a breast cancer risk factor and imaging challenge...1976 may: 37(5) 2486-92 mccormack, va et al,...

Dense Breasts

A Breast Cancer Risk Factor

and Imaging Challenge

Renee Pinsky, MD University of Michigan Department of Radiology Division of Breast Imaging

All slides are property of presenter. Do not duplicate any portion without express written consent.

No Disclosures


“ARE YOU DENSE?”

• QUIZ:

– a. Breast Imaging question regarding the

mammographic appearance of breast

tissue.

– b. Current legislative issue in many states.

– c. A teenager‟s disrespectful response

when you do not know how to download an

app to your smart phone.

– d. a and b


ARE YOU DENSE?

• Nancy Capello founder

– 2004 dx‟d stage 3c breast cancer

– Normal mammogram 2 months earlier

– Found out after treatment that she

had dense breasts

– Founded organization


http://areyoudenseadvocacy.org/


• Mission Statement: „dedicated to

informing the public about dense

breast tissue and its significance for

the early detection of breast

cancer.‟


http://www.facebook.com/pages/ARE-YOU-DENSE-INC/116749895026438?v=wall&ref=ts

http://www.facebook.com/pages/ARE-YOU-DENSE-INC/116749895026438?v=wall&ref=ts

https://twitter.com/

https://twitter.com/



Why are we interested?

• An average woman‟s lifetime risk

for developing breast cancer is

1: 8


INCIDENCE

• American Cancer Society estimate

for 2012 was 229,060 new cases of

breast cancer in US

– 3/4 Invasive cancer

– 1/4 Ductal Carcinoma In Situ

www.cancer.org


http://www.cancer.org/


MICHIGAN Incidence

• NCI State Cancer Profiles (2005-

2009)

– 120 per 100,000 female

population/year

– 6,993 women / year

– ↓ 0.7%/year – not significant

http://statecancerprofiles.cancer.gov accessed February 23, 2013


http://statecancerprofiles.cancer.gov/

http://statecancerprofiles.cancer.gov/

INCIDENCE

• Incidence drop in early

2000‟s felt to be related to

WHI Report and decreased

HRT use.

• Rate relatively steady for last

10 years.


MORTALITY

• Estimated U.S. breast cancer

deaths in 2012 is 39,920

www.cancer.org




SEER 2011

ACS 2012

-2.2% / year

1990-2008

-35%

Screening and

Treatment

USA Female Breast Cancer

Mortality Rate


WHO IS AT RISK?

• 99 % of breast cancers develop in

women

– Median age 61 years

• 1 % in men


Major Risk Factors for Breast Cancer

• Increasing age (age 25 = 1 in 19,608 vs. age 45 = 1 in 93)

• Family history (especially first degree relatives and premenopausal)

• Personal history

• Prior breast biopsy with atypia or LCIS

• Genetic mutations BRCA 1 and 2 (5-10% of all cases. )

• Thoracic Radiation Therapy (age < 30)

• Dense Breasts


Other Risk Factors

• Early menarche (<12yo)

• Late menopause (> 52/55yo)

• Late age at first full term pregnancy (> 30yo)

• Nulliparity

• Post-menopausal obesity

• Hormone replacement therapy – Estrogen + Progesterone implicated in Women‟s Health

Initiative Study (2003)


Mammography Screening

• Only modality with many years of

multiple large randomized clinical

trials demonstrating mortality

benefit.


Mammography

• Diminished sensitivity in dense

breasts compare to fatty.

• Despite this it has been proven to

save lives

• **The breast density issue should

NOT discourage women from

getting mammograms**


What is Breast density?

• Assessed on mammography

• Different X-ray absorption of fibrous

and glandular tissue vs fat.

• Density is the relative amount of

white (FG) vs black/gray (fat)


How is breast density measured

and reported?

• Visual estimation of density

– Wolfe‟s Classification (1976)

• Hutzel Hospital, Detroit



and reported?

• Wolfe’s Classification-Qualitative • N1-mostly fat

• P1- <¼ of breast is dense

• P2- >¼ of breast is dense

• DY- marked mammary dysplasia

– 37x Greater incidence of cancer in

DY vs N1 group

Wolfe JN Breast Patterns as a Index of risk for Developing Breast Cancer. AJR 1976:126:1130-1137



and reported?

• Visual estimation of density

– Wolfe‟s Classification (1976)

– BI-RADS

• Computer Assisted

– MDEST (Mammographic Density

ESTimation)

– Cumulus®


BI-RADS (Breast Imaging Reporting and Data System)

• Qualitative – 1- Almost entirely fat

– 2- Scattered fibroglandular densities

– 3- Heterogeneously dense

– 4- Extremely dense

American College of Radiology. Breast imaging Reporting and Data System (BI-RADS) 4th Ed. Reston, VA: American

College of Radiology: 2003

Ciatto et al The Breast vol 21, issue 4 August 2012, Pages 503–506



BI-RADS

1 2 3 4


BI-RADS

• Quantitative

– 1- Almost entirely fat <25% dense

– 2- Scattered fibroglandular densities 25-50%

– 3- Heterogeneously dense 50-75%

– 4- Extremely dense >75%

American College of Radiology. Breast imaging Reporting and Data System (BI-RADS) 4th Ed. Reston, VA: American College of Radiology: 2003



How good are we at

estimating density? • 706 mammograms

• Assessed inter-observer agreement for

cancer detection and breast density using BI-

RADS

• Observed agreement-75%

• Agreement expected by chance-39%

• Κ=0.59 (0.55-0.62)

– Moderate agreement

Kerlikowske 1998 JNCI


BI-RADS • Subjective

• Moderate reproducibility

• Qualitative > Quantitative

• More reliable in the lowest and

highest density. (Cat 1 and 4)


Example of cranio-caudal image mammographic density readings in the 2-D

threshold percent density and the volumetric Standard Mammographic Form

methods.

Aitken Z et al. Screen Film Mammographic Density and Breast Cancer Risk:

A Comparison of the Volumetric Standard Mammographic Form and the

Interactive Threshold Measurement Methods Cancer Epidemiol Biomarkers

Prev 2010;19:418-428

2-D vs. 3-D


Computerized methods

• Aitkin 2010

– 367 cancers/661 controls

– Compared % density 2D semi automated

system with 3D fully automated system

– % density 2D method better at predicting

risk of cancer.


Density measurements

• No perfect measure yet

• BIRADS

– Current clinical standard

– Subjective

• Automated systems not ready for

the clinic


BIRADS breast

density† # of women %

1 57,961 10

2 259,018 44

3 216,395 37

4 53,995 9

Adapted from Breast Cancer Risk by Breast Density, Menopause, and Postmenopausal Hormone

Therapy Use, Kerlikowske K. et al

J Clin Onc August 20, 2010 vol. 28 no. 24 3830-3837

587,369 women

>1 million mammo exams

Looking at 5 year breast cancer risk

Distribution of Breast Density


http://jco.ascopubs.org/content/28/24/3830/T1.expansion.html

http://jco.ascopubs.org/content/28/24/3830/T1.expansion.html

Breast Density

Scattered

densities Heterogeneously

Dense

Predominantly

fatty

Extremely

Dense

# of

women

Breast Density


Density and Breast Cancer Risk

• MASKING- Dense tissue hiding a

cancer on a mammogram


Palpable left breast mass

36 years old

Heterogeneously dense

RT LT



• Intrinsic increased risk of Cancer



• Wolfe 1976 37x risk

• McCormack 2006 4-6x risk – Meta analysis

• 11 studies

• >14,000 cases

Wolfe, JN Risk for Breast Cancer Development Determined by Mammographic Parenchymal Pattern. Cancer

1976 May: 37(5) 2486-92

McCormack, VA et al, Breast Density and Parenchymal Patterns as Markers of Breast Cancer Risk. Cancer

Epidem Biomarkers Prev 2006; 15:1159-1169


Association of Density classifications with breast cancer risk in general (incidence and prevalence)

McCormack V A , and dos Santos Silva I Cancer Epidemiol

Biomarkers Prev 2006;15:1159-1169

©2006 by American Association for Cancer Research

Relative risk



• Wolfe 1976 37x risk

• McCormack 2006 4-6x risk

• Boyd 2007 4.7 odds ratio – Risk >75% dense vs < 10% dense

Boyd NF, Mammographic Density and the Risk and Detection of Breast Cancer N Engl J Med 356;3January 18,2007


So far

• What is breast density

• How is it measured

• Importance in breast cancer risk

– Extremely dense breasts- highest risk


What is being done with this

information?


Breast Density

• Imaging

• Patient Counseling

• Patient demand

• Legislation


Breast Imaging

• Digital Mammography

– X ray image converted into an

electronic signal > projected on

screen > manipulated

– 85% of units in USA are digital


Breast Imaging


– DMIST Trial- 2005

• ~43,000 women/33 centers/2 years

• Accuracy- Film Screen vs Digital

Pisano,ED et al, Diagnostic Performance of Digital vs Film Mammography for Breast Cancer Screening

N Engl J Med 2005; 353:1773-83


Breast Imaging


– DMIST Trial

• Accuracy higher for digital imaging

–Under age 50

–Dense breasts (>50% dense)

–Pre or peri-menopausal


Film Screen Digital


Supplemental Screening

• In addition to mammography!


Breast Ultrasound

• Hand held US

– Inexpensive

– Available

– User dependent

– Time consuming


Screening US

• Kolb 2002- 5,712 women/dense

breasts

– Screening Mammogram

– Screening hand held US

– PE


Screening US

• Kolb: Cancers in dense breasts-

Sensitivity

– Mammo alone-64%

– US alone- 37%

– PE alone- 28%

– Mammo + US- 97.3%

– Mammo + PE- 74.7%

• P< .001

– False + approx 5%


Screening US

• ACRIN 666

– Screening mammogram

– Screening US

– 2637 Women

• High risk AND >50% dense

• Based on personal hx, previous high risk

biopsy, Gail model

Berg WA, et al, Combined Screening With Ultrasound and Mammography vs

Mammography Alone in Women at Elevated Risk of Breast Cancer JAMA, 2008;

299, 2151-2163


Screening US

• ACRIN 666

– 4.2 additional cancers/1000 women

supplemental yield by adding US

Berg WA, et al, Combined Screening With Ultrasound and Mammography vs

Mammography Alone in Women at Elevated Risk of Breast Cancer JAMA, 2008;

299, 2151-2163


Screening US

False + PPV

Mammo alone 4.4 22.6 %

US alone 8.1 8.9 %

Mammo + US 10.4 11.2 %

ACRIN 666


Connecticut Experience

• First Year after RU Dense Law

• 935 Women

• All risk levels

• Hand held whole breast

• 63 biopsies or aspirations

• 3/63 malignant – All <1cm

– All post menopausal

– 1 cancer per risk category


Connecticut Experience

• Cancer detection rate: 3/1000

• PPV- 6.5% (low)


Screening US • Benefits:

– Available

– Inexpensive

– No radiation

• Down sides:

– Time to perform study

• 19 minutes bilateral (ACRIN)

– Qualified physician/tech shortages

– False +

– Not standardized


Automated US

• Speeds up exam

• Assisted robotic guidance of probe

over breast

U- Systems

SonixEmbrace


Automated US

• Kelly et al, 2009

– 6,425 studies

– Increased cancer detection from 3.6

to 7.2/1000 compared to mammo

alone

– 7-8 minutes physician time

– PPV biopsy = 38.4%


MRI

• Magnetic Resonance Imaging

• Increased availability in past 10 years


MRI


MRI

50 yo

Extensive non mass like

enhancement

DCIS


CC MAG

MRI

62 yo Heterogeneously dense, 25% lifetime risk, screening


MRI

MR Biopsy- High grade DCIS.


MRI

• Benefits

– High sensitivity for cancer

– Not affected by density

– No Radiation


MRI

• Down sides

– IV contrast required

– False +

– Claustrophobia

– Availability

– Cost

Berg WA Detection of Breast Cancer with Addition of annual Screening Ultrasound or a

Single Screening MRI to Mammography in Women with Elevated Breast Cancer Risk

JAMA 2012 ; 307:1394-1404


MRI

– Berg 2012

– Expanded ACRIN trial: high risk AND

dense

– Added MRI screening after 3 rounds

of M/US



JAMA 2012 ; 307:1394-1404


MRI

• Results

– 612 women in MRI added group

– 16/612 had Cancer

– 9/16 (56%) seen only on MRI

• Median size 8mm

• All staged- node negative

– Supplemental cancer yield of MRI-

14.7/1000



JAMA 2012 ; 307:1394-1404


Berg 2012

Added MRI to ACRIN 666

Sensitivity Specificity PPV Recall

Rate

Mammo

alone

56% 89% 29% 11%

Mammo +

US

94% 74% 11% 16%

MRI 100% 70% 19% 31%

Berg WA Detection of Breast Cancer with Addition of annual Screening Ultrasound or a Single Screening MRI

to Mammography in Women with Elevated Breast Cancer Risk JAMA 2012 ; 307:1394-1404


MRI

• Current recommendation for

screening MRI (NCCN)

– High risk women

– >20% lifetime risk of cancer


Cost of supplemental studies


Berg 2012

“Despite its higher sensitivity, the addition of

screening MRI rather than ultrasound to

mammography in broader populations of

women at intermediate risk with dense breasts

may not be appropriate, particularly when the

current high false positive rates, cost, and

reduced tolerability of MRI are considered.”

Berg WA Detection of Breast Cancer with Addition of annual Screening

Ultrasound or a Single Screening MRI to Mammography in Women

with Elevated Breast Cancer Risk JAMA 2012 ; 307:1394-1404


Emerging Technologies

• Tomosynthesis

• Molecular Imaging


Tomosynthesis

• Digital x-ray mammogram

• Multiple projections produced by x-

ray source that moves in an arc


Basic technologic principles of breast tomosynthesis.

Park J M et al. Radiographics 2007;27:S231-S240

©2007 by Radiological Society of North America

Tomosynthesis


Tomosynthesis

• Digital x-ray mammogram

• Multiple projections produced by x-

ray source that moves in an arc

• Interpretation of multiple slices thin

through breast like CT or MRI


Tomosynthesis

*U. of Michigan Research

GE Prototype

U. Of M. Case 1

All tomo images courtesy of:

Marilyn A. Roubidoux, MD


Tomosynthesis

*U. of Michigan Research

GE Prototype

DBT

U. Of M. Case 1

All tomo images courtesy of:



Case 1

Tomosynthesis DBT slices



Tomosynthesis DBT slice

U. Of M. Case 2



Screening digital

mammogram

CC MLO

Case 4

Tomosynthesis


Case 4

CC MLO

DBT

Tomosynthesis


MLO

Case 4

DBT slice

Tomosynthesis


Case 5 Palpable lump

Tomosynthesis


Tomosynthesis DBT DBT


DBT slices

Tomosynthesis


Tomosynthesis

• Benefits

– Decrease overlapping tissue

– Increased sensitivity

– Decrease size of cancer detected

– Decreased recall rate

– Uses mammographic technology

Helvie MA Digital Mammography Imaging: breast

Tomosynthesis and Advanced Imaging Radiol Clin N Amer

48(2010 917-929


Tomosynthesis

• Skaane April 2013-

• 12,631 exams

• Digital Mammography and

Tomosynthesis


Tomosynthesis

• Results

– 27% increase in cancer detection rate

when Tomo added (p= .001)

– 15% decrease in recall rates from

screening(p<.001)

– PPV of biopsy- same for M alone vs

M+Tomo


Tomosynthesis

• Results

– Interpretation time doubled when

tomo added (45 vs 91 seconds

p<.001)


Molecular Breast Imaging

• Positron Emission Mammography

(PEM)

– 18F-fluorodeoxyglucose

– High resolution PET scanner

• Breast Specific Gamma Imaging

(BSGI)

– Tc99m Sestamibi


Molecular Breast Imaging

• Whole body exposure to ionizing

radiation

• Not indicated for annual use.

• Current trials underway to decrease

dose to allow for screening use.


Are you DENSE?

© 2011 – 2013, Are You Dense Advocacy, Inc.. All rights reserved.

Site designed and hosted by WORX Branding & Advertising.. Email the webmaster.

Accessed 4-2-2013

Pink: Enacted law

Red: Endorsed Bill

Blue: Working on Bill

White: No Action

* : Insurance Coverage Bill

CT and IL mandate insurance coverage for

Screening US


http://worxbranding.com/

http://worxbranding.com/

mailto:[email protected]

mailto:[email protected]

MICHIGAN Bill: patient notification

• "THE PHYSICIAN INTERPRETING YOUR MAMMOGRAPHY

EXAMINATION HAS DETERMINED THAT YOU HAVE DENSE

BREAST TISSUE. MAMMOGRAPHY HAS KNOWN LIMITATIONS

AND, IN A PATIENT WHO HAS DENSE BREAST TISSUE, SOME

ABNORMALITIES MAY NOT APPEAR. IF YOU WERE REFERRED

TO US BY A PHYSICIAN, A WRITTEN REPORT OF THE RESULTS

OF YOUR MAMMOGRAPHY EXAMINATION, INCLUDING

INFORMATION ABOUT YOUR BREAST DENSITY, HAS

BEEN SENT TO YOUR PHYSICIAN.

THIS NOTICE IS INTENDED TO RAISE YOUR AWARENESS AND

PROMOTE DISCUSSION BETWEEN YOU AND YOUR PHYSICIAN

REGARDING THE RESULTS OF YOUR MAMMOGRAPHY

EXAMINATION. DEPENDING UPON YOUR INDIVIDUAL RISK

FACTORS, YOUR PHYSICIAN MAY RECOMMEND ADDITIONAL

TESTS INCLUDING AN ULTRASOUND OR MAGNETIC RESONANCE

IMAGING. YOU SHOULD CONTACT YOUR PHYSICIAN IF YOU HAVE

ANY QUESTIONS OR CONCERNS REGARDING THE RESULTS OF

YOUR MAMMOGRAPHY EXAMINATION.".


Are you Dense Legislation?

• The GOOD:

– Increased clinician and patient

awareness • Strengths and shortcomings of Mammography

• Risk factors

– Increase discussion with their

clinicians • Can address other risk factors


Are you Dense Legislation?

• The Bad:

– Patient anxiety • Only 10% of screening population is extremely dense

– Significant risk seems to be directed at this group

• High false positives of supplemental studies

– Technology has not caught up- • Measuring breast density-limited

• Moderate reliability of description

• Computerized models very limited use now


Are you Dense?

• The Ugly:

–Will this discourage women and

clinicians from routine

mammography?

–Who is going to pay for

supplemental studies?


Recommendations

• Support education of public

– Data supports density as a risk factor

• Continue Annual Mammography

• Support Insurance coverage as a

necessary part of legislation to

ensure parity

• Consider limiting recommendation

to Extremely Dense breasts


Thank you


a breast cancer risk factor and imaging challenge...1976 may: 37(5) 2486-92 mccormack, va et al,...

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