PILOT STUDY OF AN INFORMATION AID FOR WOMEN AT LOW TO MODERATE ...

Magnetic Resonance Imaging (MRI) Screening

for High Risk Patients

Ellen Warner M.D.

Division of Medical OncologySunnybrook & Women’s College Health

Sciences CenterToronto, Ontario, Canada

Each year in the U.S. alone:

• 5.3 million affected

• 40,000 deaths

Motor Vehicle Injuries

Breast Cancer

Primary Prevention:• obey traffic laws • tamoxifen• don’t drink & drive • oophorectomy

Secondary Prevention: • seat belts ± air bags • breast screening

Is MRIScreening

of the Breast

an EffectiveSeat BeltFor High

RiskWomen?

Definition of ‘High Risk’

• Known BRCA mutation carrier

or• Close relative of mutation carrier

or

• Family history suggestive of inherited predisposition

Cumulative Risk of Breast Cancer

0%

10%

20%

30%

40%

50%

60%

70%

30 40 50 60 70

Age

1. Antoniou et al. Am J Hum Genet, 20032. SEER Cancer Stats Review, 2004. BRCA1

BRCA1 +oophorectomy

generalpopulation

no familymutation

High Risk Screening Guidelines

U.S. (NCCN, 2004)

U.K. (NICE, 2004)

France (Eisinger, 2004)

Mammography (annual)

25+ 30+ 30+

CBE (q 6months) 25+ - 20-25+

BSE (monthly) 18+ - -

Ultrasound (annual)

- - 30+ (dense breasts)

Mammography Screening for High Risk Women

The Ideal• 100% sensitivity• DCIS

• invasive ≤ 1cm,

node -ve

The Reality• 50% sensitivity

• DCIS rarely found

• 50% > 1 cm

• 40% node +ve

Brekelmans et al. JCO, 2001

Scheuer et al. JCO, 2002

Komenaka et al. Cancer, 2004

Limitations of Mammographyfor ‘High Risk’ Screening

• young age = dense breasts

Mammographic Visibility of Palpable Breast Cancers

0%

20%

40%

60%

80%

100%

BRCA1

sporadic

ChangLancet, ‘99

GoffinJNCI ‘01

Tilanus -Linthorst Int J Cancer ‘02

P=.03P=.01 P=.01

Limitations of Mammographyfor HBC Surveillance

• young age = dense breasts

• tumour pathology (BRCA1)

– less DCIS

– fleshy, ‘pushing’ borders

Advantages of Breast MRI

• Contrast agent concentrates in areas of tumor angiogenesis

• tomographic images (3-D)

• less influenced by breast density

• no ionizing radiation

Disadvantages of MRI

• $$$

• lower specificity• biopsy more difficult

• logistics – menstrual phase– weight

• claustrophobia

Breast MRI Screening Studiesfor High Risk Women

Kriege et al. The Netherlands

Kuhl, et al. Bonn, Germany

Leach et al. U.K.

Podo et al. Italy

Schnall, Lehman et al. U.S.

Warner, Plewes, et al. Toronto, Canada

Breast MRI Screening Studiesfor High Risk Women

Similarities• prospective, non-randomized• not restricted to mutation carriers• annual mammography + MRI

Differences• single / multiple centers• patient population• additional modalities• MRI technique

Dutch National Study Kriege et al. NEJM 351: 427, 2004.

• 6 centers

• unaffected women

• ages 25-70

• ≥ 15% lifetime risk • MRI + mammography + CBE

Dutch National Study: Results• 1909 women

– 358 mutation carriers – mean age 40

– mean # screens = 2

•

4 (9%) interval cancers!

• 45 evaluable cancers

• 39 invasive, 6 DCIS• 50% in carriers• 50% 1st screen

Sensitivity of Individual Modalities

Dutch Study: Results

71%

40%

18%

0%

20%

40%

60%

80%

MRI Mam CBE

Sensitivity: Invasive vs. In-Situ


17%

80%

33%

83%

0%

20%

40%

60%

80%

100%

Invasive In-Situ

MRI

Mammography

n=39 n=6

False Positives

Recalls Biopsies

MRI 10% 5.8%

Mammography 5% 1.7%


Invasive Tumor Stage

40%

48%

43%

14% 12%

32%

37%

49%25%

0%

20%

40%

60%

80%

100%

Study Control 1 Control 2

> 2 cm

1.1 - 2 cm

< 1 cm


n=45 n=1500 n=45

21% node + 52% node + 56% node +

Toronto StudyWarner et al. JAMA 292: 1317, 2004

• single center

• affected & unaffected women• ages 25 - 65

• >25% lifetime risk

• MRI + mammography + CBE + US

The Toronto Study

Medical Biophysics

Donald Plewes PhD.

Martin Yaffe PhD.

Elizabeth Ramsay MSc

Cameron Piron MSc

Medical Imaging

Petrina Causer M.D.

Roberta Jong M.D.

Belinda Curpen M.D.

Joan Glazier MRT

Garry Detzler MRT

Caron Murray MRT

Joanne Muldoon MRT

Study Co-ordinator

Kimberley Hill, BScGenetics

Steven Narod M.D.

Sandra Messner M.D.

Wendy Meschino M.D.

Andrea Eisen M.D.

Pathology

John Wong M.D.

Judit Zubovits M.D.

General Surgery

Glen Taylor M.D.

Claire Holloway M.D.

Frances Wright M.D.

Biostatistics

Gerrit DeBoer PhD

Alice Chung BSc

Funding

CBCRANBCFAmersham HealthPapoff Family

Nurse Examiner Marg Cutrara R.N.

Toronto Study: Results• 437 women

– 318 BRCA mutation carriers

– mean age 43

– mean # screens = 3

Only 1 interval cancer!

• 37 cancers – 32 in carriers – mean age 48 (34-64) – 28 invasive (2 lobular), 9 DCIS

Sensitivity of Individual Modalities

Toronto Study: Results

84%

30%8%

33%

0%

20%

40%

60%

80%

100%

MRI Mam CBE US

Sensitivity of CombinedModalities


97%92% 92%

57%

38%

0%

20%

40%

60%

80%

100%

All butCBE

All butMam

All butUS

All butMRI

Mam+CBE

Sensitivity: Invasive vs. In-Situ


86%78%

25%33%

50%

0%0%

20%

40%

60%

80%

100%

invasive In-Situ

MRI

MMG

US

n=28 n=9

Sensitivity by Age


80%88%

24%35%

29%

45%

0%

20%

40%

60%

80%

100%

<50 (n=20) 50+ (n=17)

MRI

MMG

US

Toronto Study:: Results

Sensitivity by Year of Screening

89%79%

28% 32%28%42%

0%

20%

40%

60%

80%

100%

year 1 (n=18) year 2-5 (n=19)

MRI

MMG

US

False Positives: Recalls


1% 1%

19%

9%

2%2% 2%

6%

0.00%

5.00%

10.00%

15.00%

20.00%

Year 1 Years 2 - 5

MRI

M

CBE

US

False Positives: Biopsies


11%

5%6% 6%3%

16%

10%

4% 3%1% 1% 0

0%

5%

10%

15%

20%

Year 1 Year 2 Years 3-5

Any

MRI

M

US

74%

43%

22%

32%

3%

25%

0%

20%

40%

60%

80%

100%

Toronto the Netherlands

> 2 cm

1.1 - 2 cm

< 1 cm

Invasive Tumour Size


Yr. # cancers DCIS Mean Invasive Size Node +

1 18 22% 1.1 (0.4 - 3.0) cm 3

2 9 11% 1.2 (0.4 - 2.0) cm 1

3-5 9 44% 0.8 (0.7 - 1.0) cm 0

Tumor Stage by Year

No recurrences to date. Median f/u 3yrs. (range 1 to 7)

Effect of MRI Screening on Survival

0

5

10

15

1 2 3 4 5

years

log

cell

num

ber

M e t s

MRI

mammo

Costs$$$

MRI Screening

Benefits????

Cost-Benefit Analysis

Cost-Benefit Estimate

$$$

• 62 million women

ages 30-60 in U.S.

• 1% high risk (620,000)

• $1200 per screen

____________________

$744 million/year

• 620,000 high risk

• 1% (6,200) have cancer• mortality 30% → 10%• 1240 more cured • mean years saved = 25________________________

31,000 life years saved

$24,000 / year of life saved

Summary

Breast MRI for high risk women:

• most sensitive screening modality

• finds cancers at an earlier stage

• has acceptable specificity

• saves lives?

Other Research Questions

• Optimal MRI screening schedule for subgroups? – age– mutation status

– breast density

• Role of other screening modalities?

• Role of MRI for other high risk women?– Atypical hyperplasia, LCIS– Chest irradiation < age 30– Very dense breasts

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