Title: Ultrasound for Breast Cancer Screening: Clinical Effectiveness. Date: 4 January Context and policy issues:

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1 Title: Ultrasound for Breast Cancer Screening: Clinical Effectiveness Date: 4 January 2008 Context and policy issues: It is estimated that 22,300 women will be diagnosed with breast cancer and approximately 5,300 women will die from breast cancer in is the most common method and the gold standard to screen women for breast cancer. 2,3 is of limited usefulness in women with dense breast tissue due to reduced sensitivity. 2,4,5 In addition, uses radiation which is a significant disadvantage for high risk younger women. 2 Ultrasound () is usually used for the diagnosis of breast cancer, and typically not for breast cancer screening. 5 Ultrasonography has been shown to be useful to differentiate cysts from tumors. 3 A high number of false-positive and false-negative results with may limit its use in breast cancer screening, 3 however, there may be a role for ultrasound in screening. 6 may be useful for screening high risk women and women with dense breast tissue. 6,7 A disadvantage to is that it is operator dependent causing poor reliability. 3,4,5 has an important advantage over, in that it does not use ionizing radiation. The use of in conjunction with may improve accuracy of breast cancer screening. 3 It has been suggested that may not be useful on its own for breast cancer screening, but may improve breast imaging when used in combination with. 2 Research questions: 1. What is the clinical effectiveness of ultrasound for screening women for breast cancer? 2. Is there any evidence of a benefit to using ultrasound in women with dense breast tissue? Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 Methods: A limited literature search was conducted on key health technology assessment resources, including Pre-Medline, Medline, Embase, the Cochrane Library (Issue 2, 2007), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI, EuroScan, international HTA agencies, and a focused Internet search. Results include articles published between 2002 and the present, and are limited to English language publications only. Filters were applied to limit the retrieval to systematic reviews/hta, randomized controlled trials (RCTs), and observational studies. Summary of findings: There were two systematic reviews (SR) and one observational study found on the use of for breast cancer screening. Systematic reviews A systematic review from the New Zealand Health Technology Assessment was published in 2007 and reviewed the evidence on, magnetic resonance imaging (MRI) and ultrasound for surveillance of women at high risk for breast cancer. 5 Although there was no definition provided for high risk, studies on women with BRCA1/2 mutations and those with a family history were included. The authors used the term surveillance because these women are monitored for breast cancer because of an increased risk and therefore they do not consider this to be the same as screening. Studies in this review included those that had at least 20 patients who were asymptomatic who had a high risk of breast cancer and used, MRI, or a combination. Two reviewers appraised the articles, however, data extraction and appraisal was not validated between the reviewers. There were nine studies included that used and for surveillance of high risk women. Of these nine studies, seven are detailed in the Appendix; the remaining two studies were published in 1998 and 2001 and are therefore beyond the date limits of this report. The first study (Kolb et al; 1998) found one tumor among 565 women with dense breasts who had normal clinical breast examination (CBE) and results. This study suggested that may be useful as an adjunct test with CBE and in women at high risk of breast cancer with dense breasts. Another study (O Driscoll et al; 2001) of 149 women detected one tumor by which was not detected by. The small sample size limits this information but this study suggested that can detect tumors not detected by in high risk women. A third study 8 detected 21 tumors using, and CBE in 935 women and 19 of these were detected by. This study suggested that was more accurate than in high risk women. Another study 9 found 8 tumors in 105 women using,, MRI and CBE. and each detected only one of these tumors. The authors concluded that and were similar for surveillance of high risk women. A study of 1517 women with dense breasts and normal resultsfound four cancers in high risk women by. 10 This study suggested that is useful in women with dense breasts. Twenty-three women were studied in another study 11 and four cancers were detected. None of these cancers were detected by or (MRI and CBE detected) which suggested that these are not effective surveillance techniques. A retrospective study 4 examined cancer detection rates using and. There was limited data provided and the number of cancers detected was not reported. The detection rate was 0.24 for and 0.17 for. This study suggested that there is a role in breast cancer screening for. A study of 236 women 12 found 22 cancers using,, Ultrasound for breast cancer screening 2

3 MRI and CBE. Seven of the 22 cancers were detected by (2 detected by alone) and 8 were detected by (2 detected by alone). This study concluded that and were similarly effective for breast cancer surveillance. A more recent study 13 found 43 tumors in 529 women using,, MRI and CBE. detected 17 of these cancers. This study suggested that does not improve sensitivity and specificity is reduced. This systematic review found heterogeneity in the studies, but overall the report suggested that in combination with can increase cancer detection rate. A major limitation to all of the studies included in this systematic review is that the reference standard was different for diagnosis if a positive result was found than if a negative result was found. Biopsy or surgical excision was done following positive results whereas clinical follow-up was done in cases of negative results. Therefore, all studies would be subject to verification bias. 5 A systematic review (2004) was published on the accuracy of different technologies for breast cancer screening. 14 Studies were included that reported sensitivity and specificity of, or CBE in asymptomatic women. Only one study (Hou et al) out of the five included in this systematic review is included in the Appendix as the others were outside of the date limitation. This SR found that the studies that used were mainly conducted in women with dense breast tissue (determined by ) or were at high risk for breast cancer. It was suggested that may be more effective in this group of women, with a higher sensitivity than although the specificity was lower. Additional cancers were identified using both and together; however, the false-positive rate is increased. The authors recognized that is dependent on the operator which may affect results and suggested that be used with for women with dense breast tissue. Observational studies Data from the observational studies included in the first SR described above 5 are included in the Appendix. Only data from and are reported. Data from studies that were not included in the SRs are described here. Studies were only included that examined the use of for breast cancer screening, and studies that used for diagnosis or characterization in women who already had breast cancer were excluded. Only one observational study was identified. A recent (2007) observational study investigated the use of, and MRI for screening high risk women. 15 Women were included who had either a BRCA1/2 mutation or a relative with a mutation; risk of having a BRCA1/2 mutation based on a family history of breast and ovarian cancer; a family with 2+ cases of breast or ovarian cancer; 1+ relative with breast or ovarian cancer and Ashkenazi Jewish.,, MRI and CBE were all conducted within 90 days on all participants (n = 171). There were 6 cancers detected, and one was detected with and two were detected by. The cancer detected by was also detected by. The authors concluded that further studies were needed to determine whether would be useful for screening women at high risk of breast cancer. Limitations There was only one recent systematic review and only one recent observational study identified on the use of in breast cancer screening. In addition, there were no randomized controlled trials and observational studies do not control for potential bias. A limitation to all studies is the Ultrasound for breast cancer screening 3

4 potential for verification bias because biopsy was not conducted in all study participants. Clearly, biopsy should not be conducted when screening test results are negative, but this can introduce verification bias. In addition, calculating sensitivity and specificity without the gold standard test can be difficult and these results may not be accurate. A further limitation is the small sample size in the studies; a screening program would involve a larger population. Conclusions and implications for decision or policy making: There was one large SR published in 2007 on screening for breast cancer. 5 The studies included in this SR were somewhat variable. Some studies suggested that was similar to for breast cancer screening (Podo et al., Sim et al., Warner et al.) whereas others suggested that was better than (Hou et al.). was found to detect breast cancers that would have been missed by screening (Sim et al., O Driscoll et al.) but one study found that neither nor was effective for breast cancer screening(trecate et al.). Overall, this SR suggested that was effective when used in combination with for breast cancer screening and that breast cancer detection rates could be increased with the use of with. Another SR suggested that should be used with in women with dense breast tissue. 14 Only one observational study was identified that was not reported in the systematic reviews. This report found that cancers that were detected with were also detected by and concluded that more research in this area is needed. Overall, the studies suggested that may be useful when used in combination with and that it may be particularly useful in women with dense breast tissue. Factors to take into consideration may be the additional resources and training required for the addition of to breast cancer screening. In addition, it would have to be determined whether to use to screen only women at high risk of breast cancer or women with dense breasts. Prepared by: Lesley Dunfield, PhD, Research Officer Emmanuel Nkansah, MLS, MA, Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Ultrasound for breast cancer screening 4

5 References: 1. Canadian Cancer Society, National Cancer Institute of Canada. Canadian Cancer Statistics Toronto: Canadian Cancer Society; Available: pdf (accessed 2007 Dec 4). 2. Smith JA, Andreopoulou E. An overview of the status of imaging screening technology for breast cancer. Ann Oncol 2004;15(Suppl):I18-I26. Available: (accessed 2007 Dec 4). 3. Flobbe K, Nelemans PJ, Kessels AG, Beets GL, Von Meyenfeldt MF, van Engelshoven JM. The role of ultrasonography as an adjunct to in the detection of breast cancer. a systematic review. Eur J Cancer 2002;38(8): Sim LS, Hendriks JH, Fook-Chong SM. Breast ultrasound in women with familial risk of breast cancer. Ann Acad Med Singapore 2004;33(5): Available: (accessed 2007 Dec 7). 5. Davidson E, Hancock S. Surveillance of women at high risk of breast cancer. New Zealand Health Technology Assessment Technical Brief 2007;6(1):i-285. Available: (accessed 2007 Nov 30). 6. Elmore JG, Armstrong K, Lehman CD, Fletcher SW. Screening for breast cancer. JAMA 2005;293(10): Carney PA, Abraham LA, Miglioretti DL, Yabroff KR, Sickles EA, Buist DS, et al. Factors associated with imaging and procedural events used to detect breast cancer after screening. AJR Am J Roentgenol 2007;188(2): Hou MF, Chuang HY, Ou-Yang F, Wang CY, Huang CL, Fan HM, et al. Comparison of breast, sonography and physical examination for screening women at high risk of breast cancer in Taiwan. Ultrasound Med Biol 2002;28(4): Podo F, Sardanelli F, Canese R, D'Agnolo G, Natali PG, Crecco M, et al. The Italian multicentre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk. J Exp Clin Cancer Res 2002;21(3 Suppl): Crystal P, Strano SD, Shcharynski S, Koretz MJ. Using sonography to screen women with mammographically dense breasts. AJR Am J Roentgenol 2003;181(1): Available: (accessed 2007 Dec 6). 11. Trecate G, Vergnaghi D, Bergonzi S, De Simone T, Fengoni E, Costa C, et al. Breast MRI screening in patients with increased familial and/or genetic risk for breast cancer: a preliminary experience. Tumori 2003;89(2): Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound,, and clinical breast examination. JAMA 2004;292(11): Ultrasound for breast cancer screening 5

6 13. Kuhl CK, Schrading S, Leutner CC, Morakkabati-Spitz N, Wardelmann E, Fimmers R, et al., breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer. J Clin Oncol 2005;23(33): Available: (accessed 2007 Nov 29). 14. Irwig L, Houssami N, van Vliet C. New technologies in screening for breast cancer: a systematic review of their accuracy. Br J Cancer 2004;90(11): Lehman CD, Isaacs C, Schnall MD, Pisano ED, Ascher SM, Weatherall PT, et al. Cancer yield of, MR, and in high-risk women: prospective multi-institution breast cancer screening study. Radiology 2007;244(2): Ultrasound for breast cancer screening 6

7 Appendix 1: Data from the observational studies included in the systematic reviews Study Patient population Kuhl et al, family history of breast cancer (n = 529) Screening techniques + Findings Sensitivity 32.6 Specificity 96.8 PPV 23.7 Sensitivity 39.5 Specificity 90.5 PPV 11.3 Sensitivity 48.8 Specificity 89.0 PPV 11.9 General results and conclusions 43 cancers detected: detected 17, detected 17, combined and detected 21. Sim et al, Family history of breast or ovarian cancer, or BRCA1/2 mutation (n = 179; 84 underwent ) + Sensitivity 53.9 Specificity 85.7 PPV 63.6 NPV 80.0 AUC ( ) Sensitivity 83.3 Specificity 65.5 PPV 50 NPV 90.5 AUC ( ) Sensitivity 92.9 Specificity 62.5 PPV 52.0 NPV 95.2 AUC ( ) 15 cancers diagnosed (not reported which techniques detected the cancers); concluded to be a better test than based on AUC Warner et al, BRCA1 and BRCA2 mutation carriers (n = 236) Sensitivity 25 Specificity 95 PPV 23 NPV 96 Sensitivity 38 Specificity 99.6 PPV 83 NPV cancers detected: 7 detected by, 8 detected by Crystal et al, Asymptomatic women with dense breast tissue and normal (n = 1517) Sensitivity 100% Specificity 94.4% 7 cancers detected by (4 in high risk and 3 in usual risk women). Authors concluded that can be useful in women with dense breast tissue Ultrasound for breast cancer screening 7

8 Trecate et al, BRCA1/2 mutation carriers or at high risk of being a mutation carrier due to family history (n = 23) NR NR 4 cancers detected: none were detected by or Hou et al, Female relatives of breast cancer patients (n = 935) Sensitivity 90.4 Specificity 86.3 Sensitivity 52.4 Specificity cancers detected: detected 19 and detected 11. Authors concluded that more sensitive than. Podo et al, Women and men at very high genetic risk for breast cancer (n = 105) NR NR 8 cancers detected: 1 by and PPV positive predictive value NPV negative predictive value NR not reported ultrasound Ultrasound for breast cancer screening 8