May 3, 2016 1

Risk Assessment,

Genetics, and Prevention

Katherine D. Crew, MD MS

Director, Clinical Breast Cancer

Prevention Program

Columbia University Medical Center

Outline

Breast cancer risk factors

Hereditary breast cancer genes (BRCA1/2)

Benign breast disease

Risk-reducing strategies

Breast cancer risk assessment in primary

care

2 May 3, 2016

Case #1

A 32-year-old premenopausal

woman of Ashkenazi Jewish

descent has a strong family

history of breast and ovarian

cancer. Her mother has a

positive BRCA2 mutation

(6174delT). She had

menarche at age 14 and her

first child at age 25. She

denies OCP use or any

breast complaints.

3 May 3, 2016

Age1

Stomach

cancer

MBC 70

OC 59

BC 60

BRCA2+

BC 20

BC 50s BC 40s

BC 80s

AJ AJ

BRCA2+

Age 32

Age 8

Breast Cancer Risk Factors

5 May 3, 2016

BRCA1/BRCA2 mutations

Account for 2-7% of breast cancers, 10-

15% of ovarian cancers

Prevalence is 1:400 in the general

population, 1:40 in Ashkenazi Jews

Lifetime risk of breast cancer 40-60%,

ovarian cancer 20-40%

6 May 3, 2016

Pai Cancer 2005

Nelson Ann Intern Med 2005

Risch JNCI 2006

Chen JCO 2007

Red Flags for Hereditary Breast and

Ovarian Cancer (HBOC) Syndrome

7 May 3, 2016

NCCN USPSTF

Ovarian cancer

Breast cancer, age<45

Bilateral breast cancer

Triple negative breast cancer,

age<60

Male breast cancer

Pancreatic cancer with additional

HBOC-associated cancer

Ashkenazi Jewish anscenstry with

HBOC-associated cancer

Previously identified BRCA

mutation in the family

Non-Ashkenazi Jewish: 2 first-degree relatives with breast

cancer, 1 diagnosed at age<50

3 or more first/second-degree relatives

with breast cancer

2 or more first/second-degree relatives

with ovarian cancer

Both breast/ovarian cancer among

first/second-degree relatives

First-degree relative with bilateral

breast cancer

Male relative with breast cancer

Ashkenazi Jewish: any

first/second-degree relatives with

breast or ovarian cancer

www.nccn.org

USPSTF Ann Intern Med 2005

Bellcross CEBP 2013

Possible Genetic Test Results

8 May 3, 2016

Family member’s

test results

Your test result Your risk

stratification

Informative positive - BRCA +

Informative negative BRCA + BRCA -

Uninformative

negative* No known mutation BRCA -

Variant of Uncertain

Significance* No known mutation VUS

* Testing a family member affected by cancer may help to further define your risk.

HIGH

RISK

AVERAGE

RISK

MODERATE

RISK

MODERATE

RISK

Cancer Risk among

BRCA Mutation Carriers

9 May 3, 2016

Struewing NEJM 1997

Liede JCO 2004

Tai JNCI 2007

Evans J Med Gen 2010

NCI (SEER) 2012

Risk Management:

Intensive Screening

10 May 3, 2016

PROCEDURE AGE TO BEGIN FREQUENCY

Breast cancer Self breast exam 18 years Monthly

Clinical breast

exam 25 years

Every 6-12

months

Mammography 25 years Yearly

Breast MRI 25 years Yearly

Ovarian cancer Pelvic exam 30 years

(no BSO) Every 6 months

Transvaginal USG

and CA-125

30 years

(no BSO) Every 6 months

www.nccn.org

Surgical Management:

Risk-Reducing Surgeries

11 May 3, 2016

Hartmann JNCI 2001

Kauff NEJM 2002

Rebbeck NEJM 2002

Rebbeck JCO 2004

Finch JAMA 2006

Rebbeck JNCI 2009

Domchek JAMA 2010

Finch JCO 2014

Ca

nc

er

Ris

k R

ed

uc

tio

n (

%)

12 May 3, 2016

Easton NEJM 2015

Case #2

A 63-year-old Hispanic postmenopausal

woman has a screening mammogram with

heterogeneously dense breasts and new

calcifications in the right breast. Core

breast biopsy and subsequent excisional

biopsy revealed atypical ductal hyperplasia.

Her age of menarche was 12 and she has

2 children with her first delivery at 35. She

has no family history of breast cancer.

According to the Gail model, her 5-year risk

of invasive breast cancer is 3.2% and

lifetime risk is 14.1%.

13 May 3, 2016

Spectrum of Benign Breast Disease

15 May 3, 2016 Dupont & Page NEJM 1985

Lopez-Garcia Histopathology 2010

Non-proliferative lesions Proliferative lesions w/o atypia ADH DCIS IDC

LOBULAR NEOPLASIA

Low grade DCIS

Intermediate grade DCIS

High grade DCIS

RR 10.0

Epithelial hyperplasia

Intraductal papilloma

Sclerosing adenosis

Radial scar

RR 1.5-2.0

Mild ADH

Moderate ADH

Severe ADH

Borderline lesion

RR 4.0-5.0

16

Estimating Breast Cancer Risk:

Gail Model

Age 45

Race Hispanic

Age of first menstrual period 13

Age of first live birth 30

Number of first-degree relatives with

breast cancer 1

Number of breast biopsies 1

Presence of atypical cells Yes

www.cancer.gov/bcrisktool 5-Year Risk = 3.6%

Lifetime Risk = 28.6%

May 3, 2016

Medical Management: Antiestrogens

for breast cancer prevention

17 May 3, 2016

Exemestane

Anastrozole

Selective estrogen receptor

modulators (SERM)

Raloxifene

Risks and Benefits of Tamoxifen

for Chemoprevention

18 May 3, 2016

Fisher JNCI 2005

Rate

per

1000

RISKS BENEFITS

*P<0.05

* *

*

*

Risks and Benefits of Tamoxifen

for Chemoprevention

19 May 3, 2016

Fisher JNCI 2005

Rate

per

1000

RISKS BENEFITS

*P<0.05 *

Long-Term Follow-Up with

Tamoxifen for Chemoprevention

20 May 3, 2016

Cuzick Lancet Oncol 2015

Tota

l # o

f C

ases

Endometrial Cancer

*P<0.05

*

Breast Cancer

*

* Median follow-up of 16 yrs

Tamoxifen vs. Raloxifene for

Chemoprevention

21 May 3, 2016

Vogel Cancer Prev Res 2010

Rate

per

1000

RISKS BENEFITS

*P<0.05

* *

*

*

Risks and Benefits of Aromatase

Inhibitors for Chemoprevention

22 May 3, 2016

Tota

l # o

f C

ases

*P<0.05 Median follow-up of 5 yrs

*

Tota

l # o

f C

ases

Median follow-up of 35 mo

* *

Goss NEJM 2011

Cuzick Lancet 2014

23

Premenopausal Postmenopausal

No SERM

Risk Assessment

Hysterectomy

osteoporosis Exemestane or

Anastrozole >

Raloxifene

Uterus intact

No osteoporosis Tamoxifen

History of

blood clots

Tamoxifen >

Raloxifene

Choice of Chemopreventive Agent

Raloxifene >

Tamoxifen

Uterus intact

osteoporosis

May 3, 2016

24 May 3, 2016

Integration into Clinic Workflow

PATIENTS: RealRisks decision aid

PROVIDERS: BNAV tool

Genetics Clinic: Pre/post-test genetic

counseling

Mammography:

Avon Breast Imaging Tablet-based survey

Breast Clinic: Screening, Risk-reducing

surgeries, Chemoprevention,

Lifestyle modification

Primary Care Clinic:

ACN/clinics BNAV alert

Reinforce health behaviors

made by specialist High-risk alert

to PCP

Facilitate shared decision

making with patient

High-risk women

referred to DA Facilitate shared decision

making with specialist

Facilitate shared decision

making with PCP

RealRisks decision aid

25 May 3, 2016

RealRisks decision aid

26 May 3, 2016

Narrative of Rose

27 May 3, 2016

Chemoprevention Module

28 May 3, 2016

Chemoprevention Module

29 May 3, 2016

Interactive Games

30 May 3, 2016

Eliciting Patient Preferences

31 May 3, 2016

Action Plan

32 May 3, 2016

BNAV Toolbox for PCPs

33 May 3, 2016

Chemoprevention Toolbox

34 May 3, 2016

Learning Objectives with Slide Presentation

35 May 3, 2016

Videos of Expert Opinions

36 May 3, 2016

Case-Based Learning

37 May 3, 2016

References

38 May 3, 2016

39

Summary

Recent increase in breast cancer incidence,

but decreasing mortality due to screening and

better treatments

Expanding options for risk-appropriate breast

cancer prevention strategies

Under-utilization of genetic testing and

chemoprevention

Breast cancer is preventable!

May 3, 2016

INTERESTED IN LEARNING MORE ABOUT

HOW TO REDUCE BREAST CANCER RISK?

40 May 3, 2016