Current Options for Breast Cancer Risk Reduction

1
Current Options for Breast Cancer Risk Reduction

• Rowan T. Chlebowski, MD, PhD
• Professor of Medicine
• David Geffen School of Medicine at UCLA
• Chief, Division of Medical Oncology and
  Hematology
• Harbor-UCLA Medical Center
• Los Angeles, California

2
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

3
Faculty Disclosure

• Dr Chlebowski consultant AstraZeneca, Eli Lilly
  and Company, Novartis Pharmaceuticals
  Corporation, sanofi-aventis research Eli Lilly
  and Company, Organon speakers bureau
  AstraZeneca, Genentech, Inc., Novartis
  Pharmaceuticals Corporation.

4
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

5
(No Transcript)
6
WHI Hormone Program Design
YES
CE (conjugated estrogens) 0.625 mg/d
N 10,739
Placebo
Hysterectomy
CE 0.625 mg/d medroxyprogesterone acetate (MPA)
2.5 mg/d

NO
N 16,608
Placebo
Initially CE only (N 331), CE MPA, or
placebo.
WHI Womens Health Initiative. Chlebowski R et
al. JAMA. 20032893243-3253 WHI Writing Group.
JAMA. 2002288321-333.
7
Available online _at_ http//jama.ama-assn.org/
8
Usage of Hormonal Agents in the United States
After WHI E P Results
80
60
40
No. 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.
9
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
50
Quarterly Rate Per 100,000 Women
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. .
10
Decreased Age-Adjusted Breast Cancer Incidence
Rates 2001 to 2004
Ravdin P et al. N Engl J Med. 20073561670-1674.
11
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.
12
What chemopreventive agents for breast cancer
have you prescribed?

• Raloxifene
• Tamoxifen
• Aromatase inhibitors
• All
• None

13
Tamoxifen Significantly Reduced Incidence of New
Contralateral Breast Cancer in Adjuvant Breast
Cancer Trials

• Basis for First Intervention Trials

14
National Surgical Adjuvant Breast and Bowel
Project P-1 (NSABP-P1) Breast Cancer Prevention
Trial (BCPT-1) Design 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
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
15
NSABP-P1 BCPT-1 Trial

• First clinical trial to demonstrate that
  incidence of breast cancer can be reduced in a
  chemopreventive setting
• gt13,000 women at high-risk randomized to
  tamoxifen vs placebo for 5 years

Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
16
NSABP-P1 BCPT-1 Trial

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

Invasive Cancer
Noninvasive Cancer
50
50
No. Events Placebo 250 Tamoxifen 145 P lt.0001
No. Events Placebo 93 Tamoxifen 60 P .008
40
40
30
30
Cumulative Rate Per 1000
Cumulative Rate Per 1000
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.
17
NSABP-P1 BCPT-1 Benefits and Risks in Women ?50
Years
Benefits
Risks
Tamoxifen
Placebo
Events
Fractures
Endometrial Cancer
Vascular Events
Invasive Breast Cancer
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
18
NSABP-P1 BCPT-1 Benefits and Risks in Women Aged
35-49 Years
Benefits
Risks
Tamoxifen
Placebo
Events
Endometrial Cancer
Invasive Breast Cancer
Fractures
Vascular Events
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
19
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.
20
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.
21
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.
22
In postmenopausal women, what are the FDA-
approved agents for chemopreventive therapy?

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

23
Raloxifene and Breast Cancer Risk
24
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.
25
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 Per1000 Women
Years in Study
Martino S et al. J Natl Cancer Inst.
2004961751-1761.
26
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
27
STAR Eligibility Criteria

• Postmenopausal, age 35 years
• 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
28
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
29
STAR Invasive Breast Cancers
Relative risk (RR) 1.02 95 CI 0.82-1.28
312
P .96
163
168
No. events
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
30
STAR Noninvasive (In Situ) Breast Cancers
RR 1.40 95 CI 0.98-2.00
P .052
3
80
2
57
Average Annual Rate per 1000
1
0
Tamoxifen
Raloxifene
No. events
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
31
Average Annual Rate and Number of Noninvasive
(In Situ) Cancers
P-2 STAR
3
30
50
2
80
Av Annual Rate Per 1000
57
1
0
Tamoxifen
Raloxifene
Relative Risk 1.40 95 CI 0.98-2.00Expected
Based on NSABP P-1
No. events
Fisher B et al. J Natl Cancer Inst.
1998901371-1388.
CP1230355-39
32
NSABP P-2 Safety
P 0.01
Adapted from Vogel VG et al. JAMA.
2006232727-2741. http//www.nsabp.pitt.edu/STAR/
Index.html
33
Raloxifene for Use in the Heart (RUTH)

• Patient population (10,101)
• Postmenopausal women with coronary heart disease
  (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
Barrett-Connor E et al. N Engl J Med.
2006355125-137.
34
RUTH Safety
Barrett-Connor E et al. N Engl J Med.
2006355125-137.
35
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

36
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
Deep vein thromboses
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 Per 1000
Adapted from Vogel VG et al. JAMA.
2006232727-41. http//www.nsabp.pitt.edu/STAR/In
dex.html
37
FDA Approves Osteoporosis Drug Raloxifene To
Reduce the Risk of Invasive Breast Cancer

• The US Food and Drug Administration (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

http//www.fda.gov/bbs/topics/NEWS/2007/NEW01698.h
tml
38
Future Considerations
39
Contralateral Tumors in AromataseInhibitor Trials
Cuzick J. Presented at European Breast Cancer
Conference, 2006.
40
International Breast CancerIntervention Study
IBIS-2 N 6000

• Eligibility
• Risk by family history
• Postmenopausal women
• Age 40-70

RANDO MIZE
Anastrozole
Placebo
5 years
National cancer research network trials
portfolio. Available at www.ncrn.org.uk/portfoli
o/data.asp?ID848.
41
EXCEL Prevention TrialNCIC CTG MAP.3

• Eligibility
• Postmenopausal women
• Age ?35
• At ? risk
• Gail score gt1.66
• or
• Age gt60
• or
• Prior ADH, LCIS, DCIS (mastectomy only)

n 4560
RANDO MIZE
Exemestane
Placebo
Exemestane 25-mg qdfor 5 years
ADH atypical ductal carcinoma DCIS ductal
carcinoma in situ LCIS lobular carcinoma in
situ. Lonning PE. Clin Cancer Res.
200511(suppl)918s-924s.
42
For what percentage of your female patients have
you done breast cancer risk assessments?

• 0-15
• 16-39
• 40-55
• 56-75
• gt75

43
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 old, ovarian
  cancer)

Gail, MH. J Natl Cancer Inst. 1989241879-86.
http//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
44
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. 1989241879-86. htt
p//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
45
Breast Cancer Risk Factors

• Issues related to the 5-7 of breast cancers
  that are hereditary (strongly related to genetic
  abnormalities like BRCA 1/2)
• Focus on the 93-95 of breast cancers that are
  sporadic or have family clusters

46
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
• Any first-degree relative (or second-degree
  relative on same side of the family) with breast
  or ovarian cancer

US Preventive Services Task Force. Ann Intern
Med. 2005143355-361.
47
Risk Calculator (Modified Gail Model)

• Does the woman have a medical history of any
  breast cancer or of ductal carcinoma in situ
  (DCIS) or lobular carcinoma in situ (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/
48
Predicted 5-Year Risk of ER Invasive Breast
Cancer Using Simplified Model
First-degree relative and 55 years gt1.8 risk
Chlebowski R et al. Presented at ASCO 2007.
Abstract 1507.
49
Predicted 5-Year Risk of ER Invasive Breast
Cancer Using Simplified Model
1 biopsy and 55 years gt1.8 risk
Chlebowski R et al. Presented at ASCO 2007.
Abstract 1507.
50
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
• Diet, exercise, limit HT use
• Preventive therapy with tamoxifen or raloxifene
• Prophylactic surgery (for women at highest risk)
• Bilateral mastectomies with reconstruction
• Oophorectomy

HT hormone therapy. Available at
www.cancer.gov/bcrisktool/ or Breastcancerpreventi
on.com
51
Which Preventive Agent to Choose?

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

52
Breast Cancer Risk Factors

• Issues related to the 5-7 of breast cancers
  that are hereditary (strongly related to genetic
  abnormalities like BRCA 1/2)
• Focus on the 93-95 of breast cancers that are
  sporadic or have family clusters

53
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
• Any first-degree relative (or second-degree
  relative on same side of the family) with breast
  or ovarian cancer

US Preventive Services Task Force. Ann Intern
Med. 2005143355-361.
54
Risk Calculator (Modified Gail Model)

• Does the woman have a medical history of any
  breast cancer or of ductal carcinoma in situ
  (DCIS) or lobular carcinoma in situ (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/
55
Resources http//www.cancer.gov/bcrisktool/ or
Breastcancerprevention.com
56
Case Studies
57
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
• s/p hysterectomy for uterine fibroids, ovaries
  are intact
• No menopausal-type symptoms

58
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

59
What type of breast cancer risk reduction should
Mary be advised to pursue?
Decision Point

• 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

60
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

61
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

62
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

63
What type of treatment regimen would you
recommend for the prevention of breast cancer?
Decision Point
Sue has come in for a checkup. Her menopause
symptoms have been severe and she is wondering
what her options are.

• 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

64
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

65
Case Study Margaret

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

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

66
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

67
How could Margaret best pursue breast cancer
risk reduction?
Decision Point

• 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

68
Case Study Margaret (contd)

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

69
QA

70
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
• Tamoxifene
• Aromatase inhibitors are currently 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 age 35
  without a gene mutation

71
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

72
BreakDont forget to complete and returnyour
CME/CE evaluation form and follow-up
questionnaire to the registration desk at the end
of our program
73
Fall 2007Symposia Series

• St

• Crowne Plaza Hotel Philadelphia-Center City
  Philadelphia, PennsylvaniaOctober 20, 2007

11/15/2009