Download Imaging: applications in breast oncology

Imaging: applications in breast
oncology
Nola Hylton, Ph.D.
Professor of Radiology and Biomedical Imaging
OVERVIEW
•  Breast imaging in clinical practice
•  Quantitative imaging approaches and imaging
biomarkers
•  MRI applications in breast oncology
–  Diagnosis and tumor characterization
–  Treatment response assessment for locallyadvanced breast cancer
–  MRI of DCIS
Breast imaging in clinical practice
•  Mammography and ultrasound are the conventional
methods for screening, diagnosis and staging breast
cancer
•  Magnetic resonance imaging (MRI) has been adopted
more recently; its role is still being established
•  Other methods including positron emission tomography
(PET) and optical imaging are not routinely used in
clinical practice (for primary breast cancer), but are
active areas of research
Screening Mammography
75 y.o. woman
(Teaching case provided by Bonnie Joe, MD, PhD.,
Chief of Women’s Imaging, UCSF)
Screening mammogram
Latero-medial oblique (LMO) view
Screening mammogram
Cranio-caudal (CC) view
Findings and Assessment
CC
LM
•  Suggestion of
architectural
distortion in right
upper, slightly
inner breast
•  BIRADS 0:
Incomplete. Need
additional imaging
evaluation.
CC spot mag
LM spot mag
Ultrasound
Findings, Assessment and Follow-up
•  FINDINGS:
•  Mammo: spiculated mass,
right upper inner breast
•  US: irregular, hypoechoic
mass with shadowing
•  ASSESSMENT:
•  BIRADS 5; highly suggestive
of malignancy
•  RECOMMENDATION:
•  US guided biopsy
•  PATHOLOGY:
•  Invasive ductal carcinoma
MRI of primary breast cancer
•  MRI has an evolving clinical role in primary breast cancer
–  uses gadolinium contrast agent to enhance cancers
–  high sensitivity (93-100%), moderate and variable specificity (30-95%)
–  more effective than clinical exam, mammography, or ultrasound for
staging extent of disease in the breast
•  More advanced functional MRI approaches can be used to
characterize primary breast cancer to improve diagnostic specificity
or assess response to treatment
Mammography and MRI reflect different
and complementary biologic processes
Patient with Paget’s disease of
the nipple and underlying DCIS
Breast MRI clinical applications
•  High-risk screening
–  2007 ACR recommendation for MRI screening in women with >20%
lifetime risk of breast cancer; contralateral breast screening
•  Diagnosis/problem-solving
–  As adjunct to mammography and ultrasound for indeterminate findings
•  Pre-surgical staging
–  determine extent of disease; eligibility for breast conserving surgery
•  Treatment response assessment
–  Response to neoadjuvant chemotherapy and hormonal treatment
Diagnostic assessment
Spiculated
margins
Rim
enhancement
Ductal
distribution
Smooth
margins; dark
internal
septations
Pre-contrast
Early post-contrast (~ 2 min)
Late post-contrast (~7 min)
Qualitative assessment of contrast kinetics (gradual, plateau, washout)
Quantitative Approaches for Breast Imaging
•  Digital X-ray
–  Full field digital mammography (FFDM)
–  Digital breast tomosynthesis (DBT)
–  Breast computed tomography (BCT)
•  Magnetic resonance imaging (MRI)
–  Dynamic contrast-enhanced MRI (DCE-MRI)
–  Diffusion-weighted MRI (DW-MRI)
–  Magnetic resonance spectroscopy (MRS)
•  Near infrared (NIR) optical imaging
•  Positron emission tomography (PET) and
positron emission mammography (PEM)
Br Can Risk by Dense Volume
4.5
4
3.5
3
Relative 2.5
2
Risk
1.5
1
0.5
0
%SXA
Dense Vol
1
2
3
Quartiles
J. Shepherd, UCSF
4
3D X-ray: tomosynthesis and breast CT
•  Instrumentation technologies not fully developed
•  Limited angle (DBT) or full angle (BCT) projections
•  Addresses problem of tissue superposition
•  Low dose (~ equal to dose of 2-view mammography)
•  Not yet FDA-approved; initial clinical testing being performed
•  Limitations:
–  X-ray scatter can reduce sensitivity/resolution for microcalcifications
–  Poor visualization of chest wall and axilla with BCT
Quantitative MRI techniques for breast
cancer evaluation
MRI Technique
Measurement
Tissue/Tumor Property
Dynamic Contrast Enhanced
(DCE) MRI
SER, ktrans, ve
Microvascular permeability,
blood volume
Diffusion-weighted (DW) MRI
Apparent Diffusion
Coefficient (ADC)
Cellularity
1H
Total choline concentration Cell membrane synthesis,
[tCho]
proliferation
MR Spectroscopy (MRS)
T2-wt
DCE
DWI
ADC Map
Dynamic contrast-enhanced (DCE) MRI
Tumor
• 
Temporal resolution ~10 seconds
• 
Requires baseline T1 measurement and arterial input function (AIF)
• 
Signal intensity-time curve fit to a 2-compartmental pharmacokinetic model
• 
Transfer constant Ktrans and EES blood volume ve are estimated
Temporal and spatial resolution trade-offs
Pre-contrast
Pre-contrast
T=0
T=15’
T=30’
Post-contrast
T=1’45”
T=2’45”
T=3’45”
•  High temporal resolution (~15 sec)
•  Low temporal resolution (~4 min)
MR Image Formation
2DFT
ky
y
kx
ky
k-space
Scan Time = (Nkx) x (Nky) x (Nkz) x (TR)
x
kx
(Navg)
from www.fmrib.ox.ac.uk/members/karla/
k-space
Image
Full-FOV,
high-res
Full sampling
Reduce
kmax
Increase Δk
2DFT
Full-FOV,
low-res:
blurred
Low-FOV,
high-res:
may be
aliased
from www.fmrib.ox.ac.uk/members/karla/
Empiric quantitative approaches
Signal Intensity
Signal Intensity versus Time
90-second temporal resolution
200
180
160
140
120
100
80
60
40
20
0
Tumor ROI 1
AUC
Tumor ROI 2
Normal
0
100
200
300
400
500
Time (seconds)
TTP = 90 sec
SER = SIearly - SIbaseline
SIlate - SIbaseline
• 
Temporal resolution ~ 1 minute (higher spatial resolution obtained)
• 
No baseline T1 or AIF measured
• 
Empiric parameters measured: Area under the curve (AUC), signal
enhancement ratio (SER), time-to-peak enhancement (TTP), etc
Measuring tumor response by MRI
Pre-treatment
Complete response
(Volume change = 100%)
Partial response
(Volume change = 69%)
Progressive disease
(Volume change = -178%)
Post-treatment
I-SPY SCHEMA
CALGB 150007/ACRIN 6657
Anthracycline
Clinical
Study
MRI
Taxane
Surgery
MRI
Core
Core
biopsy biopsy
MRI
MRI
3-time point method using the signal
enhancement ratio (SER)
baseline
early (t1) late (t1)
S1
S2
S
S0
t0
t1
t2
S0
S1
S2
1.3
Washout
1.0
SER>1.1
PE =
Plateau
0
0.9≤SER≤1.1
SER =
SER map
Gradual
SER<0.9
•  Morphologic pattern and
BIRADS-MRI classifications
•  Tumor diameter
•  Functional tumor volume
•  Microvascular parameters
(PE, SER)
Pre-treatment
Early treatment
Inter-regimen
Pre-surgery
Volume = 57.08 cc
Volume = 14.20 cc
Volume = 0.20 cc
Volume = 0.03 cc
Imaging results from I-SPY 1
Predictor Variable
pCR = 0/1
OR
p-value
Clin Size2/Clin Size1
1.07
0.924
Log(LD2/LD1)
8.67
0.054
Log(Vol2/Vol1)
19.81
<0.0001
0.72
0.650
Peak SER2/Peak SER1
Response to Therapy is Associated with
Better Relapse Free Survival
pCR is a Better Predictor by Subtype
ISPY-2 Adaptive Trial Design
AC
(4 cycles)
Paclitaxel *
(12 weekly cycles)
Screening
R
A
N
D
O
M
I
Z
E
O
N
S
T
U
D
Y
MRI
Biopsy
Blood Draw
MUGA/ECHO
CT/PET
Paclitaxel* +
Investigational Agent A
(12 weekly cycles)
U
AC
(4 cycles)
R
G
Paclitaxel* +
Investigational Agent B
(12 weekly cycles)
MRI
Biopsy
Blood Draw
Consent #2
Treatment Consent
S
E
AC
(4 cycles)
MRI
Blood Draw
R
MRI
Blood Draw
* HER2 positive participants will also receive Trastuzumab. An
investigational agent may be used instead of Trastuzumab.
Opportunity to evaluate imaging biomarkers
Y
Tissue
•  Ductal carcinoma in situ (DCIS) is a pre-invasive
form of breast cancer with excellent prognosis.
•  Research questions:
  How well does MRI detect DCIS?
  Can MRI help improve breast-conservation outcomes for
DCIS?
  Can functional MRI techniques (DCE, DWI, ASL)
improve ability to distinguish between benign
proliferative disease, DCIS and invasive breast cancer?
  Can MRI be used to measure the effects of hormonal
treatment for DCIS? (pending CALGB trial; PI: S.
Hwang)
Diffusion-weighted MRI
•  Diffusion-weighted MRI is sensitive to the
Contrast-enhanced
T1-weighted
movement of water in tissue and can be a
relative measure of tissue cellularity.
•  Multiple images with different diffusion
weighting are acquired, and used to
compute a map of the Apparent Diffusion
Coefficient (ADC).
ADC Map
a
Tumor
b
c
Apparent Diffusion
Coefficient (ADC) is computed
from 2 or more diffusionweighted MR images.
Tumor ADC:
1.22 x10-3 mm2/s
‘Normal’ ADC:
1.90 x10-3 mm2/s
d
Tumor
ADC gives a relative measure
of water diffusion and reflects
tissue cellularity
Breast ADC response to chemotherapy
Normal Tissue
Tumor
Tumor ADC vs Treatment
Patient
1
2
1.8
2
1.8
1.6
3
4
1.4
5
1.2
6
1
7
0.8
8
0.6
9
0.4
10
11
0.2
12
0
0
1
2
3
4
Cycles of Chemotherapy
↑ADC in tumors
Average increase of:
10% after first cycle of chemo (p=.003)
14% after 4 cycles (p=.05, Paired t-Test)
13
ADC (x10-3 mm2/s)
2
ADC (x10-3 mm2/s)
Normal ADC vs Treatment
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0
1
2
3
4
Cycles of Chemotherapy
↓ADC in normal tissue
Average decrease of:
4% after first cycle of chemo (p=.24)
18% after 4 cycles (p=.002, Paired t-Test)
High resolution DWI to assess
tumor heterogeneity
standard FOV, b=0
standard FOV, b=600
standard FOV, ADC
rFOV, b=0
rFOV, b=600
rFOV, ADC
3.13x3.13x3 mm 1.09x1.09x4 mm Lisa Singer, PhD, UCSF High-resolution DWI for response assessment
Pre-­‐chemotherapy Post 1-­‐cycle Lisa Singer, PhD, UCSF Choline measurement by 1H MR Spectroscopy 18
16
residual water 14
cho 12
10
No lipid 8
6
4
10
8
6
4
2
ppm
0
-2
-4
Choline as a marker of early response"
1H
Study by Meisamy et
al found change in
[tCho] at 24 hours
was significantly
correlated with final
change in tumor size
and was significantly
different between
responders and nonresponders
MRS
Cho
6
4
2
Frequency (ppm)
0
Meisamy et al. Radiology 2004
Positron Emission Tomography (PET)
•  Uses an injected positron-emitting radiopharmaceutical (FDGtracer of glucose metabolism)
•  PET camera detects annihilation photon event
•  Image signal intensity reflects tracer concentration; quantified
by standardized uptake value (SUV)
FDG PET to Monitor Response to
Neo-Adjuvant Chemotherapy
Pathologic CR
Pre-Rx"
2 months Rx"
4 months Rx"
breast!
lesion!
axillary!
node!
(axial slices)
(Mankoff, UW/SCCA)
Combined breast MRI and FDG PET
for assessing neoadjuvant response
(Semple, Annals Oncol, 17: 1393, 2006)
Diffuse Optical Spectroscopy (DOS)
Source Light
Detected Light
Pulsed light travels in waves
Tromberg, Neoplasia, 2002
Phase and amplitude
change based on
absorption and scattering
•  Based on frequency domain diffuse optical spectroscopy
•  Scans regions of the breast at depth of 1 to 2 centimeters
•  Highly sensitive to subtle physiological changes in breast tissue, such as
cellular metabolism and increased blood vessel density
* Cerussi A. et al, J. Biomedical Optics, 7(1):60-70, 2002
**Shah N. et all, PNAS 2001
C. Klifa, UCSF
Diffuse Optical Spectroscopic Imaging (DOSI)
Treatment response assessment
by combined MRI/DOS
Post 1 cycle
Post 4 cycles
Contrastenhanced
MRI
80
70
Water Content (%)
Post 4 Chemo
60
Post 1 Chemo
50
40
30
FWHM =3.0cm
FWHM =5.0cm
20
10
1
2
3
4
5
6
7
8
9
10
11
Position (1.0cm)
Optical Line Scan
Shah et al., Radiology, 1995
Hylton Lab
Catherine Klifa
Lisa Wilmes
David Newitt
Lisa Singer
Rebekah McLaughlin
Margarita Watkins
Sachiko Suzuki
Krysta Banfield
Evelyn Proctor
Sheye Aliu
Miyoung Li
Radiology
Bonnie Joe
Belinda Chang
Dorota Wisner
Chris Flowers
John Shepherd
Sentinelle Medical
Cameron Piron
Gal Sela
Michelle McPherson
Neil Witcomb
Surgery, Oncology,
Cancer Center
Laura Esserman
Shelly Hwang
Laura Van t’Veer
Catherine Park
Meredith Buxton
Sarah Davis
Julia Lyandres
Hope Rugo
Mark Moasser
Funding: NIH NCI, ACRIN, US Army BCRP, Komen for the Cure