Imaging Women with Dense Breasts - University of Virginia

Objectives
Imaging Women with Dense Breasts:
MRI, Tomosynthesis, and US
• Describe the potential added benefit of MR,
tomosyntheis, and US for women with
dense tissue based on prior studies
• Discuss the negative aspects of ancillary
screening for women with dense tissue
Jennifer A. Harvey, M.D., FACR
Professor of Radiology
University of Virginia
Managing Women with Dense
Breast Tissue
• Annual digital
mammography, age
40 and older
• MRI?
• Ultrasound?
• Tomosynthesis?
• Other ancillary
screening?
Perceived Risk of Breast Cancer
• 72% of average risk women accurately
perceive their risk of breast cancer
– 28% overestimate risk
• Only 43% of high risk women accurately
perceive their risk
– 57% underestimate risk
Haas JS. J Women’s Health. 2005
Breast Cancer Risk Factors
Personal
• Parity
• Age at
menarche
• Age at
menopause
• Hormone
therapy
• Obesity
Breast Disease
• LCIS
• ALH
• ADH
• DCIS
• Breast density
• Radiation
exposure
Genetic
• BRCA carrier
• Li-Fraumeni
syndrome
• Cowden
Syndrome
• Bannayan-
Riley-
Ruvalcaba
Breast Cancer Risk Stratification
Lifetime Risk
Average Risk < 15%
Associated Risk Factors
Moderate Risk 15 – 20% • LCIS, ADH, ALH
• Prior breast cancer
• Dense breast tissue
• Intermediate family history
High Risk > 20-25% • Hereditary Breast and Ovarian
Cancer (HBOC) syndrome (e.g.
BRCA)
• Other genetic mutations
• Chest Radiation at a young age
• Combination of risk factors

ACS: Annual Screening MRI
Genetic Risk in the Population
• BRCA mutation
• 1 st degree relative of BRCA carrier, but untested
• Women with >20 - 25% lifetime risk by BRCAPro
or other model dependent on family hx
• Li-Fraumeni, Cowden, and Bannayan-Riley-
Ruvalcaba syndromes and 1 st degree relatives
• Radiation to chest between age 10 and 30 years
Saslow D. CA Cancer 2007
0.5%
Genetic
Susceptibility
Not Likely BRCA
or Other Known
Mutation Carrier
Genetic Syndromes
Genetics and Cancer
Autosomal
Dominant
Lifetime
Risk
Other Cancers
BRCA1 X 55-85% Ovary, liver, testis (male)
BRCA2 X 25-60% Male breast, pancreas
Li-Fraumeni X 60-90% Leukemia, sarcoma, adrenal
Tumor
Suppressor
Genes
Normal Breast Tissue
DNA Damage: Hit 1
Hormones,
alcohol use,
environmental
factors?
Cowden
Syndrome
Bannayan-
Riley-
Ruvalcaba
X
X
30-50% Thyroid (and B9),
meningioma
30-50% Thyroid (also colon polyps,
lipomas, macrocephaly,
developmental disorders)
DNA Damage: Hit 10
Cancer
Cancer Risk by Site for BRCA Carriers
Consider Genetic Counseling/Testing
• Breast cancer in two or more close relatives
• Family with breast cancer that is premenopausal,
bilateral, or multiple family members
• Ovarian cancer
• Male breast cancer
• Ashkenazi Jewish ancestry and family history of
breast and/or ovarian cancer
• Personal diagnosis of breast cancer before age 30
From Risch et al. JNCI 2006

The Quick Genetic Risk Screen
• Is there a family history of
breast cancer?
– Young at onset
– Bilateral
– Multiple relatives
– Male breast cancer
• Ashkenazi Jewish ancestry
• Are there other cancers in
your family?
Radiation Exposure at Young Age
• Hodgkins Disease treated with mantle radiation (RR
5.2)
• Risk increases beginning 7-8 years after treatment
• Risk peaks at about 15 years post treatment
• Younger age at treatment = higher risk
• Childrens Oncology Group
– Annual mammography and MR beginning at age 25
or 8 years after radiation treatment (the later of the
two) if >20 Gy to the chest/mediastinum
Clemons M. Cancer Treat Rev 2000
Goss PE. J Clin Onc 1998
HR Screening
• 48 yo, lifetime risk
37%
T1 Post
High Risk MRI Screening Results
• 9 trials to date
• 4485 women with 192 cancers
DCIS, High Grade
MIP
• 20 – 60 Cancers/1000 women screened
– compared to 3-7/1000 with mammography
• Mean tumor size 0.7-2.0 cm
• 65-100% node negative
Screening of High Risk Women by Modality
• 9 Trials
• 192 cancers
• 4485 women
Adapted from Berg WA.
AJR 2009.
Cancers %
Detected
Mammo 70 36%
US 34/86 40%
Mammo + US 45/86 52%
MRI 155 81%
Mammo + MRI 178 93%
Breast Cancer Risk Stratification
Lifetime Risk
Average Risk < 15%
Associated Risk Factors
Moderate Risk 15 – 20% • LCIS, ADH, ALH
• Prior breast cancer
• Dense breast tissue
• Intermediate family history
High Risk > 20-25% • Hereditary Breast and Ovarian
Cancer (HBOC) syndrome (e.g.
BRCA)
• Other genetic mutations
• Chest Radiation at a young age
• Combination of risk factors

Breast Cancer Risk Factors
Personal
• Parity
• Age at
menarche
Gail • Age Model at
menopause
• Hormone
therapy
• Obesity
Breast Disease
• LCIS
Tyrer-Cuzick • ALH Model
• ADH
• DCIS
• Breast density
• Radiation
exposure
Genetic
• BRCA carrier
• Li-Fraumeni
syndrome
• Cowden Claus,
BRCA Syndrome Pro,
BOADICEA
Model
Gail Model
http://www.cancer.gov/bcrisktool/
Tyrer-
Cuzick
Model
Automated Reporting
http://www.ems-trials.org/riskevaluator/
jackcuzick@cancer.org.uk
Accuracy of Risk Models
Model Evaluates Accuracy
Gail
Claus/BRCA Pro/
BOADICEA
Personal risk factors
(age, parity, etc)
0.48
Family history 0.56
Tyrer-Cuzick Comprehensive 0.81
Models that Incorporate Breast
Density Improve Accuracy
• Breast Cancer
Screening
Consortium
(BCSC) (Barlow
WE. JNCI,
2006).
• BCDDP (Chen J.
JNCI 2006)

Breast Cancer Risk Factors
Personal
• Parity
• Age at
menarche
Gail • Age Model at
menopause
• Hormone
therapy
• Obesity
Breast Disease
• LCIS
Tyrer-Cuzick • ALH Model
• ADH
• DCIS
• Breast density
• Radiation
exposure
Genetic
• BRCA carrier
• Li-Fraumeni
syndrome
• Cowden Claus,
BRCA Syndrome Pro,
BOADICEA
Model
ACS Guidelines for Screening MRI
• Insufficient evidence to recommend for or against
MRI screening
– Lifetime risk 15-20% by BRCAPRO or other
model based on family history
– LCIS or ALH
– ADH
– Heterogeneously or extremely dense
breast tissue on mammography
– Personal history of breast cancer, including
DCIS
Supplemental Screening
Breast Density: Impact on Mammography
• Anatomic
– Mammography
– Tomosynthesis
– US
– CT
• Functional
– MRI
– Diffusion Weighted
Imaging
– Gamma imaging
– PET
87% 63%
Sensitivity
97% 89%
Specificity
Carney PA. Ann Int Med 2003
Digital Mammography
• ACRIN DMIST
• Digital is more
sensitive than filmscreen
for dense tissue
independent of age
and menopausal status
Tomosynthesis
• Improves specificity by decreasing recall
rate
• May improve sensitivity, probably more for
heterogeneous than extremely dense tissue
Pisano Ed. NEJM, 2005

Digital Breast Tomosynthesis
Tomosynthesis
• Angled images
• Reformatted as “slices”
• Recall reduction 30-40%
• May increase cancer
detection
• Increased radiation dose
by 50%
Poplack SP. AJR 2007
Tomosynthesis
Screening US
ACRIN 6666/Avon trial
• 2662 moderate and high-risk
women had annual mammo +
screening US, over 3 years
• 111 cancers (110 women)
• Additional cancers by US
– 5.3 CA/1000 Year 1
– 3.7 CA/1000 Y 2 & 3
• Additional 14.7 CA/1000 by MR
Berg WA. JAMA 2008
Berg WA. JAMA 2012
US has Low Specificity
More Connecticut Experience
• 8.9% PPV for US lesions
• Women having screening mammogram and
US
– 10% will have a biopsy
– 10-20% will have BI-RADS 3
– 2.8% due to mammo finding
– 7.8% due to US (7.0% for incident)
• Six CT practices with
12 practice sites
• 72,030 screening
mammograms
– 29,532 dense (41%)
– 8,647 had screening
US (29% of dense)
Weigert J. Breast J 2012
• Outcome
– BI-RADS 1 or 2: 86%
– BI-RADS 3: 9%
– BI-RADS 4 or 5: 5%

More Connecticut Experience
Outcome by Site
• 429 Biopsies
recommended
• 11 lost to f/u
• 28 (25) Cancers
– Age 42-78 y
– Mean size 1.9 cm,
(range 4mm to 8 cm)
– 21 invasive
– Sensitivity 96.6%
– PPV 6.7% (5.6%)
– NPV 99.9%
– 3.25 CA/1000 (2.9)
Cystic Lesions
Simple Cysts
Simple
Clustered
microcysts
BI-RADS 2
• Peak between age 35-50
• ACRIN 6666
– 47% of participants over 3 years
(48% bilateral)
• 39% of postmenopausal
• 65% of premenopausal
Complicated
Complex Mass
Berg WA. Rad Clinics NA 2010
Clustered Microcysts
Clustered Microcysts
Study
Total
Lesions
Number Malignant (%)
Berg, 2005 79 0 (0%)
Chang, 2007 15 0 (0%)
Daly, 2008 15 0 (0%)
Berg, 2010 (ACRIN 6666) 104 1 (0.8%)

Clustered Microcysts:
When to Consider Biopsy
• Thick or nodular
septations
• Solid component
Complicated Cysts
Complicated Cysts
Complicated Cysts
Study Total Lesions Number Malignant (%)
Kolb, 1998 126 0 (0%)
Venta, 1999 308 1 (0.3%)
Buchberger, 1999 133 0 (0%)
Berg, 2003 38 0 (0%)
Chang, 2007 35 0 (0%)
Daly, 2008 228 1 (0.4%)
Berg, 2010 (ACRIN 6666) 475 2 (0.4%)
Berg WA. Rad Clinics NA 2010
• ACRIN 6666 protocol
– If within a background of
simple cysts, then BI-RADS
2
– Solitary complicated cyst on
first US, then BI-RADS 3
– New or enlarging
complicated cyst, then BI-
RADS 4 with aspiration
Berg WA. Rad Clinics NA 2010
Types of Complex Masses
Thick Walled Cyst + thick septations
Intracystic Mass
Mixed Cystic and Solid
Complex Mass
Study Total Lesions Number Malignant (%)
Intracystic Mass
Omori, 1993 21 10 (42%)
Berg, 2003 18 4 (22%)
Tea, 2009 19 4 (21%
Thick Walled
Berg, 2003 23 7 (30%)
Chang, 2007 27 7 (26%)
Tea, 2009 36 11 (31%)
Complex Mass
Omori, 1993 35 14 (40%)
Berg, 2003 38 7 (18%)
Chang, 2007 53 33 (62%)
Berg WA. Rad Clinics NA 2010

Solid Mass with Benign Features
• Benign
– Round or oval shape
– Parallel orientation
– Circumscribed margin
– Abrupt interface
– Homogeneous echo pattern
– Posterior acoustic
enhancement
– No suspicious features
2 3 4A
Study
Solid Breast Masses:
Benign Features on US
Palpable vs.
Non-palp
Total
Lesions
Number Malignant
(%)
Stavros, 1995 Both 426 2 (0.5%)
Graf, 2004 Palpable 157 0 (0%)
Mainiero,
2005
Both 148 1 (0.7%)
Graf, 2007 Non-palp 448 1 (0.2%)
Raza, 2008 Both 356 3 (0.8%)
Harvey, 2009 Palpable 375 1 (0.3%)
TOTAL 1910 8 (0.4%)
27 yo Bilateral Palp Lumps
Multiple Bilateral
Circumscribed Masses
Left 2:00
Right 9:00
Left 4:00
Right 11:00
BI-RADS 2
62 yo strong FH Solid Masses- When to Biopsy
• NEW or enlarging finding
on mammography
• Suspicious features
(margins, etc)
• Palpable??
• Older??

Automated Breast US (ABUS)
ABUS
• 239 lesions in 213
women scheduled for
surgical biopsy
(Chinese population)
• 85 cancers (35.6%)
HHUS ABUS
Sensitivity 90.6% 95.3%
Specificity 82.5% 80.5%
Accuracy 85.3% 85.8%
Wang HY. Eur J Rad 2012
PPV 74.0% 73.0%
ABUS
• 61 women scheduled to undergo US CNB
• 14 cancers in 13 women
• Three readers
– Only 8-11 cancers were detected with
ABUS
– Additional 4-10 false positives
Chang JM. Acta Radiol 2011
• 55 consecutive women scheduled for
diagnostic US
• Bilateral HH and ABUS
• Five readers, blinded to HHUS and
mammography outcome
• 145 lesions; ABUS 74-88% detected
ABUS: Cross Correlation with
HHUS
• 395 women, heterogeneously or extremely dense tissue
• Mammo + ABUS
• If recalled, then HHUS performed
– 110 lesions recalled due to abnormal ABUS
• 44 (40%) not reproducible
• 42 (38%) cysts
• 22 (20%) solid masses
• 2 (2%) duct ectasia
– 15 biopsies, 4 cancers
• 2 of 4 detected on ABUS, mammographically occult
Roquemore A. RSNA 2011
ABUS Dense Breasts
• 594 women
• 10 cancers in 7 women
– 3 cancers both mammo and ABUS
– 2 cancers mammo only
– 5 cancers ABUS only
Barclay-White B. RSNA 2011

Breast CT
Supplemental Screening
• Small studies to-date
• 79 women
• CT significantly better
for visualizing masses
• Mammo better for
calcifications
• Anatomic
– Mammography
– Tomosynthesis
– US
– CT
• Functional
– MRI
– Diffusion Weighted
Imaging
– Gamma imaging
– PET
Lindfors KK. Radiology 2008
MRI/Diffusion Weighted Imaging
Gamma Imaging
Fornasa F. J Clin Imag Sci 2011
LumaGEM MBI System
Contrast-Enhanced Mammography
• GammaMedica
– Single or Dual head
• Pixel size 1.6 x 1.6
mm
• Detector area 15 x 20
cm
www.gammamedica.com
www.gehealthcare.com

Screening Recall
US/Tomosynthesis
1
1
2
2
3
1: Mammo
MRI
So Many Modalities…
4
FP
Our Approach to Screening
UVa Mammography Project

Breast Cancer Risk Stratification
Lifetime
Risk
Cancer
risk
Low Risk ? 20-25% HG disease • Hereditary Breast and Ovarian Cancer (HBOC)
syndrome (e.g. BRCA)
MRI
• Other genetic mutations
• Chest Radiation at a young age
• Combination of risk factors
“The entire issue is complex,
but the thing I’m most proud
of is that we’re informing
women, so a discussion starts
from a great place. When
advocacy runs ahead of
science, it’s dangerous, but
when advocacy pushes
science, it’s good.”
ACR Bulliten
Conclusions
• Mammography is less able to detect cancer in dense
breast tissue, and has more false positive recalls
• Management of women with dense breast tissue is
currently annual, preferably digital, mammography
• 10% of women having screening mammo + US will have
a biopsy. PPV only 5-8%.
• Tomosynthesis may improve cancer detection for
heterogeneous tissue, with less false positives
• MRI is an alternative, but very expensive
• Risk-based screening strategies make sense, but not ready
for prime time