Download Protocol Overview

ACRIN Protocol 6666
Screening Breast Ultrasound
in High-Risk Women
Made possible by grants from the
Avon Foundation
and
National Cancer Institute (CA80098)
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
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
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
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
Screen-detect
Clinically found
Good
50%
19
Intermed
32%
34
Poor
18%
47
Tabar, Rad Clin N Amer 2000;38:625-651
American College of Radiology Imaging Network
ACRIN 6666: Screening Breast Ultrasound
Survival by Prognostic Category
Tabar Rad Clin NA 2000;38:625-652
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+<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+ or N+
none___
N-, <20
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
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
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
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
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
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
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)
Buchberger et al 2000
32/ 8,103 (0.39)
8/
Kaplan et al 2001
867 (0.9)
6/ 1,862 (0.3)
Kolb et al 2002
37/13,547 (0.27)
Crystal et al 2003
7/ 1,517 (0.46)
LeConte et al 2003
16/ 4,236 (0.38)
Total
150/42,838 (0.35)
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
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
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)
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
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
American College of Radiology Imaging Network
ACRIN 6666: Screening Breast Ultrasound
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
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
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
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
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
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)
American College of Radiology Imaging Network
ACRIN 6666: Screening Breast Ultrasound