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Screening Breast Ultrasound in High-Risk Women

Screening Breast Ultrasound in High-Risk Women. Made possible by grants from the Avon Foundation and National Cancer Institute (CA80098). ACRIN Protocol 6666. Contacts. Site Contacts Principal Investigator: Research Associate: Trial Personnel:

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Screening Breast Ultrasound in High-Risk Women

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

  2. 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. 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. 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. 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 Good Intermed Poor Screen-detect 50% 32% 18% Clinically found 19 34 47 Tabar, Rad Clin N Amer 2000;38:625-651

  6. Survival by Prognostic Category Tabar Rad Clin NA 2000;38:625-652

  7. Prognostic Categories GoodIntermed.Poor DCIS Node - Node + Gr 1 < 20 mm N-20+; N+<15 N+, ≥15 Gr II < 15 mm 15-29 mm ≥ 30 mm Gr III < 10 mm N-10+, N+<15 N+, ≥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. 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. 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

  10. 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. 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. 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. 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. Summary of US Screening Studies

  15. 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. 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. 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. 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. 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. Protocol 6666 • Approximately 2800 women at high risk of breast cancer • Annual mammogram and whole breast bilateral screening US, physician performed, independently read • Screenings at 0, 12, 24 months

  21. 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. 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. 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. 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. 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)

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