Low Dose
Molecular Breast
Imaging
Conflict of Interest
Dr. M.K. O’Connor
Royalties - Gamma Medica
Research funding – GE Healthcare
Research support – MTTI
This work has been funded in part by the following:
National Institute of Health
Dept. of Defense
Susan G Komen Foundation
Mayo Foundation
Friends for an Earlier Breast Cancer Test
Michael O’Connor, Ph.D
Dept. of Radiology
Mayo Clinic
Breast Density Classification
• ACR BI-RADS (qualitative score)
• Used by radiologists as part of routine practice
BI-RADS 2
BI-RADS 3
<25%
25-49%
50-74%
≥75%
82%
69%
62%
Sens = 88%
Breast Density
Breast Density Legislation
Comparative Relative Risks
Risk factor
BI-RADS 4
BI-RADS 1
Relative risk
BRCA mutation
Lobular carcinoma in situ
Dense breast parenchyma
20
8-10
4-6
Personal history of breast cancer
Family history (1° relative)
3-4
2.1
Postmenopausal obesity
1.5
“Mammographic density is perhaps the most
undervalued and underutilized risk in studies
investigating the causes of BC.”
Connecticut enacted similar legislation in 2009 and
a comparable breast density patient education bill,
SB 173, is scheduled to be heard in the California
Assembly this month.
Sensitivity of Mammogram, US, and MRI
in Women at Increased Risk
Subjects
Subjects Sensitivity
Sensitivity Sensitivity
Sensitivity Sensitivity
Sensitivity
(no.)
MMG
US
MRI
(no.)
MMG (%)
(%)
US (%)
(%)
MRI (%)
(%)
Author/year
Author/year
Country
Country
Kuhl,
Kuhl, 2000
2000
Germany
Germany
192
192
33
33
33
33
100
100
Warner,
Warner, 2004
2004
Canada
Canada
236
236
36
36
33
33
77
77
Kriege,
Kriege, 2004
2004
Netherlands
Netherlands
1,909
1,909
40
40
NA
NA
71
71
Kuhl,
Kuhl, 2005
2005
Germany
Germany
529
529
33
33
40
40
91
91
Leach
Leach 2005
2005
U.K.
U.K.
649
649
40
40
NA
NA
77
77
3571
40
43
81
Sardanelli, 2006
Breast MRI
ƒ Poor specificity (highly variable: 50% - 90%)
ƒ Patient acceptance of MRI?
• ACRIN 6666 trial
• 42% declined free MRI (25% due to claustrophobia)
ACRIN 6666
3-Year Screening Study of Ultrasound and Mammography in 2500
High-Risk Women
41 cancers detected
20 by mammography (sens 50%)
20 by ultrasound
(sens 50%)
Mammography:
Ultrasound:
3% biopsy,
5% biopsy,
29% positive
9% positive
Study PI – Wendie Berg: "Women contemplating breast ultrasound screening must
be aware of the substantial risk of false positives“
Study Co-I – Etta Pisano: “based on the study results, it is difficult to determine
whether screening ultrasound is worthwhile”
Molecular Imaging of the Breast
ƒ PEM (Positron Emission Mammography)
• Coincidence detection using 2 scanning arrays of LYSO crystals
• Clinical unit developed by Naviscan
ƒ BSGI (Breast Specific Gamma Imaging)
• Single detector, multicrystal NaI based gamma camera
• Developed by Dilon Technologies
ƒ MBI (Molecular Breast Imaging)
• Dual detector Cadmium Zinc Telluride based gamma cameras
• Clinical units developed by Gamma Medica and GE Healthcare
ƒ Expensive (~10 times that of mammography)
PEM (Positron Emission Mammography)
Molecular Imaging of the Breast
FOV: 16 cm x 24 cm
2 scanning arrays of LYSO
ƒ PEM (Positron Emission Mammography)
2.4 mm resolution (in plane)
8.0 mm resolution (cross-plane)
(JNM 2009;50:1666-1675)
ƒ BSGI (Breast Specific Gamma Imaging)
Patient fasting 4-6 hr.
Inject 10 mCi F-18 FDG
Wait ~60 minutes
Obtain CC / MLO views
Scan time ~10 minutes / view
• Coincidence detection using 2 scanning arrays of LYSO crystals
• Clinical unit developed by Naviscan
• Single detector, multicrystal NaI based gamma camera
• Developed by Dilon Technologies
ƒ MBI (Molecular Breast Imaging)
• Dual detector Cadmium Zinc Telluride based gamma cameras
• Clinical units developed by Gamma Medica and GE Healthcare
BSGI (Breast Specific Gamma Imaging)
FOV: 15 cm x 20 cm
Single array of NaI crystals
Molecular Imaging of the Breast
ƒ PEM (Positron Emission Mammography)
• Coincidence detection using 2 scanning arrays of LYSO crystals
• Clinical unit developed by Naviscan
3 mm intrinsic resolution
~18% energy resolution
ƒ BSGI (Breast Specific Gamma Imaging)
• Single detector, multicrystal NaI based gamma camera
• Developed by Dilon Technologies
No patient fasting required
Inject 25-30 mCi Tc-99m sestamibi
Image ~5 minutes post injection
Obtain CC / MLO views
Scan time ~10 minutes / view
ƒ MBI (Molecular Breast Imaging)
• Dual detector Cadmium Zinc Telluride based gamma cameras
• Clinical units developed by Gamma Medica and GE Healthcare
Breast Phantom: Comparison between Systems*
Cadmium Zinc Telluride (CZT) Detector
*Hruska CB, et al. Nucl Med Commun, 2005; 26: 441-445
Tumor
Depth
2.54 cm
1cm
3 cm
• Excellent Intrinsic Resolution = 1.6 mm / 2.5 mm
• Excellent Energy Resolution 4.0% / 6.5%
• Can be operated at room temp
5 cm
• No dead space – ideal for breast imaging
• Expensive – currently limited to small field of view detectors
MC-NaI
NaI
CZT
MC-CsI
Molecular Breast Imaging Procedure
• First commercial systems using CZT developed for nuclear cardiology
MBI Systems Currently at Mayo Clinic
• Patient receives an IV injection of a
radiotracer (Tc-99m sestamibi)
• The tracer preferentially
accumulates in cancer cells and is
not influenced by breast density
• The breast is lightly compressed
between the 2 gamma cameras,
only light pain-free compression is
necessary
• Imaging starts ~5 minutes post
injection. Acquire CC and MLO
views of each breast for 10 minutes
/ view
GE Research Unit
GM-I Research Unit
GM-I Clinical Unit
Can MBI find lesions not visible on mammography?
1.1cm nodular density in upper inner right breast 9.5cm from the nipple
Comparison of Screening MBI and Mammography
ƒ ~1000 patients - asymptomatic
ƒ Compare MBI and mammography in patients with
dense breasts at increased risk of breast cancer
ƒ MBI performed with 20 mCi Tc-99m sestamibi
ƒ Breast status assessed @ 12-months
Question – is MBI a viable screening adjunct to
mammography in patients with dense breasts?
Can MBI find lesions not visible on mammography?
2 x 1 cm IDC with multiple satellite lesions confirmed as DCIS at surgery
Diagnostic accuracy of screening
mammography and MBI
Mammography
alone
MBI alone
Mammography
plus MBI
Sensitivity (all
cancers)
25% (3/12)
83% (10/12)
92% (11/12)
Sensitivity
(Invasive cancers)
25% (2/8)
100% (8/8)
100% (8/8)
25% (1/4)
50% (2/4)
75% (3/4)
Sensitivity (DCIS)
Specificity
91% (839/925) 93% (861/925) 85% (789/925)
Recall Rate
9.5% (89/936)
7.8% (73/936)
16% (146/936)
PPV
18 % (3/17)
28% (10/36)
24% (11/45)
Rhodes et al, Radiology 2011;258:106-118
Mammographically occult cancers detected on MBI
10 mm + 16 mm
IDC
17 mm IDC + DCIS
9 mm ILC
7 mm
tubulolobular ca
9 mm DCIS
9 mm IDC
13.5 mm ILC (total
extent 5.1 cm)
Relative Radiation Risks
Hendrick R.E.
Radiation Doses and Cancer Risks from
Breast Imaging Studies
Radiology. 2010 Oct; 257(1):246-53.
O'Connor MK, Li H, Rhodes DJ, Hruska
CB, Clancy CB, Vetter RJ.
Comparison of radiation exposure and
associated radiation-induced cancer
risks from mammography and molecular
imaging of the breast.
Med Phys. 2010 Dec;37(12):6187-98.
Radiation risk to patients
ƒ Mammogram
ƒ PEM (10 mCi F-18 FDG)
ƒ BSGI (25-30 mCi Tc-99m mibi)
ƒ MBI (20 mCi Tc-99m mibi)
~ 0.5 mSv
~ 7 mSv
~ 9 mSv
~ 6 mSv
For pop. of 100,000 women undergoing above procedures at
age 40, estimated cancer mortality
ƒ Mammogram
~2
ƒ PEM (10 mCi F-18 FDG)
~ 30
ƒ BSGI (25-30 mCi Tc-99m mibi)
~ 35
ƒ MBI (20 mCi Tc-99m mibi)
~ 24
100,000
women
aged 30
Where does the
estimate of cancer
mortality come from ?
Single
dose of
100 mGy
Based on Table 12D from
BEIR VII
Over their
lifetime
Risk Models
• Lifetime Attributable Risk (LAR)
• “Because of the various sources
of uncertainty it is important to
regard specific estimates of LAR
with a healthy skepticism, placing
more faith in a range of possible
values”
values” (BEIR VII, page 278)
…range of plausible values for LAR is labeled a “subjective
confidence interval” to emphasize its dependence on
opinions in addition to direct numerical observation (BEIR
VII, page 278)
Relative Radiation Risks
Cancer mortality in 100,000 subjects
U.S. Cancer Mortality
18000.00
Minnesota - 3 mSv/year
16000.00
Colorado - 4.5 mSv/year
50 mSv at age 40
ƒ Background radiation
ƒ U.S. Average (3.1 mSv/year) ~1010
Cumulative Cancer Mortality
For pop. of 100,000 women exposed to naturally
occurring background radiation from age 0-80, estimated
cancer mortality
14000.00
12000.00
Estimated deaths
due to background
radiation.
No epidemiological
evidence to support
these numbers
10000.00
8000.00
6000.00
4000.00
240 deaths
ƒ Colorado (~4.5 mSv/year)
~1460
2000.00
ƒ Florida (~2.5 mSv/year)
~ 810
0.00
0
20
40
60
80
100
Age(years)
MBI: Implications for Radiation Exposure to the
Technologist from 8 patients / day, 20 mCi / patient
Reduce dose / increase scan time ?
- already at ~40 minutes !!
400
mrem
Improve the technology
- detector / collimator optimization
- energy window optimization
- noise reduction algorithms
- composite image from opposing detectors
MBI
Tech
200
100
General
NMT
Cardiology
NMT
Radiographer
0
Pletta CK, et al. J Nucl Med 2009; 50 (Suppl 2): 428P.
Molecular Breast Imaging
Optimal pixel size for near-field imaging (0-3 cm)
Detector / Collimator Optimization
Monte Carlo simulations (MCNP) used to
optimize detector and collimator design
What is the optimal pixel size and collimation to
achieve a spatial resolution = 5 mm at 3 cm?
100%
65%
45%
0
Clinical studies show average breast thickness = 6 cm
Hence each collimator optimized over range 0 – 3 cm
0.3
Annual Technologist Dose
500
300
Radiation Dose Reduction
Molecular Breast Imaging
Molecular Breast Imaging
Conventional
Collimation
Conventional
Collimation
CZT:
1.6 x 1.6 mm pixel
CZT:
1.6 x 1.6 mm pixel
Hexagonal hole
Collimator:
2.5 mm hole diameter
Square hole
Collimator:
~1.6 mm hole diameter
Molecular Breast Imaging
Collimator specifications
Results from
Simulation
Better resolution
@ 3 cm
Molecular Breast Imaging
Matched Collimation on CZT detectors
Tungsten collimator
Square holes
Each hole matched
to individual pixel on
CZT detector
Factor of ~2 gain
in sensitivity
expected
Molecular Breast Imaging
Effect of Optimal Collimation – CZT Detector
MBI – Radiation Dose Reduction
Four dose reduction techniques have been developed and
evaluated in order to reduce the administered dose of Tc99m sestamibi needed for MBI
- collimator optimization
- energy window optimization
- noise reduction algorithms
- composite image from opposing detectors
Wide energy
window
(110-154 kev)
~1.4 gain in
sensitivity
System sensitivity – effect of collimation and energy
window
Detector
CZT
1.6 mm
pixel
CZT
2.5 mm
pixel
Collimator
Energy
Window
counts/
min/μCi
Relative
gain in
counts/pixel
Standard
Standard, 140 ± 10%
312
1.0
Standard
Wide, 110 – 154 keV
391
1.3
Tungsten design
Standard 140 ± 10%
905
2.9
Tungsten design
Wide, 110 – 154 keV
1132
3.6
Standard
Standard, 140 ± 10%
254
1.0
Standard
Wide, 112 – 154 keV
331
1.3
optimized design
Standard 140 ± 10%
534
2.1
optimized design
Wide, 112 – 154 keV
705
2.8
GMI LumaGem
@
1 cm
GMI LumaGem
@
3 cm
Contrast to Noise Ratio – Lumagem 3200s
MBI Dose Reduction
Contrast to Noise Ratio – Discovery 750b
MBI Dose Reduction
Relative Gain = 4.9 + 1.6
Comparison of count densities in patient studies
System
GM CZT
# Studies
38
Ratio of Cts (New: Old)
4.9 + 1.6
Dose
20 mCi
8 mCi
MBI – Radiation Dose Reduction
Four dose reduction techniques have been developed and
evaluated in order to reduce the administered dose of Tc99m sestamibi needed for MBI
- collimator optimization
- energy window optimization
- noise reduction algorithms
- composite image from opposing detectors
Noise Reduction / Combined Images
from Opposite Detectors
Combined Images:
Gaussian Neighborhood Geometric Mean (GNGM)
Noise Reduction:
Non-Local Means (NLM) denoising filter
Wide Beam Reconstruction (UltraSPECT)
Image Generation & analysis
Filter parameters and order of application of noise
reduction algorithms yet to be optimized
Gaussian Neighborhood / Geometric Mean
Algorithm
Comparison of Noise Reduction algorithms
8 mCi
Raw data
4 mCi
GNGM / NLM
4 mCi
WBR
Comparison of Low-dose MBI and Mammography
in a Screening Environment
Comparison of Low-dose MBI and Mammography
in a Screening Environment
Question – is low-dose MBI (~4 mCi) a viable screening
adjunct to mammography in patients with dense breasts?
ƒ Compare MBI and mammography in asymptomatic
patients with dense breasts on prior mammogram
ƒ 2400 patients over next 2 years
ƒ 1100 patients imaged as of 7/25/11
ƒ 14/15 cancers detected on MBI
ƒ 1/15 cancer detected on mammography
ƒ 1 cancer missed by MBI and mammography
Comparison of Low-dose MBI and Mammography
in a Screening Environment
Screening Mammogram
(negative)
Comparison of Low-dose MBI and Mammography
in a Screening Environment
2 cm IDC
MBI (positive)
Screening
Mammogram
(negative)
MBI (20 mCi)
(negative)
March 2008
MBI (4 mCi)
(positive)
March 2011
Comparison of Low-dose MBI and Mammography
in a Screening Environment
Screening
Mammogram
(negative)
MBI (4 mCi)
(positive)
Ultrasound
6.5 mm Invasive
Tubular carcinoma
Comparison of Low-dose MBI and Mammography
in a Screening Environment
Screening
Mammogram
(negative)
Comparison of Low-dose MBI and Mammography
MBI (2 mCi)
(positive)
Ultrasound
~3 cm Invasive
Lobular carcinoma
Advantages of MBI
• Compared to mammography:
• Higher sensitivity in dense breasts
• Comparable radiation burden to the body
• Less compression, improved patient comfort
• Compared to MRI
• Comparable sensitivity, better specificity
• Offers option if contraindication to MRI
(claustrophobia, pacemaker, clips)
MBI (2 mCi)
Screening Mammogram
(negative)
• Avoids gadolinium and potential for NSF
• Easy to interpret – 8 images vs 1000s for MRI
• 5-7 fold less expensive than MRI
MBI
Multifocal DCIS with ADH
Screening for Breast Cancer
• Mammography has proven to be an
excellent screening technique for the
majority of women
• SubSub-optimal in women with dense breast
tissue
• Alternative techniques are required
• Possible techniques include ultrasound,
MRI and lowlow-dose molecular imaging
• Cost and specificity will be key factors to
acceptance of any adjunct screening
technique