breast density and risk stratification - arrs...breast density and risk stratification part 1: risk...
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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
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?
How Should Women Be Screened?
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?
BRCA1 carrier: “87% lifetime risk for breast cancer, 39-50% for ovarianDouble mastectomy reduces risk by 90-95%
Personal Genomic Tests
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)
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.
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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2005 2006 2007 2008 2009 2010 2011 2012 2013
Submitted Awarded
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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.
Cumulative number of cancer risk and susceptibility prediction models
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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.
How is “Absolute Risk” calculated?
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
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
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
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
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
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
Relative Risk Factors
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BRCA 1/2 insitu hx ADH+FHx ADH FHx HRT
Re
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Courtesy of S. Domchek, M.D.
Common risks more important in population…
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BRCA1/2 insituhx ADH+FHx ADH FHx HRT
PercentAffected
Courtesy of S. Domchek, M.D.
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
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….
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
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
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
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.
Estimates of the total number of U.S. women eligible for tamoxifen chemoprevention Trial, by race and age
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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
Tamoxifen Chemoprevention Eligibility and Positive Benefit/risk Index
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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
Graubard et al. CEBP 2010;19:2430-6
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”???
What is “Breast Density”?
NI PI P2 DY
Wolfe, 1976 AJR
Lowest risk Highest risk
Imaging in Risk Assessment
Wolfe’s Parenchymal Classifications
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”
57% 31% 2%10%
Distribution of Breast Density: Univ of Penn
1 2 3 4
67% 33%
Breast Density Categories
Data from 3,865,070 screening mammos from BCSC. (Ref: BI-RADS 5th Edition)
80%
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
Relative Risk Factors
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BRCA 1/2 hx in situ ADH + FHx ADH FHx HRT >50% dense
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Risk Factor
Common risks may be more important in population…
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BRCA 1/2 hx in situ ADH + FHx ADH FHx HRT >50% dense
Pe
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Aff
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Risk Factor
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:
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)
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
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.
Kerlikowske NEJM 2007
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…
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
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
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
Next – How do we measure Breast Density???