St

1
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007

2
Breast Cancer Women at Risk and New Strategies
for Prevention

• Anne McTiernan, MD, PhD
• Director, Prevention Center
• Public Health Sciences Division, Cancer
  Prevention
• Fred Hutchinson Cancer Research Center
• Seattle, Washington

3
What percentage of your female patients forwhom
you have done breast cancer risk assessments may
be eligible for more than lifestyle changes?
?

• 0-15
• 16-39
• 40-55
• 56-75
• gt75

4
Faculty Disclosure

• Dr McTiernan has no relevant financial interests
  with any commercial interests to disclose.

5
Learning Objectives

• Evaluate women for breast cancer risk reduction
• Advise women on appropriate lifestyle alterations
  to lower breast cancer risk
• Explain the rationale and current clinical trial
  results of pharmacologic interventions for breast
  cancer risk reduction

6
(No Transcript)
7
WHI Hormone Program Design
YES
CE 0.625 mg/d
N 10,739
Placebo
Hysterectomy
CE 0.625 mg/d MPA 2.5 mg/d

NO
N 16,608
Placebo
Initially CE only (N 331), CE MPA, or
placebo.
CE conjugated estrogens MPA
medroxyprogesterone acetate WHI Womens Health
Initiative. Chlebowski R et al. JAMA.
20032893243-3253 WHI Writing Group. JAMA.
2002288321-333.
8
Available online _at_ http//jama.ama-assn.org/
9
Usage of Hormonal Agents in the United States
After WHI E P Results
80
60
40
No. of Prescriptions (millions)
20
0
2000
2001
2002
2003
2004
Reporting Year
Number of prescriptions issued in the United
States for the estrogen/progesterone combination
E P estrogen/progesterone combination. Ravdin
P et al. N Engl J Med. 20073561670-1674.
10
Quarterly Incidence of Breast Cancer (Age
50-69 Years) by Receptor Status
All patients ER-positive tumors
ER-negative tumors
100
90
80
70
60
Quarterly Rate /100,000 Women
50
40
30
20
10
0
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
2000
2001
2002
2003
2004
ER estrogen receptor. Ravdin P et al. N Engl J
Med. 20073561670-1674. .
11
Decreased Age-Adjusted Breast Cancer Incidence
Rates 2001-2004
Ravdin P et al. N Engl J Med. 20073561670-1674.
12
Drop in Breast Cancer Incidence Linked to Hormone
Use

• Not a drop in mammography screening
• Kerlikowske and colleagues examined 603,411
  screened mammograms between 1997 and 2003
• Change in breast cancer incidence correlated
  with menopausal hormone therapy decline
• Not a drop in breast biopsies done
• From Nationwide Medicare Master Files between
  1999 and 2004, breast biopsy utilization rate per
  100,000 Medicare beneficiaries increased by 43

Kerlikowske K et al. J Natl Cancer Inst.
2007991335 -1339 Levin D et al. J Am Coll
Radiol. 20063707-709.
13
What chemopreventive agents for breast cancer
have you prescribed?
?

• Raloxifene
• Tamoxifen
• Aromatase inhibitors
• All
• None

14
Tamoxifen Significantly Reduced Incidence of New
Contralateral Breast Cancer in Adjuvant Breast
Cancer Trials

• Basis for First Intervention Trials

15
NSABP-P1 BCPT-1 Breast Cancer Prevention Trial
Schema
Eligible women at high risk (5-year risk 1.66)
Randomization n 13,388
Tamoxifen 5 years (20 mg/d) n 6681
Placebo 5 years n 6707
BCPT-1 Breast Cancer Prevention Trial NSABP-P1
National Surgical Adjuvant Breast and Bowel
Project 1. Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
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NSABP-P1 BCPT-1 Trial

• First clinical trial to demonstrate that
  incidence of breast cancer can be reduced with
  chemopreventive therapy
• gt13,000 women at high risk randomized to
  tamoxifen versus placebo for 5 years

Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
17
NSABP-P1 BCPT-1 Trial

• Tamoxifen proven to reduce risk of breast cancer
• Enrolled pre- and postmenopausal women 35 years
  of age and at increased risk of breast cancer.
  Patients treated with tamoxifen (20 mg/d) for 5
  years

Invasive Cancer
Noninvasive Cancer
50
50
No. of Events Placebo 250 Tamoxifen 145 P lt.0001
No. of Events Placebo 93 Tamoxifen 60 P .008
40
40
30
30
Cumulative Rate/1000 Women
Cumulative Rate/1000 Women
20
20
10
10
0
0
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
Time to Breast Cancer (years)
Time to Breast Cancer (years)
Fisher B et al. J Natl Cancer Inst.
2005221652-1662.
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NSABP-P1 BCPT-1 Benefits and Risks in Women ?50
Years of Age
Benefits
Risks
Tamoxifen
Placebo
No. of Events
Fractures
Endometrial Cancer
Vascular Events
Invasive Breast Cancer
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
19
NSABP-P1 BCPT-1 Benefits and Risks in Women
35-49 Years of Age
Benefits
Risks
Tamoxifen
Placebo
No. of Events
Endometrial Cancer
Invasive Breast Cancer
Fractures
Vascular Events
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
20
Overview of Tamoxifen Breast CancerPrevention
Trials All Breast Cancers
Royal Marsden NSABP-P1 Italian IBIS-1 All
tamoxifen preventive All tamoxifen adjuvant
IBIS-1 International Breast Cancer Intervention
Study-1. Cuzick J et al. Lancet. 2003361296-300.
21
Overview of Tamoxifen BreastCancer Prevention
Trials VTEs
Royal Marsden NSABP-P1 Italian IBIS-1 All
tamoxifen preventive
0.5
1.0
1.94
3.0
5.0
Hazard Ratio
VTE venous thromboembolic event. Cuzick J et
al. Lancet. 2003361296-300.
22
Overview of Tamoxifen Breast CancerPrevention
Trials Endometrial Cancers
Royal Marsden NSABP-P1 IBIS-1 All tamoxifen
preventive All tamoxifen adjuvant
0.5
1.0
2.41
5.0
10.0
0.3
Hazard Ratio
Cuzick J et al. Lancet. 2003361296-300.
23
In postmenopausal women, what are the FDA-
approved agents for chemopreventive therapy?
?

• Raloxifene
• Tamoxifen
• Aromatase inhibitors
• Raloxifene tamoxifen
• Raloxifene tamoxifen aromatase inhibitors

24
Raloxifene and Breast Cancer Risk
25
Multiple Outcomes of Raloxifene (MORE) Plus
Continuing Outcomes Relevant to Evista (CORE)
Study Design
MORE(n 7705) 3 TreatmentGroups
CORE(n 4011) 2 TreatmentGroups
Gap MOREConclusion COREScreening
Placebo
Placebo
RaloxifeneHCI (60 mg/d)
RaloxifeneHCI 60 mg/d
RaloxifeneHCI (120 mg/d)
8-Year Total Follow-up
Martino S et al. J Natl Cancer Inst.
2004961751-1761.
26
Cumulative Incidence of Invasive Breast Cancers
in MORE/CORE
Placebo(n 2576) 4.2 cases/1000 women-years
66 Reduction Invasive Breast Cancer Incidence
HR 0.34 (95 CI 0.22-0.56) P lt.001
Raloxifene(n 5129) 1.4 cases/1000 women-years
Cumulative Incidence/1000 Women-Years
Years in Study
Martino S et al. J Natl Cancer Inst.
2004961751-1761.
27
STAR Schema
Risk-eligible postmenopausal womenN 19,747
STRATIFICATION Age Gail model risk Race
History
Tamoxifen20 mg/d x 5 yearsN 9872
Raloxifene60 mg/d x 5 yearsN 9875
STAR Study of Tamoxifen and Raloxifene
trial. Vogel VG et al. JAMA. 2006232727-2741.
http//www.nsabp.pitt.edu/STAR/Index.html
28
STAR Eligibility Criteria

• Postmenopausal, 35 years of age
• 5-year risk of invasive breast cancer 1.7 LCIS
  treated by local incision
• No prior DVT, pulmonary embolus, CVA, TIA,
  atrial fibrillation
• No uncontrolled hypertension, diabetes mellitus

CVA cerebrovascular accident DVT deep vein
thrombosis LCIS lobular carcinoma in situ
TIA transient ischemic attack. Vogel VG et al.
JAMA. 2006232727-2741. http//www.nsabp.pitt.edu
/STAR/Index.html
29
STAR (NSABP P-2) Results

• All patients had increased breast cancer risk
• Age (years)
• lt49 9
• 50-59 50
• 60-69 32
• 70 9
• Prior hysterectomy 51.3
• Prior LCIS 9.2
• Prior atypical hyperplasia 22.5

Vogel VG et al. JAMA. 2006232727-2741.
http//www.nsabp.pitt.edu/STAR/Index.html
30
STAR Invasive Breast Cancers
RR 1.02 95 CI 0.82-1.28
312
P .96
Average Annual Rate/1000 Person-Years
163
168
Gail Model 5-YearPredicted Risk
Tamoxifen
Raloxifene
No. of events
RR relative risk. Adapted from Vogel VG et al.
JAMA. 2006232727-2741. http//www.nsabp.pitt.edu
/STAR/Index.html
31
STAR Noninvasive (In Situ) Breast Cancers
RR 1.40 95 CI 0.98-2.00
P .052
3
80
2
57
Average Annual Rate/1000 Person-Years
1
0
Tamoxifen
Raloxifene
No. of events
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
32
Average Annual Rate and Number of Noninvasive
(In Situ) Cancers
P-2 STAR
3
30
50
2
80
Average Annual Rate/1000 Person-Years
57
1
0
Tamoxifen
Raloxifene
RR 1.40 95 CI 0.98-2.00Expected Based on
NSABP P-1
No. of events
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
CP1230355-39
33
NSABP P-2 Safety
P .01
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
34
Raloxifene for Use in the Heart (RUTH)

• Patient population (n 10,101)
• Postmenopausal women with CHD or risk factor for
  CHD
• 38 of women were gt70 years of age

Invasive breast cancers reduced 44 with absolute
risk reduction of 0.6
CHD coronary heart disease. Barrett-Connor E et
al. N Engl J Med. 2006355125-137.
35
RUTH Safety
Barrett-Connor E et al. N Engl J Med.
2006355125-137.
36
Tamoxifen and Raloxifene

• Both reduce invasive breast cancer to a similar
  degree
• Both have a similar effect on fractures
• Cardiovascular mixed, overall similar?
• There are differences (trade-offs)
• Unlike tamoxifen, raloxifene is not used for the
  treatment of breast cancer

37
Tamoxifen vs Raloxifene Trade-Offs
In Favor of Tamoxifen
Tamoxifen
1.51
Noninvasive breast cancer
Raloxifene
2.13
In Favor of Raloxifene
2.00
Uterine cancer
1.50
2.29
DVT
1.69
1.41
Pulmonary emboli
0.96
12.98
Cataracts
9.38
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Average Annual Rate/1000 Person-Years
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
38
FDA Approves Osteoporosis Drug Raloxifene to
Reduce the Risk of Invasive Breast Cancer

• The FDA has approved raloxifene to reduce the
  risk of invasive breast cancer in 2 populations
  postmenopausal women with osteoporosis and
  postmenopausal women at high risk for invasive
  breast cancer
• In 4 trials, raloxifene reduced invasive breast
  cancer by 44 to 71 and reduced invasive
  breast cancers equivalent to tamoxifen

FDA US Food and Drug Administration. http//www.
fda.gov/bbs/topics/NEWS/2007/NEW01698.html
39
Future Considerations
40
Contralateral Tumors in AromataseInhibitor Trials
ARNO/ABCSG Arimidex-Nolvadex/Austrian Breast
Cancer Study Group ATAC Arimidex, Tamoxifen,
Alone or in Combination BIG Breast
International Group. Cuzick J. J Clin Oncol.
2005 231636-1643.
41
International Breast CancerIntervention Study
IBIS-2 N 6000

• Eligibility
• Risk by family history
• Postmenopausal women
• 40-70 years of age

RANDO MIZE
Anastrozole
Placebo
5 years
National Cancer Research Network Trials
Portfolio. Available at www.ncrn.org.uk/portfolio
/data.asp?ID848.
42
EXCEL Prevention Trial NCIC CTG MAP.3

• Eligibility
• Postmenopausal women
• ?35 years of age
• At ? risk
• Gail score gt1.66
• or
• gt60 years of age
• or
• Prior ADH, LCIS, DCIS
• (some restrictions)

n 4560
RANDO MIZE
Exemestane
Placebo
Exemestane 25 mg qdfor 5 years
ADH atypical ductal hyperplasia DCIS ductal
carcinoma in situ NCIC CTG National Cancer
Institute of Canada Clinical Trials Group.
Lonning PE. Clin Cancer Res. 200511(suppl)918s-
924s.
43
For what percentage of your female patients have
you done breast cancer risk assessments?
?

• 0-15
• 16-39
• 40-55
• 56-75
• gt75

44
What to Do Now to Reduce Breast Cancer Risk?

• Perform breast cancer risk assessment
• Gail model (for all women gt35 years of age)
• WHI model (postmenopausal women only)
• based only on age, first-degree relatives with
  breast cancer, and prior breast biopsy
• Genetic evaluation if indicated by strong family
  history (breast cancer lt50 years of age, ovarian
  cancer)

Gail, MH. J Natl Cancer Inst. 1989241879-1886.
http//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
45
Identification of Postmenopausal Women at Higher
Breast Cancer Risk

• Gail model risk estimate
• Breast cancer family history
• Breast biopsy results (DCIS and LCIS)

Gail, MH. J Natl Cancer Inst. 1989241879-1886. h
ttp//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
46
Predicted 5-Year Risk of ER Invasive Breast
Cancer Using Simplified Model
First-degree relative and 55 years of age
gt1.8 risk
Chlebowski R et al. Presented at ASCO 2007.
Abstract 1507.
47
Predicted 5-Year Risk of ER Invasive Breast
Cancer Using Simplified Model
1 biopsy and 55 years of age gt1.8 risk
Chlebowski R et al. Presented at ASCO 2007.
Abstract 1507.
48
What to Do Now to Reduce Breast Cancer Risk?

• If risk is elevated, discuss risk reduction
  options
• Screening
• Clinical breast exams, mammograms, possibly MRIs
• Behavioral or lifestyle changes
• Preventive therapy with tamoxifen or raloxifene
• Prophylactic surgery (for women at highest risk)
• Bilateral mastectomies with reconstruction
• Oophorectomy

Available at www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
49
Risk ReductionMaintain a Healthy Weight

• Maintain BMI lt25 kg/m2
• Avoid weight gain, especially postmenopausal

BMI body mass index. Available at
www.cancer.gov/cancertopics/types/breast
50
Risk Reduction Diet

• Eat a variety of healthful foods, with an
  emphasis on plant sources
• Eat 5 or more servings of vegetables and fruits
  per day
• Choose whole grains instead of processed grains
  and sugar
• Limit consumption of red meat, especially meat
  high in fat and processed meat

Available at www.cancer.org
51
Risk Reduction Exercise

• Regular exercise reduces breast cancer risk
  10-25
• At least moderate activity 45 minutes 5 days a
  week

Available at www.cancer.org
52
Risk Reduction Alcohol in Moderation

• Women
• Men
• 1 drink
• 12 oz regular beer
• 5 oz wine
• 1.5 oz liquor

Available at www.cancer.gov/cancertopics/types/br
east
53
Which Preventive Agent to Choose?

• Premenopausal consider tamoxifen (also consider
  lt5-year risk)
• Postmenopausal with uterus consider raloxifene
• Postmenopausal with no uterus consider
  raloxifene or tamoxifen
• In all cases, carefully consider risk/benefit
  balance

54
Breast Cancer Risk Factors

• Issues related to the 5-7 of breast cancers
  that are strongly related to BRCA1/2 genetic
  abnormalities
• Focus on the 93-95 of breast cancers that are
  sporadic or have family clusters with
  unidentified genetic linkages

55
Family History Patterns Suggesting Referral for
BRCA Testing

• 2 first-degree relatives with breast cancer, 1
  lt50 years of age
• 3 first- or second-degree relatives with breast
  cancer
• Combination of both breast and ovarian cancer
  among first- and second-degree relatives
• First-degree relative with bilateral breast
  cancer
• Two or more first- or second-degree relatives
  with ovarian cancer
• Breast cancer in a male relative
• For Jewish Heritage
• First-degree relative with breast or ovarian
  cancer
• 2 second-degree relatives on same side of the
  family with breast or ovarian cancer

US Preventive Services Task Force. Ann Intern
Med. 2005143355-361.
56
Risk Calculator (Modified Gail Model)

• Does the woman have a medical history of any
  breast cancer or DCIS or LCIS?
• What is the womans age? (This tool only
  calculates risk for women 35 years of age.)
• What was the womans age at the time of her first
  menstrual period?
• What was the womans age at the time of her first
  live birth of a child?
• How many of the womans first-degree
  relativesmother, sisters, daughtershad breast
  cancer?
• Has the woman ever had a breast biopsy?
• 6a. How many breast biopsies ( or -) has the
  woman had?
• 6b. Has the woman had at least 1 biopsy with
  atypical hyperplasia?
• What is the womans race/ethnicity?

http//www.cancer.gov/bcrisktool/
57
http//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
58
Case Studies
59
Case Study Mary

• 45-year-old white female
• Menarche at age 11
• Parity at age 32
• Mother diagnosed with DCIS at age 56
• No other family history of breast cancer

• No significant health problems or concerns
• Nonsmoker
• Status posthysterectomy for uterine fibroids
  ovaries are intact
• No menopausal-type symptoms

60
Case Study Mary (contd)

• Health concerns
• Reducing her breast cancer risk, including risk
  of DCIS
• Breast cancer risk
• Gail risk assessment
• 5-year risk 1.8
• Lifetime risk 11.9

61
What type of breast cancer risk reduction should
Mary be advised to pursue?
?

• No risk reduction necessaryyearly mammograms
  and lifestyle changes (weight reduction,
  moderate alcohol consumption, etc) are
  sufficient
• Chemopreventive therapy with tamoxifen
• Chemopreventive therapy with raloxifene
• Prophylactic surgery

62
Case Study Mary (contd)

• Clinical management
• Counseling regarding healthy lifestyle
• Counseling regarding chemoprevention
• Patient elected tamoxifen
• Reduces risk of invasive and noninvasive
  breast cancer
• Risks of tamoxifen not increased in women lt50
  years of age who have had a hysterectomy

63
Case Study Sue

• 55-year-old white female
• Menarche at age 11
• Parity at age 32
• No family history of breast cancer
• No significant health problems
• Nonsmoker

• Status post-total abdominal hysterectomy with
  bilateral salpingo-oophorectomy
• Experiencing significant menopausal-type
  symptoms, manifested primarily by hot flashes and
  vaginal dryness

64
Case Study Sue (contd)

• Health concerns
• Improving her quality of life
• Breast cancer risk
• Gail risk assessment
• 5-year risk 1.8
• Lifetime risk 12.2

65
Sue has come in for a checkup. Her menopause
symptoms have been severe and she is wondering
what her options are. What type of treatment
regimen would you recommend for the prevention of
breast cancer?
?

• No risk reduction necessary yearly mammograms
  and lifestyle changes (weight reduction,
  moderate alcohol consumption, etc) are
  sufficient
• Chemopreventive therapy with tamoxifen
• Chemopreventive therapy with raloxifene
• Prophylactic surgery

66
Case Study Sue (contd)

• Clinical management
• Counseling regarding healthy lifestyle
• Counseling regarding chemoprevention and hormonal
  therapy
• Patient elected estrogen replacement therapy /-
  vaginal estrogen
• Best therapy for management of hormonal symptoms
• Data from WHI indicate that estrogen alone does
  not increase breast cancer risk
• Patient counseled to consider tapering off
  estrogen in a couple of years to assess severity
  of menopausal symptoms

67
Case Study Margaret

• 50-year-old white female
• Menarche at age 12
• Parity at age 32
• No family history of breast cancer

• Nonsmoker
• Atypical ductal hyperplasia on breast biopsy
• History of osteopenia

68
Case Study Margaret (contd)

• Health concerns
• Reducing her risk of breast cancer
• Reducing her risk of osteoporotic bone fracture
• Breast cancer risk
• Gail risk assessment
• 5-year risk 1.7
• Lifetime risk 15.2

69
How could Margaret best pursue breast cancer
risk reduction?
?

• No risk reduction necessaryyearly mammograms
  and lifestyle changes (weight reduction,
  moderate alcohol consumption, etc) are
  sufficient
• Chemopreventive therapy with tamoxifen
• Chemopreventive therapy with raloxifene
• Prophylactic surgery

70
Case Study Margaret (contd)

• Clinical management
• Counseling regarding healthy lifestyle
• Counseling regarding chemoprevention
• Patient elected raloxifene
• Risk reduction for both breast cancer and
  osteoporosis

71
QA

72
PCE Takeaways

• Risk reduction interventions should be tailored
  to the patient
• Lifestyle changes, chemoprevention, prophylactic
  surgery
• Chemopreventive therapies
• A promising alternative to other methods
• Multiple approaches are available and under
  investigation
• Assess risk/benefit for each patient
• Proven to reduce risk
• Raloxifene
• Tamoxifen
• Aromatase inhibitors are under investigation for
  breast cancer risk reduction but are not
  appropriate for such at this time
• Risk assessment for breast cancer
• Should encompass inherited and population-based
  risk factors
• Genetic counseling should be considered in women
  with a significant family history of breast
  cancer
• Gail model should be done in women 35 years of
  age without a gene mutation

73
What percentage of your female patients for whom
you have done breast cancer risk assessments may
be eligible for more than lifestyle changes?
?

• 0-15
• 16-39
• 40-55
• 56-75
• gt75

74
Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007