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Molecular Breast Imaging Molecular Breast Imaging

Michael OMichael O’’Connor, PhDConnor, PhDDepartment of RadiologyDepartment of Radiology

Mayo ClinicMayo ClinicRochester, MNRochester, MN

This work has been funded in part by the following:National Institute of Health

Dept. of DefenseSusan G Komen Foundation

Mayo FoundationFriends for an Earlier Breast Cancer Test

Mammography: The ProblemMammography: The ProblemMammography: The Problem

Breast cancer and tumors appear white on mammogram

Cancer clearly visible in non-dense breast

Cancer would be occult in dense breast

Sensitivity Sensitivity80%-90% 40%-70%

Breast CancerComparative Relative Risks

Breast CancerBreast CancerComparative Relative RisksComparative Relative Risks

Risk factor Relative riskBRCA mutation 20

Lobular carcinoma in situ 8-10

Dense breast parenchyma 4-6

Personal history of breast cancer 3-4

Family history (1° relative) 2.1

Postmenopausal obesity 1.5

Prempro (WHI) 1.26

Risk factor Relative riskBRCA mutation 20

Lobular carcinoma in situ 8-10

Dense breast parenchyma 4-6

Personal history of breast cancer 3-4

Family history (1° relative) 2.1

Postmenopausal obesity 1.5

Prempro (WHI) 1.26

Sensitivity of MMG, US, and MRIin Women at Increased Risk

Sensitivity of MMG, US, and MRISensitivity of MMG, US, and MRIin Women at Increased Riskin Women at Increased Risk

Subjects Sensitivity Sensitivity SensitivityAuthor/year Country (no.) MMG (%) US (%) MRI (%)

Kuhl, 2000 Germany 192 33 33 100

Warner, 2004 Canada 236 36 33 77

Kriege, 2004 Netherlands 1,909 40 NA 71

Kuhl, 2005 Germany 529 33 40 91

Leach 2005 U.K. 649 40 NA 77

Sardanelli, 2006 Italy 3571 40 43 81

Subjects Sensitivity Sensitivity SensitivityAuthor/year Country (no.) MMG (%) US (%) MRI (%)

Kuhl, 2000 Germany 192 33 33 100

Warner, 2004 Canada 236 36 33 77

Kriege, 2004 Netherlands 1,909 40 NA 71

Kuhl, 2005 Germany 529 33 40 91

Leach 2005 U.K. 649 40 NA 77

Sardanelli, 2006 Italy 3571 40 43 81

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American Cancer SocietyAmerican Cancer SocietyAmerican Cancer SocietyNew guidelines issued on March 28th, 2007

Recommend annual MRI screening for women with a high lifetime risk of breast cancer – defined as 20% or more

June 2008

MRI: Main DisadvantagesMRI: Main DisadvantagesMRI: Main DisadvantagesComplexity

• Typical contrast enhanced breast MRI may contain over 1500

images

Cost (Medicare reimbursement rate)• Analog Mammogram ~$90

• Digital Mammogram ~$140

• Bilateral breast ultrasound ~$200

• Bilateral MRI > $1,000

Specificity• (tertiary centers) ~ 90%

• (community centers) ~ 50%

Complexity• Typical contrast enhanced breast MRI may contain over 1500

images

Cost (Medicare reimbursement rate)• Analog Mammogram ~$90

• Digital Mammogram ~$140

• Bilateral breast ultrasound ~$200

• Bilateral MRI > $1,000

Specificity• (tertiary centers) ~ 90%

• (community centers) ~ 50%

Nuclear Medicine / Molecular ImagingScintimammography

Nuclear Medicine / Molecular ImagingNuclear Medicine / Molecular ImagingScintimammographyScintimammography

• Tc-99m sestamibi approved by the FDA for breast imaging in 1997

• Several large multicenter studies undertakenin late 1990s

Taillefer: Sem Nucl Med 29:16, 1999(2009 patients)Sensitivity = 85%, specificity = 89%

• Tc-99m sestamibi approved by the FDA for breast imaging in 1997

• Several large multicenter studies undertakenin late 1990s

Taillefer: Sem Nucl Med 29:16, 1999(2009 patients)Sensitivity = 85%, specificity = 89%

Brem: J Nucl Med 43:909, 2002

Sensitivity 35-64% for lesions <1 cm

Taillefer: Sem Nucl Med 29:16, 1999

Sensitivity ~55% for masses <1.5 cm

Impact of Tumor Size on Metastatic DiseaseImpact of Tumor Size on Metastatic DiseaseImpact of Tumor Size on Metastatic Disease

% with Metastatic Disease

% with % with Metastatic Metastatic DiseaseDisease

Tumor size (cm)Tumor size (cm)

20%20%

33%33%45%45%

52%52%60%60%

70%70%

0

30

60

90

<0.5 0.5-1.0 1-2 2-3 3-4 4-5 >5

<10 mm: 5-year survival = 98%30 mm : 5-year survival = 70%Aust. Inst. Health Welfare, Oct 2007

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Conventional ScintimammographyConventional ScintimammographyConventional Scintimammography Small Field of View Gamma CamerasSmall Field of View Gamma Cameras

DigiradMulticrystal

Cesium Iodide+ Photodiodes

DigiradMulticrystal

Cesium Iodide+ Photodiodes

Dilon Inc.Multicrystal

Sodium Iodide+ PMTs

Dilon Inc.Multicrystal

Sodium Iodide+ PMTs

CZT TechnologyCadmium ZincTelluride (CZT)Semiconductor

CZT TechnologyCadmium ZincTelluride (CZT)Semiconductor

Breast Phantom: Comparison between Systems*Breast Phantom: Comparison between Systems*

Tumor Depth

1cm

3 cm

5 cm

MC-NaI NaI CZT MC-CsI

*Hruska CB, et al. Nucl Med Commun, 2005; 26: 441-445Cadmium Zinc Telluride (CZT) DetectorCadmium Zinc Telluride (CZT) Detector

• Excellent Intrinsic Resolution = 1.6 mm

• Excellent Energy Resolution 4.0%

•• Can be operated at room temp

• No dead space – ideal for breast imaging

• Expensive – currently limited to small field of view detectors

• First commercial gamma cameras usingCZT developed for nuclear cardiology

2.54 cm

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Energy Resolution Energy Resolution -- CZT DetectorCZT Detector

�� MBI Prototypes developed at Mayo MBI Prototypes developed at Mayo over last 6 yrs using detectors from over last 6 yrs using detectors from Gamma Medica and GE Healthcare Gamma Medica and GE Healthcare

�� Cadmium Zinc Telluride (CZT) gamma Cadmium Zinc Telluride (CZT) gamma camera technologycamera technology

• Expensive – currently limited to small

field of view detectors

�� DualDual--detector design optimized for detector design optimized for breast imagingbreast imaging

�� Anticipated cost ~$400 / studyAnticipated cost ~$400 / study

Molecular Breast Imaging – 2009Molecular Breast Imaging Molecular Breast Imaging –– 20092009

Dual-detector MBI System

How does Molecular Breast Imaging Work?How does Molecular Breast Imaging Work?

�� Patient receives an IV injection of a Patient receives an IV injection of a radiotracer (Tcradiotracer (Tc--99m sestamibi)99m sestamibi)

�� The tracer preferentially The tracer preferentially accumulates in cancer cells and is accumulates in cancer cells and is notnot influenced by breast densityinfluenced by breast density

�� The breast is lightly compressed The breast is lightly compressed between the 2 MBI gamma between the 2 MBI gamma cameras, cameras, only light painonly light pain--free free compression is necessarycompression is necessary

�� Imaging starts ~5 minutes post Imaging starts ~5 minutes post injection. Acquire CC and MLO injection. Acquire CC and MLO views of each breast for 10 minutes views of each breast for 10 minutes / view/ view

�� Procedure performed by nuclear Procedure performed by nuclear medicine technologist trained in medicine technologist trained in mammographic positioning mammographic positioning techniquestechniques

Can MBI find small breast tumors?Can MBI find small breast tumors?

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*Palmedo et al: EJNM 25:375, 1998

67%67%

44%44%

No dataNo data

Tumors < 5 mm Tumors < 5 mm in sizein size

90%90%

82%82%

All Tumors (128 All Tumors (128 in 88 patients)in 88 patients)

DualDual--head MBIhead MBI

SingleSingle--head MBIhead MBI

Standard Standard γγ--Camera*Camera*

TechnologyTechnology

87%87%

76%76%

55%55%

Tumors 5Tumors 5--10 mm 10 mm in sizein size

10 mm18 mm 8 mm 5 mm 3 mm

Vol 191, 1808-1815

Comparison of Screening MBI and Mammography

Comparison of Screening MBI and Mammography

� ~1000 patient screening study � Funded by Susan G Komen Foundation� Compare MBI and mammography in patients with

dense breasts at high risk of breast cancer� Prior history of breast cancer� Family history in one FDR or two SDR� Gail lifetime risk > 20%� Prior atypia or LCIS

Question – is MBI a viable screening adjunct to mammography in patients with dense breasts?

� ~1000 patient screening study � Funded by Susan G Komen Foundation� Compare MBI and mammography in patients with

dense breasts at high risk of breast cancer� Prior history of breast cancer� Family history in one FDR or two SDR� Gail lifetime risk > 20%� Prior atypia or LCIS

Question – is MBI a viable screening adjunct to mammography in patients with dense breasts?

ResultsResults� In 958 patients studied, a total of 14 cancers in

12 patients were diagnosed. • 8 cancers detected by MBI alone

• 1 cancer detected by mammography alone

• 2 cancers detected by both MBI and mammography

0

20

40

60

80

100

% of Cancers Detected

MMG MBI Combination

Imaging Modality

21 % (3 / 14)

71 % (10 / 14)

79 % (11 / 14)

Screening Patient Examples (1)Screening Patient Examples (1)

Digital Screening Mammography (Negative)Molecular Breast Imaging (Positive)

17 mm IDC with DCIS extension

Rt CC Rt MLO

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Digital Screening Mammography

(Negative)

Rt MLOMolecular Breast Imaging(Positive)

9 mm Ductal Carcinoma In Situ

Screening Patient Examples (2)Screening Patient Examples (2)MBI MBI vs.vs.

SPECTSPECT

Parathyroid scan with Tc-99m sestamibi performed 4 weeks

prior to MBI study in Screening Patient Example #3

A

L R

P

Screening Patient Examples (3)Screening Patient Examples (3)

Digital Screening Mammography

(Negative)

Rt MLO

9 mm Invasive Ductal Carcinoma

Molecular Breast Imaging(Positive)

Lt CC Lt MLO

7 mm Tubulolobular Carcinoma

Screening Patient Examples (4)Screening Patient Examples (4)

Digital Screening Mammography (Negative)Molecular Breast Imaging (Positive)

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Sensitivity: All cancers detected by any means in the 12-month period since the MBI study.

10 / 14 cancers detected by MBI (sensitivity = 71%)

3 / 14 cancers detected by mammography (sensitivity = 21%)

Specificity: Patients with a negative follow-up mammogram at 1 year and no clinical symptoms at 12-months were assumed to be disease free

Specificity - MBI 93% Recall Rate – 7.5 %

Specificity - mammography 90% Recall Rate – 9.2 %

Sensitivity: All cancers detected by any means in the 12-month period since the MBI study.

10 / 14 cancers detected by MBI (sensitivity = 71%)

3 / 14 cancers detected by mammography (sensitivity = 21%)

Specificity: Patients with a negative follow-up mammogram at 1 year and no clinical symptoms at 12-months were assumed to be disease free

Specificity - MBI 93% Recall Rate – 7.5 %

Specificity - mammography 90% Recall Rate – 9.2 %

Results in 958 Patients with 12-month Follow-up Molecular Breast Imaging in Patients undergoing Molecular Breast Imaging in Patients undergoing Myocardial Perfusion ImagingMyocardial Perfusion Imaging

�� Negative screening mammogramNegative screening mammogram

�� Myocardial perfusion scan and MBI 1 Myocardial perfusion scan and MBI 1 week laterweek later

�� FollowFollow--up up DxDx mmgmmg/US positive, 8 mm /US positive, 8 mm IDC/DCISIDC/DCIS

�� Breast MRI correlated with MBIBreast MRI correlated with MBI

�� MBIs performed in women presented for myocardial MBIs performed in women presented for myocardial perfusion studies, no additional dose neededperfusion studies, no additional dose needed

�� Of 158 patientsOf 158 patients

•• 3 cancers detected, 1 only detected by MBI3 cancers detected, 1 only detected by MBI

•• 1 patient with uptake in papilloma and atypia1 patient with uptake in papilloma and atypia

•• 154 patients with negative findings154 patients with negative findings

MBI MBI -- Potential Screening ApplicationPotential Screening Application

�� MBI has 2MBI has 2--3 times sensitivity of mammography in the 3 times sensitivity of mammography in the highhigh--risk and dense breast populationsrisk and dense breast populations

�� MBI appears to have comparable sensitivity (80%) to MBI appears to have comparable sensitivity (80%) to that reported for MRI in women at increased risk of that reported for MRI in women at increased risk of breast cancerbreast cancer

�� American Cancer Society guidelines recommend American Cancer Society guidelines recommend annual MRI if lifetime risk exceeds 20%: would impact annual MRI if lifetime risk exceeds 20%: would impact up to 1.5 million women annually in the U.S.up to 1.5 million women annually in the U.S.

�� Cost of MBI estimated at ~1/5Cost of MBI estimated at ~1/5thth cost of Breast MBIcost of Breast MBI

�� Currently no clinical systems availableCurrently no clinical systems available

-- First clinical systems in late 2009 ?First clinical systems in late 2009 ?

MBI MBI -- Limitations and DisadvantagesLimitations and Disadvantages

�� False positive findings in some cases of False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. fibroadenomas, papillomas, fat necrosis.

�� Uptake of Sestamibi is influenced by hormonal Uptake of Sestamibi is influenced by hormonal changeschanges

�� MBI MBI -- high radiation dose relative to high radiation dose relative to mammographymammography

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Cumulative Cancer Incidence per 100,000 women from annual screening with Mammography or Tc-99m sestamibi starting at age 40

0

500

1000

1500

2000

2500

3000

3500

40 45 50 55 60 65 70 75 80

Age (years)

Cum

ula

tive

Can

cer

Inci

den

ce /

100,

000

2 - 4 mCi Sestamibi

Mammogram 3.8 – 6.6 mGy

25 mCi Sestamibi

Background Radiation

0

100

200

300

400

500

MBI Tech

General NMT

Cardiology NMT

Radiographer

mrem

Annual Technologist Dose

MBI: Implications for Radiation Exposure to the MBI: Implications for Radiation Exposure to the Technologist from 8 patients / day, 20 mCi / patientTechnologist from 8 patients / day, 20 mCi / patient

MBI MBI –– Radiation DoseRadiation Dose

Radiation risk to patients / technologistsRadiation risk to patients / technologists

�� MBI with 20 mCi TcMBI with 20 mCi Tc--99m sestamibi = 6.5 99m sestamibi = 6.5 mSvmSv

�� Mammogram is < 1.0 Mammogram is < 1.0 mSvmSv

�� Dose reduction techniques have been developed Dose reduction techniques have been developed to reduce administered dose of Tcto reduce administered dose of Tc--99m 99m sestamibi to 2sestamibi to 2--4 4 mCimCi

-- collimator optimizationcollimator optimization

-- energy window optimizationenergy window optimization

-- noise reduction algorithmsnoise reduction algorithms

-- composite image from opposing detectorscomposite image from opposing detectors

MBI Dose ReductionMBI Dose Reduction

20 mCi DoseUpper Rt. MLO

Lower Rt. MLO

Upper Rt. MLO

Lower Rt. MLO

4 mCi Dose

Rt. MLOCombined/filtered

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MBI MBI -- Future DirectionsFuture Directions

�� Clinical applicationsClinical applications

•• Screening in highScreening in high--risk women risk women

•• PrePre--operative staging to exclude multifocal/contralateral operative staging to exclude multifocal/contralateral cancerscancers

•• NeoNeo--adjuvant chemotherapy evaluationadjuvant chemotherapy evaluation

�� Alternative radiotracers Alternative radiotracers

•• Improved detection of lesions < 5 mmImproved detection of lesions < 5 mm

•• Improved detection of DCIS and atypiaImproved detection of DCIS and atypia

Molecular Breast ImagingFuture Developments – New Radiopharmaceuticals

Molecular Breast ImagingMolecular Breast ImagingFuture Developments Future Developments –– New RadiopharmaceuticalsNew Radiopharmaceuticals

�Tc-99m Sestamibi�Tc-99m Bombesin�Tc-99m αV-β3 Integrin�Tc-99m Annexin V�Tc-99m Glucarate�Tc-99m EC-glucosamine�Tc-99m (V)-DMSA�Tc-99m Vitamin B12� I-123 Iodo-estradiol� I-123 Methoxy-vinylestradiol� I-123 Dimethyl-Tamoxifen� I-123 Iodo-methoxybenzamide

�Tc-99m Sestamibi�Tc-99m Bombesin�Tc-99m αV-β3 Integrin�Tc-99m Annexin V�Tc-99m Glucarate�Tc-99m EC-glucosamine�Tc-99m (V)-DMSA�Tc-99m Vitamin B12� I-123 Iodo-estradiol� I-123 Methoxy-vinylestradiol� I-123 Dimethyl-Tamoxifen� I-123 Iodo-methoxybenzamide