acrin protocol 6666 acrin protocol 6666 screening breast ultrasound in high-risk women made possible...

ACRIN Protocol ACRIN Protocol 66666666

Screening Breast Ultrasound Screening Breast Ultrasound in High-Risk Womenin High-Risk Women

Made possible by grants from the Avon Foundation

and National Cancer Institute (CA80098)

American College of Radiology Imaging Network ACRIN 6666: Screening Breast Ultrasound

ContactsContacts Site ContactsSite Contacts

• Principal Investigator:• Research Associate:

Trial Personnel: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


ObjectivesObjectives BackgroundBackground

•Review principles of screening•What we have learned from mammography

•Review results from single center trials of screening US

Protocol 6666 OverviewProtocol 6666 Overview•Aims•Eligibility•Participant Enrollment


ScreeningScreening

Early detection and resulting treatment will Early detection and resulting treatment will alter the course of the diseasealter the course of the disease

Healthy women will not be harmedHealthy women will not be harmed

Early detection will allow breast conservation Early detection will allow breast conservation more often and less harmful treatmentsmore often and less harmful treatments


MammographyMammography Mammography is the only screening test to date Mammography is the only screening test to date

which has been shown to reduce deaths due to breast which has been shown to reduce deaths due to breast cancercancer

Screen-detected cancers have better prognosis than Screen-detected cancers have better prognosis than clinically-detected cancersclinically-detected cancers

GoodGood IntermedIntermed PoorPoor

Screen-detectScreen-detect 50% 50% 32% 18% 32% 18%

Clinically foundClinically found 19 19 34 34 47 47

Tabar, Rad Clin N Amer 2000;38:625-651Tabar, Rad Clin N Amer 2000;38:625-651


Survival by Prognostic CategorySurvival by Prognostic Category

Tabar Rad Clin NA 2000;38:625-652Tabar Rad Clin NA 2000;38:625-652


Prognostic CategoriesPrognostic Categories

GoodGood Intermed.Intermed. PoorPoor

DCISDCIS

Node -Node - Node +Node +

Gr 1 < 20 mmGr 1 < 20 mm N-20+; N+<15 N-20+; N+<15 N+, ≥15N+, ≥15

Gr II < 15 mmGr II < 15 mm 15-29 mm 15-29 mm ≥ 30 mm≥ 30 mm

Gr III < 10 mmGr III < 10 mm N-10+, N+<15 N-10+, N+<15 N+, ≥15N+, ≥15

Lobular < 10 mm 10-29 mmLobular < 10 mm 10-29 mm ≥ 30 mm≥ 30 mm

Medullary N-, < 20 N-, ≥ 20Medullary N-, < 20 N-, ≥ 20 N+_____N+_____

Mucinous N-, <10 N-10+, N+<20 Mucinous N-, <10 N-10+, N+<20 N+,≥20_N+,≥20_

Tubular N-, <20Tubular N-, <20 N-, 20+ or N+ N-, 20+ or N+ none___none___


DCISDCIS Left untreated, majority of DCIS will progress Left untreated, majority of DCIS will progress

to invasive carcinoma, but time course may be to invasive carcinoma, but time course may be 20 years or more20 years or more

First prevalent screen, estimated 37% of DCIS First prevalent screen, estimated 37% of DCIS non-progressivenon-progressive

Only 4% of new DCIS detected at annual Only 4% of new DCIS detected at annual screens non-progressive screens non-progressive

Over treatment may occur at first screen, but is Over treatment may occur at first screen, but is uncommon if test performed annuallyuncommon if test performed annually

Yen et al Eur J Cancer 2003;39:1746-1754Yen et al Eur J Cancer 2003;39:1746-1754


DCISDCIS Analysis of Swedish two-county trialAnalysis of Swedish two-county trial

Majority of mortality reduction was due to stage Majority of mortality reduction was due to stage shifting from stage II invasive or worse to stage I shifting from stage II invasive or worse to stage I invasive cancerinvasive cancer

Detection of DCIS might account for 5-12% of deaths Detection of DCIS might account for 5-12% of deaths avertedaverted

Duffy et al Eur J Cancer 2003;39:1755-1760Duffy et al Eur J Cancer 2003;39:1755-1760


What can we infer?What can we infer? Poor prognosis cancers are node positive and Poor prognosis cancers are node positive and

larger in size, but fundamentally the same larger in size, but fundamentally the same histology as those of good prognosishistology as those of good prognosis

Left undetected, good prognosis cancers will Left undetected, good prognosis cancers will progress to those with poor prognosisprogress to those with poor prognosis

Detection of small (< 1 cm) invasive cancers is Detection of small (< 1 cm) invasive cancers is critical to achieving mortality reduction from critical to achieving mortality reduction from screeningscreening


Prognosis and TreatmentPrognosis and Treatment

Prognosis and treatment of a given cancer will Prognosis and treatment of a given cancer will depend primarily on size and nodal status depend primarily on size and nodal status

Should be independent of the method of Should be independent of the method of detectiondetection


Mortality Reduction: Mortality Reduction: MammographyMammography

22% reduction in breast cancer mortality ≥ 5022% reduction in breast cancer mortality ≥ 50

15% reduction in breast cancer mortality 15% reduction in breast cancer mortality

40-49 yrs of age40-49 yrs of age

US Preventive Services Task Force summary report Ann Intern Med US Preventive Services Task Force summary report Ann Intern Med 2002;137:347-3602002;137:347-360


Mammographic SensitivityMammographic Sensitivity 98% in women ≥ 50 with fatty breasts98% in women ≥ 50 with fatty breasts

30-69% sensitivity in women with dense 30-69% sensitivity in women with dense breasts, particularly low if < 50 or at breasts, particularly low if < 50 or at increased riskincreased 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


Summary of US Screening Summary of US Screening StudiesStudiesInvestigator, YrInvestigator, Yr PrevalencePrevalence

Gordon, Goldenberg 1995Gordon, Goldenberg 1995 44/12,706 (0.35)44/12,706 (0.35)

Buchberger et al 2000Buchberger et al 2000 32/ 8,103 (0.39)32/ 8,103 (0.39)

8/ 867 (0.9)8/ 867 (0.9)

Kaplan et al 2001Kaplan et al 2001 6/ 1,862 (0.3)6/ 1,862 (0.3)

Kolb et al 2002Kolb et al 2002 37/13,547 (0.27)37/13,547 (0.27)

Crystal et al 2003Crystal et al 2003 7/ 1,517 (0.46)7/ 1,517 (0.46)

LeConte et al 2003LeConte et al 2003 16/ 4,236 (0.38)16/ 4,236 (0.38)

TotalTotal 150/42,838 (0.35)150/42,838 (0.35)


Screening UltrasoundScreening Ultrasound 150 US-detected cancers in 126 women150 US-detected cancers in 126 women

114 (90.5%) heterogeneously dense or 114 (90.5%) heterogeneously dense or extremely dense breastsextremely dense breasts

High-risk women are 2-3 times more likely to High-risk women are 2-3 times more likely to have US-only detected cancerhave US-only detected cancer

• 55/110 (50%) were at high-risk


Invasive Cancer vs. DCISInvasive Cancer vs. DCIS Of 150 cancers seen only on sonographyOf 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 reportedIn 25,753 exams, mammo reported• Another 56 cancers seen only on mammo

– 42 (75%) DCIS and 14 (25%) invasive


Cancers Seen Only on USCancers Seen Only on US Early invasive cancers with good prognosisEarly invasive cancers with good prognosis

Additional detection virtually all in dense and Additional detection virtually all in dense and heterogeneously dense breastsheterogeneously dense breasts

Half of the cancers seen only on US were in Half of the cancers seen only on US were in women at high risk (7-9 per 1000)women at high risk (7-9 per 1000)


Why do a multicenter Why do a multicenter trial?trial? In all but Kolb’s series, only a single prevalent In all but Kolb’s series, only a single prevalent

screen performedscreen performed• No estimate of the role of annual sonography

Single center studies, may not be generalizableSingle center studies, may not be generalizable

Prior studies not blinded to mammographic Prior studies not blinded to mammographic results, artificially inflates US performanceresults, artificially inflates US performance

Screening: need for rational basis to subject Screening: need for rational basis to subject healthy women to testinghealthy women to testing


Specific AimsSpecific Aims Primary AimPrimary Aim: Diagnostic yield of screening : Diagnostic yield of screening

mammography + US compared to mammography + US compared to mammography alonemammography alone

• Independent read, blinded to the other study

Secondary AimSecondary Aim: Diagnostic yield of US and : Diagnostic yield of US and mammography independentlymammography independently

• Effect of breast density and heterogeneity of echotexture


Protocol 6666Protocol 6666 Approximately 2800 women at high risk of Approximately 2800 women at high risk of

breast cancerbreast cancer

Annual mammogram and whole breast bilateral Annual mammogram and whole breast bilateral screening US, physician performed, screening US, physician performed, independently readindependently read

Screenings at 0, 12, 24 monthsScreenings at 0, 12, 24 months


Eligibility CriteriaEligibility Criteria Women ≥ 25 yrsWomen ≥ 25 yrs Breast tissue at least moderately dense as viewed on Breast tissue at least moderately dense as viewed on

mammogrammammogram ANDAND at least ONE of the following applies: 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


Ineligibility CriteriaIneligibility Criteria Fail to meet eligibility requirementsFail to meet eligibility requirements

MaleMale

ImplantsImplants

Clinically abnormal or indication other than Clinically abnormal or indication other than routineroutine

< 1 yr following dx breast cancer or with < 1 yr following dx breast cancer or with known distant metsknown distant mets

Pregnant or plan to be within 2 yearsPregnant or plan to be within 2 years


Ineligibility CriteriaIneligibility Criteria Contrast-enhanced breast MRI within 1 yr prior (or Contrast-enhanced breast MRI within 1 yr prior (or

plan within 2 yrs of entry)plan within 2 yrs of entry)

Bilateral whole breast US within 1 yr priorBilateral whole breast US within 1 yr prior

Injection of sonographic or mammographic contrast Injection of sonographic or mammographic contrast or tomosynthesis or plan to undergo within 2 yrs of or tomosynthesis or plan to undergo within 2 yrs of study entrystudy entry

Mammograms cannot be double read or undergo CADMammograms cannot be double read or undergo CAD

Breast procedure (other than cyst asp) within 1 yr Breast procedure (other than cyst asp) within 1 yr priorprior


ImagingImaging Pt randomized to initial US or mammogramPt randomized to initial US or mammogram

Study US and mammogram at same site within Study US and mammogram at same site within 2 weeks of each other2 weeks of each other

IndependentIndependent interpretation of US and interpretation of US and mammogram, each radiologist qualified in mammogram, each radiologist qualified in study protocol and each must read some US study protocol and each must read some US and some mammoand some mammo


Participant EducationParticipant Education Participant BrochuresParticipant Brochures

•Available from Research Associate

Letter to potential participantsLetter to potential participants•Electronic file available for practice customization from Research Associate

Clinical Trial WebsitesClinical Trial Websites•NCI: cancer.gov•CenterWatch: centerwatch.org•ACRIN: acrin.org (full protocol available)

acrin protocol 6666 acrin protocol 6666 screening breast ultrasound in high-risk women made possible...

Documents

screening test

acrin protocol

breast conservation

harmful treatments slide

phd brown unversity

mammography review results

rad clin n amer

greenspring coinvestigator