Magnetic Resonance Imaging (MRI) Screening for High Risk Patients

Ellen Warner M.D.

Division of Medical Oncology Sunnybrook & Women’s College Health Sciences Center Toronto, 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 MRI Screening of the Breast an Effective

Seat Belt

For High Risk Women?

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

70% 60% 50% 40% 30% 20% 10% 0% 30

1. Antoniou et al. Am J Hum Genet, 2003 2. SEER Cancer Stats Review, 2004.

40 50

Age

60

BRCA1

70

BRCA1 + oophorectomy no family mutation general population

High Risk Screening Guidelines Mammography (annual) U.S. (NCCN, 2004) 25+ CBE (q 6months) 25+ U.K. (NICE, 2004) 30+ France (Eisinger, 2004) 30+ - 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 Mammography for ‘High Risk’ Screening

•

young age = dense breasts

Mammographic Visibility of Palpable Breast Cancers P=.03

100% 80% 60% 40% 20% 0% Chang Lancet, ‘99 P=.01

P=.01

BRCA1 sporadic Goffin JNCI ‘01 Tilanus -Linthorst Int J Cancer ‘02

Limitations of Mammography for 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 Studies for High Risk Women Kriege et al.

Kuhl, et al.

Leach et al. Podo et al. Schnall, Lehman et al.

Warner, Plewes, et al.

The Netherlands Bonn, Germany U.K.

Italy U.S.

Toronto, Canada

Breast MRI Screening Studies for 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

• •

45 evaluable cancers

• •

39 invasive, 6 DCIS 50% in carriers

•

50% 1 st screen 4 (9%) interval cancers!

Dutch Study: Results Sensitivity of Individual Modalities 71% 80% 60% 40% 20% 0% 40% 18% MRI Mam CBE

Dutch Study: Results Sensitivity: Invasive vs. In-Situ 100% 80% 60% 40% 20% 0% 80% 33% Invasive n=39 17% 83% In-Situ n=6 MRI Mammography

Dutch Study: Results False Positives

MRI

Recalls

10% Mammography 5%

Biopsies

5.8% 1.7%

Dutch Study: Results Invasive Tumor Stage 100% 80% 60% 40% 20% 0% 21% node + 25% 32% 43% Study n=45 52% node + 56% node + 49% 37% 14% Control 1 n=1500 48% 40% 12% Control 2 n=45 > 2 cm 1.1 - 2 cm < 1 cm

Toronto Study Warner et al. JAMA 292: 1317, 2004

• • • • •

single center affected & unaffected women ages 25 - 65 >25% lifetime risk MRI + mammography + CBE + US

The Toronto Study

Study Co-ordinator

Kimberley Hill, BSc

Medical Biophysics

Donald Plewes PhD.

Martin Yaffe PhD.

Elizabeth Ramsay MSc Cameron Piron MSc

Genetics

Steven Narod M.D.

Sandra Messner M.D.

Wendy Meschino M.D.

Andrea Eisen M.D.

Medical Imaging Pathology

Petrina Causer M.D.

Roberta Jong M.D.

Belinda Curpen M.D.

Joan Glazier MRT Garry Detzler MRT Caron Murray MRT Joanne Muldoon MRT

John Wong M.D.

Judit Zubovits M.D.

General Surgery

Glen Taylor

M.D.

Claire Holloway M.D.

Frances Wright M.D.

Nurse Examiner

Marg Cutrara R.N

.

Biostatistics

Gerrit DeBoer PhD Alice Chung BSc

Funding

CBCRA

NBCF Amersham Health Papoff Family

Toronto Study : Results

•

437 women

– –

318 BRCA mutation carriers mean age 43

–

mean # screens = 3

•

37 cancers – 32 in carriers – mean age 48 (34-64) – 28 invasive (2 lobular), 9 DCIS Only 1 interval cancer!

Toronto Study: Results Sensitivity of Individual Modalities 100% 80% 60% 40% 20% 0% 84% MRI 30% Mam 8% CBE 33% US

Toronto Study: Results Sensitivity of Combined Modalities 97% 100% 80% 60% 40% 20% 0% All but CBE 92% 92% 57% All but Mam All but US All but MRI 38% Mam+ CBE

Toronto Study: Results Sensitivity: Invasive vs. In-Situ 100% 80% 60% 40% 20% 0% 86% 25% 50% invasive n=28 78% 33% In-Situ n=9 0% MRI MMG US

Toronto Study: Results 100% 80% 60% 40% 20% 0% Sensitivity by Age 88% 80% 35% 45% 24% 29% <50 (n=20) 50+ (n=17) MRI MMG US

Toronto Study:

:

Results Sensitivity by Year of Screening 100% 80% 60% 40% 20% 0% 89% 28% 28% year 1 (n=18) 79% 32% 42% year 2-5 (n=19) MRI MMG US

Toronto Study : Results False Positives: Recalls 20.00% 15.00% 10.00% 5.00% 0.00% 19% 2% 1% 6% Year 1 9% 2% 1% 2% Years 2 - 5 MRI M CBE US

Toronto Study : Results False Positives: Biopsies 20% 15% 10% 5% 0% 16% 10% 6% 1% 11% 4% 6% 1% Year 1 Year 2 5% 3% 0 3% Years 3-5 Any MRI M US

Invasive Tumour Size 100% 80% 60% 40% 20% 0% 3% 22% 74% Toronto 25% 32% 43% the Netherlands > 2 cm 1.1 - 2 cm < 1 cm

1 Toronto Study: Results Tumor Stage by Year Yr. # cancers DCIS Mean Invasive Size Node + 18 22% 1.1 (0.4 - 3.0) cm 3 2 9 3-5 11% 1.2 (0.4 - 2.0) cm 1 9 44% 0.8 (0.7 - 1.0) cm 0 No recurrences to date. Median f/u 3yrs. (range 1 to 7)

15 10 5 0 Effect of MRI Screening on Survival MRI mammo M t e s 1 2 3 years 4 5

Cost-Benefit Analysis Costs $$$ Benefits ????

MRI Screening

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