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Breast Density and Risk Stratification
Part 1: Risk Assessment in Breast Imaging
Emily F. Conant, M.D. Professor, Chief Breast Imaging
Department of RadiologyHospital of the University of Pennsylvania
Philadelphia, PACBIGComputational Breast
Imaging Group
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Outline
Introduction to Risk Assessment– Background and vocabulary– Models for the individual
Breast Density as a Risk Marker– Why?
Beyond Breast Density - “Breast Phenotyping”– What other imaging biomarkers can we use?
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How Should Women Be Screened?
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Breast Cancer Risk in 2014
Can we predict who will get breast cancer?
What “Evidence-Based” models are available to guide individualized care?
How can we begin to incorporate these tools in our practice today?
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BRCA1 carrier: “87% lifetime risk for breast cancer, 39-50% for ovarianDouble mastectomy reduces risk by 90-95%
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Personal Genomic Tests
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The Vocabulary of Risk…
Relative risk (RR):Number that tells you how much something, such as genetics, can change risk compared to the baseline risk.
RR is expressed as percentage decrease or percentage increase
Examples:– No change in risk with action, RR reduction is 0% – If action lowers risk by 30% compared to average risk, then action
reduces the RR by 30% (RR = 0.70)– If action triples risk, then the RR increases 300% (RR = 3.00)
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Prediction Models for Cancer
• Absolute Risk Assessment Models• Estimates probability developing cancer over defined period of time
• Genetic Susceptibility Risk Models• Estimates likelihood of detecting mutation in cancer susceptibility gene
in a given family or individual
• Cancer Outcome Risk Models• Prognostic- estimates likelihood of patient outcome, regardless of
treatment
• Predictive- estimates response to treatment
https://www.fredhutch.org/content/dam/public/labs-projects/PHS/Risksymposium2014/0910_what%20is%20risk%20prediction_freedman.ppt.
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Absolute Breast Cancer Risk Models
• NCI BCRAT “Gail” Model: (Gail et al. JNCI 1989)
• CASH “Claus: Model: (Claus et al. AJHG 1991)
• Group Health (Taplin et al. Cancer 1991)
• DevCan (Feuer et al. JNCI 1993)
• NHS (Rosner et al. JNCI 1996)
• BRCAPRO (Parmigiani/Berry, AJHG 1998)
• Jonker et al (CEBP 2003)
• IBIS (Tyrer/Cuzick et al. Stat Med 2004)
• BOADICEA (Antoniou et al, BJC 2004)
https://www.fredhutch.org/content/dam/public/labs-projects/PHS/Risksymposium2014/0910_what%20is%20risk%20prediction_freedman.ppt.
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0
10
20
30
40
50
60
70
80
90
100
2005 2006 2007 2008 2009 2010 2011 2012 2013
Submitted Awarded
Nu
mb
er o
f G
ran
ts
Fiscal Year
Number of Cancer Risk Prediction Grant Applications Submitted and Awarded
DCCPS (FY05 – FY13)
https://www.fredhutch.org/content/dam/public/labs-projects/PHS/Risksymposium2014/0910_what%20is%20risk%20prediction_freedman.ppt.
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Cumulative number of cancer risk and susceptibility prediction models
0
10
20
30
40
50
60
70
1983 to 2000 2001 to 2005 2006 to 2010 2011 to 2014
Breast
Colon
Lung
https://www.fredhutch.org/content/dam/public/labs-projects/PHS/Risksymposium2014/0910_what%20is%20ri%20prediction_freedman.ppt.
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How is “Absolute Risk” calculated?
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Epidemiologic Risk Factors
Relative Risk
Family hx breast cancerFirst-degree relativeSecond-degree relative
3.01.5
Age at menarche (<14 vs >14) 1.3
Age at menopause (55 vs <55) 1.5
Age at first live birth (>30 vs <30) 1.5
Benign breast diseaseBreast bxADH
1.54.0
Chest irradiation ? age of rad
HRT use 1.3
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Age and Breast Cancer Risk…
Age % Risk 1 in…
0-44 0.56 179
45-49 0.90 111
50-54 1.24 81
55-59 1.58 63
60-64 1.85 54
65-69 2.08 48
70-74 2.25 44
75-79 2.35 43
80-84 2.20 45
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What about BRCA1 and BRCA2?
BRCA 1 (1990) and BRCA2 (1994): • Genes that encode proteins that
bind to and help fix DNA breaks (tumor suppressor gene family)
If a faulty copy is inherited:• Damaged DNA isn’t repaired
properly increasing risk for cancers
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Increased risk of other cancers:Male breast cancer BRCA2>BRCA1
Pancreatic cancer BRCA2
Prostate cancer BRCA2
Melanoma BRCA2
Breast cancer: 60%-80%
Second primary breast cancer: 40%-50%
Ovarian cancer: 10-45% BRCA1>BRCA2
BRCA ½ Lifetime Risks
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What about the new PALB2?
PALB2 : “Partner /Localizer of BRCA2”• Makes protein that interacts with BRCA2
protein to mend broken strands of DNA• Belongs to family of genes FANC (ie.,
Fanconi anemia)
If a mutation is inherited:• Damaged DNA isn’t repaired properly
resulting in 2x increased in risk for cancers
http://ghr.nlm.nih.gov/gene/PALB2 accessed 8/17/14
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How many cancers are attributable to BRCA1/2?
Mutations are rare in general populations: 1/1000Therefore, explain very few of population cancers
Breast Cancers
BRCA1/2
family clusters
sporadic
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Relative Risk Factors
0
2
4
6
8
10
12
14
16
BRCA 1/2 insitu hx ADH+FHx ADH FHx HRT
Re
lati
ve R
isk
1-1
5
Courtesy of S. Domchek, M.D.
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Common risks more important in population…
0
5
10
15
20
25
BRCA1/2 insituhx ADH+FHx ADH FHx HRT
PercentAffected
Courtesy of S. Domchek, M.D.
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Breast Cancer Risk Assessment
NCI: Gail Model
Based on Patient Demographics • Age• Ethnicity• Age at first birth• Age at menopause• Age at first menarche• Family History – Number of First Degree
Relatives
• Works well at the population level
Only moderately discriminatory at the individual level (Az=0.58 )
1 Rockhill, JNCI 2001
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Example: Risk Assessment Using Gail Model
Classic Barbie, “born” in 1959, just had a stereotactic core biopsy
revealing ADH. The excision also showed ADH. Her mother, Mrs. Mattel,
had post menopausal breast cancer….
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Gail Breast Cancer Risk Assessment Model (http://cancer.gov/bcrisktool)
Risk Factor Category Relative Risk of IBC in
next 5 years
Age at menarche, y> 14
12-1312
1.00
1.101.21
No. of breast biopsies
Age at counseling, 50 y old
012
1.00
1.702.88
Age at counseling, 50 y old012
1.001.271.62
Age at first live birthNumber of 1° relatives
with breast cancer
< 20 years012
1.002.616.80
20-24 years012
1.242.685.78
25-29 years or nulliparous 012
1.552.764.91
30 012
1.932.834.17
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Baseline 5-yr risk Inv. BCA in percentages, by age and race
Baseline 5-year risk, %
Age in years Black White Hispanic
20-24 0.003 0.003 0.006
25-29 0.025 0.022 0.021
30-34 0.076 0.077 0.057
35-39 0.165 0.191 0.126
40-44 0.285 0.366 0.235
45-49 0.343 0.540 0.378
50-54 0.376 0.640 0.456
55-59 0.474 0.788 0.537
60-64 0.581 0.969 0.623
65-69 0.592 1.135 0.727
70-74 0.656 1.209 0.824
75-79 0.761 1.285 0.798
80-84 0.876 1.280 0.730
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Example: Using Gail Model
A 55-year-old white women
– Began menstruating at age 12 years, RR=1.10
– No children, 1 affected 1° relatives, RR=2.76
– One previous breast biopsy, RR=1.27
– Overall RR = 1.10 X 2.76 X 1.27= 3.86
Projected 5-yr risk IBC= 3.86 X 0.788 = 3.04%
Lifetime Risk (to 90 years) = 21.3%
Classic Barbie meets the risk levels to consider
tamoxifen tx and MR screening
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Side Effects of Tamoxifen?
Tamoxifen is a “SERM” (selective estrogen-receptor modifier)- binds to estrogen receptors preventing binding
– Shown to reduce the incidence of breast cancer by 50%-80% in high risk women (5-year risk of 1.67% or higher)
– Side effects 2-2.5x increased which include: cataracts, osteopenia,
stoke, PE, increased risk of endometrial and uterine cancer
Sestak I. Cancer Manag Res. 2014 Oct 17;6:423-30.
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Estimates of the total number of U.S. women eligible for tamoxifen chemoprevention Trial, by race and age
0
10
20
30
40
50
60
White
Black
Hispanic
35-39 40-49 50-59 60-69 70-79
Age
Pe
rce
nt
Freedman et al. JNCI 2003;95:526-32
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Tamoxifen Chemoprevention Eligibility and Positive Benefit/risk Index
0
10
20
30
40
50
60
35-39 40-49 50-59 60-69 70-78
% white women eligible for tamoxifen
% white women with a positive benefit/risk index for tamoxifen
AgeAge
Pe
rce
nt
Freedman et al. JNCI 2003;95:526-32
2.4 million women who could benefit from tamoxifen
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Graubard et al. CEBP 2010;19:2430-6
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Imaging Phenotypes
How can we use imaging data to improve risk assessment and help guide
personalized screening?
What’s all the fuss about “breast density”???
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What is “Breast Density”?
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NI PI P2 DY
Wolfe, 1976 AJR
Lowest risk Highest risk
Imaging in Risk Assessment
Wolfe’s Parenchymal Classifications
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Breast Density
BI-RADS 4th Edition BI-RADS 5th Edition1 - Almost Entirely Fatty (<25%) a – The breasts are almost entirely fatty
2 - Scattered Fibroglandular (25-50%) b- There are scattered areas of fibroglandulardensity
3 - Heterogeneously Dense (51-<75%) c – The breasts are heterogeneously dense, which may obscure small masses
4 - Extremely Dense (>75% ) d – The breasts are extremely dense, which lowers the sensitivity of mammography
New categories do not have % dictated so that category chosen may be based on mammographic “densest area”
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57% 31% 2%10%
Distribution of Breast Density: Univ of Penn
1 2 3 4
67% 33%
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Breast Density Categories
Data from 3,865,070 screening mammos from BCSC. (Ref: BI-RADS 5th Edition)
80%
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Women with >50% dense breasts are at a 3- to 5X greater risk for breast cancer than when density <25% 2
– Partially due to lower sensitivity found with increased density (masking)– Partially due to Biology - dense tissue is rich in epithelium/stroma
Boyd 1995, 2Tice Ann Intern Med. 2008
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Relative Risk Factors
0
2
4
6
8
10
12
14
16
BRCA 1/2 hx in situ ADH + FHx ADH FHx HRT >50% dense
Re
lati
ve R
isk
1-1
5
Risk Factor
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Common risks may be more important in population…
0
5
10
15
20
25
30
35
40
45
BRCA 1/2 hx in situ ADH + FHx ADH FHx HRT >50% dense
Pe
rce
nt
Aff
ect
ed
Risk Factor
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Risk Factors (i.e.,
reproductive, anthropometric,
dietary)
Genetics (including
determinants of mammo density)
Hormones and growth factors
Epithelial-cell stromal-cell proliferation
Dense Breast Tissue
Breast Cancer
Biological Hypothesis:
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Biological Hypothesis:
Breast tissue is estrogen rich due to Aromatase:
Overexpression of aromatase in mouse models has led to the formation of breast tumors
Androgens(androstenedioneand testosterone)
Estrogens(estrone and estradiol)
Aromatase Enzyme(a cytochrome P450 enzyme)
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Aromatase Immunoreactivity Differs Between Dense and Non-dense Tissue
Vachon C.M. et al. Breast Cancer Res Treat (2011) 125:243–252
Ghosh K. et al. Breast Cancer Res Treat (2012) 131:267–275
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Boyd et al., NEJM 2007
Density as a Risk Factor
Mammographic dense tissue, percent dense area (PD) is one of
strongest risk factors for breast cancer, greater even than family history.
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Kerlikowske NEJM 2007
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How does Breast Density relate to other Risk Factors?
Breast Density decreases:
– With increasing weight and age, parity, and menopause
Breast Density increases:
– With birth weight and increasing height
Other links?
– Menstrual hx and reproductive risk factors account for only 20-30% variance in BD in population• Remainder of variance most likely due to genetic variants…
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Additional Facts about Breast Density
Breast cancers arising in areas of high breast density are associated with factors associated with poorer prognosis:
– Large size, high histologic grade, lymph-vasc inv. and advanced stage
• breast density associated with higher local recurrence rate
• breast density associated with risk of 2nd breast cancer
While findings suggest that breast density is associated with poor survival, 2 large retrospective studies have not shown this…
Huo CW. Breast Cancer Res Treat (2014) 144:479–502
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HRT increases
Taxoxifenreduces
Parity reduces
Huo CW. Breast Cancer Res Treat (2014) 144:479–502
TGF-β signaling
Collagen content
CD-36 expression
ROCK1 activity
Breast Cancer
Risk
Breast Cancer progression,
mets/recurrence
Breast Density
Amoeboid-like cell activity
Cell proliferationand signaling
ECM stiffness
Increased cell migration
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Why use imaging phenotypes in Risk Assessment?
“The Two-part Risk”:
• The individual woman’s risk for breast cancer– Increase risk of local and locoregional recurrence
• But not definitely increased mortality or distant metastases…
• To identify the risk for false-positive and false-negative (interval cancers) outcomes of screening– Unnecessary call-backs, rad dose, bxs and missed cancer
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Next – How do we measure Breast Density???