, 201636

Primary MAM

5/7

71.4(29.0-96.3)

 

 

 

 

Primary US

4/4

100(39.8-100)

 

 

 

Venturini, 201327

Primary MAM

8/12

66.7(34.9-90.1)

 

4/5

20.0(0.5-71.6)

 

Primary US

2/2

100(15.8-100)

 

1/2

50.0(1.3-98.7)

Weinstein, 200933

Primary MAM

3/6

50.0(11.8-88.2)

 

3/3

100(29.2-100)

 

Primary US

3/3

100(29.2-100)

 

3/3

100(29.2-100)

Honjo, 200735

Primary MAM

3/7

42.9(9.9-81.6)

 

3/3

100(29.2-100)

 

Primary US

5/6

83.3(35.9-99.6)

 

4/4

100(39.8-100)

CI, confidential interval; MAM, mammography; US, ultrasonography.