1. ACRIN Protocol 6666 ACRIN Protocol 6666 Screening Breast Ultrasound in High-Risk Women Made possible by grants from the Avon Foundation and National Cancer Institute (CA80098)

2. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Contacts  Site Contacts Principal Investigator: Research Associate:  Trial Personnel: Principal Investigator: Wendie Berg, MD, PhD – American Radiology Services. Johns Hopkins at Greenspring Co-Investigator: Ellen Mendelson, MD – Northwestern University Statistician: Jeffery Blume, PhD – Brown Unversity

3. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Objectives  Background Review principles of screening What we have learned from mammography Review results from single center trials of screening US  Protocol 6666 Overview Aims Eligibility Participant Enrollment

4. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Screening  Early detection and resulting treatment will alter the course of the disease  Healthy women will not be harmed  Early detection will allow breast conservation more often and less harmful treatments

5. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Mammography  Mammography is the only screening test to date which has been shown to reduce deaths due to breast cancer  Screen-detected cancers have better prognosis than clinically-detected cancers GoodIntermedPoor Screen-detect 50% 32% 18% Clinically found 19 34 47 Tabar, Rad Clin N Amer 2000;38:625-651

6. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Survival by Prognostic Category Tabar Rad Clin NA 2000;38:625-652

7. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Prognostic Categories Good Intermed.Poor DCIS Node -Node + Gr 1 < 20 mm N-20+; N+<15N+, ≥15 Gr II < 15 mm 15-29 mm≥ 30 mm Gr III < 10 mm N-10+, N+<15N+, ≥15 Lobular < 10 mm 10-29 mm≥ 30 mm Medullary N-, < 20 N-, ≥ 20 N+_____ Mucinous N-, <10 N-10+, N+<20 N+,≥20_ Tubular N-, <20 N-, 20+ or N+ none___

8. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound DCIS  Left untreated, majority of DCIS will progress to invasive carcinoma, but time course may be 20 years or more  First prevalent screen, estimated 37% of DCIS non-progressive  Only 4% of new DCIS detected at annual screens non-progressive  Over treatment may occur at first screen, but is uncommon if test performed annually Yen et al Eur J Cancer 2003;39:1746-1754

9. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound DCIS  Analysis of Swedish two-county trial  Majority of mortality reduction was due to stage shifting from stage II invasive or worse to stage I invasive cancer  Detection of DCIS might account for 5-12% of deaths averted Duffy et al Eur J Cancer 2003;39:1755-1760 Duffy et al Eur J Cancer 2003;39:1755-1760

10. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound What can we infer?  Poor prognosis cancers are node positive and larger in size, but fundamentally the same histology as those of good prognosis  Left undetected, good prognosis cancers will progress to those with poor prognosis  Detection of small (< 1 cm) invasive cancers is critical to achieving mortality reduction from screening

11. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Prognosis and Treatment  Prognosis and treatment of a given cancer will depend primarily on size and nodal status  Should be independent of the method of detection

12. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Mortality Reduction: Mammography  22% reduction in breast cancer mortality ≥ 50  15% reduction in breast cancer mortality 40-49 yrs of age US Preventive Services Task Force summary report Ann Intern Med 2002;137:347-360

13. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Mammographic Sensitivity  98% in women ≥ 50 with fatty breasts  30-69% sensitivity in women with dense breasts, particularly low if < 50 or at increased risk Kerlikowske et al JAMA 1996;276:33-38 Kolb et al Radiology 2002;225:165-175 Mandelson et al JNCI 2000;92:1081-1087

14. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Summary of US Screening Studies Investigator, Yr Prevalence Gordon, Goldenberg 1995 44/12,706 (0.35) 44/12,706 (0.35) Buchberger et al 2000 32/ 8,103 (0.39) 32/ 8,103 (0.39) 8/ 867 (0.9) 8/ 867 (0.9) Kaplan et al 2001 6/ 1,862 (0.3) 6/ 1,862 (0.3) Kolb et al 2002 37/13,547 (0.27) 37/13,547 (0.27) Crystal et al 2003 7/ 1,517 (0.46) 7/ 1,517 (0.46) LeConte et al 2003 16/ 4,236 (0.38) 16/ 4,236 (0.38) Total 150/42,838 (0.35)

15. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Screening Ultrasound  150 US-detected cancers in 126 women  114 (90.5%) heterogeneously dense or extremely dense breasts  High-risk women are 2-3 times more likely to have US-only detected cancer 55/110 (50%) were at high-risk

16. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Invasive Cancer vs. DCIS  Of 150 cancers seen only on sonography 141 (94%) invasive – 99 (70%) were < 1 cm – 30/33 (91%) were stage 0 or stage I – Mean size 9-11 mm across series, range 4-25 mm  In 25,753 exams, mammo reported Another 56 cancers seen only on mammo – 42 (75%) DCIS and 14 (25%) invasive

17. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Cancers Seen Only on US  Early invasive cancers with good prognosis  Additional detection virtually all in dense and heterogeneously dense breasts  Half of the cancers seen only on US were in women at high risk (7-9 per 1000)

18. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Why do a multicenter trial?  In all but Kolb’s series, only a single prevalent screen performed No estimate of the role of annual sonography  Single center studies, may not be generalizable  Prior studies not blinded to mammographic results, artificially inflates US performance  Screening: need for rational basis to subject healthy women to testing

19. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Specific Aims  Primary Aim: Diagnostic yield of screening mammography + US compared to mammography alone Independent read, blinded to the other study  Secondary Aim: Diagnostic yield of US and mammography independently Effect of breast density and heterogeneity of echotexture

20. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Protocol 6666  Approximately 2800 women at high risk of breast cancer breast cancer  Annual mammogram and whole breast bilateral screening US, physician performed, independently read  Screenings at 0, 12, 24 months

21. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Eligibility Criteria  Women ≥ 25 yrs  Breast tissue at least moderately dense as viewed on mammogram  AND at least ONE of the following applies: Known mutation in BRCA-1 or -2 gene Personal hx breast cancer at least one year ago Stong family hx of breast cancer (25% lifetime risk as determined by the Gail or Claus models) Prior LCIS Radiation treatment to the chest (before age 30 and at least 8 years ago) Prior ADH, ALH, atypical papilloma

22. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Ineligibility Criteria  Fail to meet eligibility requirements  Male  Implants  Clinically abnormal or indication other than routine  < 1 yr following dx breast cancer or with known distant mets  Pregnant or plan to be within 2 years

23. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Ineligibility Criteria  Contrast-enhanced breast MRI within 1 yr prior (or plan within 2 yrs of entry)  Bilateral whole breast US within 1 yr prior  Injection of sonographic or mammographic contrast or tomosynthesis or plan to undergo within 2 yrs of study entry  Mammograms cannot be double read or undergo CAD  Breast procedure (other than cyst asp) within 1 yr prior

24. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Imaging  Pt randomized to initial US or mammogram  Study US and mammogram at same site within 2 weeks of each other  Independent interpretation of US and mammogram, each radiologist qualified in study protocol and each must read some US and some mammo

25. American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound Participant Education  Participant Brochures Available from Research Associate  Letter to potential participants Electronic file available for practice customization from Research Associate  Clinical Trial Websites NCI: cancer.gov CenterWatch: centerwatch.org ACRIN: acrin.org (full protocol available)