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Kathleen Calzone, PhD, RN, APNG, FAAN
April 13, 2013
Chemoprevention in Familial Breast Cancer:
Strategies to Reduce Cancer Risk
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
National Institutes of Health
National Cancer Institute
Center for Cancer Research-Genetics Branch
Breast Cancer Chemoprevention History
Cazzaniga, C. , Bonanni, B. Breast cancer chemoprevention: Old and new approaches, JBB, 2012; 985620
Figure 1:
Model of Carcinogenesis
Cazzaniga, C. , Bonanni, B. Breast cancer chemoprevention: Old and new approaches, JBB, 2012; 985620
Figure 2:
Chemoprevention Key Considerations
• Defining Risk
– Optimal candidates
• Toxicity
– Risk/benefit ratio
• Intervention
– Agents
– Behavior modifications
• Diet, exercise
• Outcome
– Clinical
– Biomarker
Breast Cancer Risk Assessment Models
Gail, M.H., Mai, P. Comparing breast cancer risk assessment models. JNCI, 2010; 102:665-8
Know Risk Factors and Model Inclusion
Risk Factor Gail Claus BRCAPro IBIS BOADICEA
Personal Factors
Age Yes Yes Yes Yes Yes
BMI No No No Yes No
Alcohol intake No No No No No
Hormonal and Reproductive
Age menarche Yes No No Yes No
AFLB Yes No No Yes No
Age
menopause
No No No Yes No
HRT No No No Yes No
OCP No No No No No
Breast feed No No No No No
Plasma
estrogen level
No No No No No
Amir et al. Assessing women at high risk of breast cancer: A review of breast cancer risk assessment models. JNCI, 2010; 102:680-691.
Know Risk Factors and Model Inclusion, cont
Risk Factor Gail Claus BRCAPro IBIS BOADICEA
Personal Hx of Breast Disease
Breast Biopsies Yes No No Yes No
Atypical
Hyperplasia
Yes No No Yes No
LCIS No No No Yes No
Breast Density No No No No No
Family History of Breast and/or Ovarian Cancer
FDR Br Yes Yes Yes Yes Yes
SDR Br No Yes Yes Yes Yes
TDR Br No No No No Yes
Age of Br onset No Yes Yes Yes Yes
Bil Br in relative No No Yes Yes Yes
Ov in relative No Yes* Yes Yes Yes
Male Br No No Yes No Yes
Amir et al. Assessing women at high risk of breast cancer: A review of breast cancer risk assessment models. JNCI, 2010; 102:680-691.
Spectrum of Breast Cancer Risk
Foulkes W. N Engl J Med 2008;359:2143-2153
Next Generation
Breast Cancer Risk Assessment Tools
• Race/Ethnicity
• SNPs
• Mammographic Density
http://www.cancer.gov/bcrisktool/
Gail, M.H. (2008). Discriminatory accuracy from single-nucleotide polymorphisms in models to predict breast
cancer risk. JNCI, 100, 1037-41
Wacholder, S, et al. (2010). Performance of common genetic variants in breast-cancer risk models. NEJM,
362, 986-93
Chatterjee, N. et al. (2011). Predicting the future of genetic risk prediction, CEBP, 20, 3-8.
Agents
• Selective Estrogen Receptor Modulators
(SERMS)
– Target estrogen action
• Tamoxifen
• Raloxifene
• Lasofoxifene
• Arzoxifene
• Aromatase Inhibitors (AIS)
– Target estrogen production
• Exemestane
• Anastrozole
• Letrozole
SERM: Tamoxifen
• Competition for circulating estrogen with estrogen receptor
binding
• Four placebo controlled randomized trials
Trial Dates Population Randomized Tam
Dose
Duration Median
FU (mo)
NSABP
P1
1992-97 35-59 with
>1.66% 5 yr
or
>60 or LCIS
13,388 20mg 5 years 84
Royal
Marsden
1986-96 High risk, Fm
Hx
2,471 20mg 5-8 years 156
Italian 1992-97 Nml risk,
Hysterectomy
5,408 20mg 5 years 132
IBIS-1 1992-
2001
>RR 2.0 7,152 20 mg 5 years 96
IBIS=International Breast Cancer Intervention Study Cuzick et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet, 2003; 361:296-300.
Sestak, I., Cuzick, J. Preventive therapy for breast cancer. COR, 2012; 14:568-573.
Primary Outcomes, NSABP P-1
Breast Cancer Relative Risk (95%CI)
All invasive breast cancer 0.57; 0.46-0.70
-ER negative 1.31; 0.86-2.01
-ER positive 0.38; 0.28-0.50
-ER unknown 0.72; 0.38-1.35
DCIS 0.63; 0.45-0.89
Fisher, B., et al. (2005). Tamoxifen for the prevention of breast cancer: current status of the National Surgical
Adjuvant Breast and Bowel Project P-1 study. JNCI, 97, 1652-1662
• Significant benefits seen in patients with
histories of risk associated lesions
– Lobular carcinoma in situ RR 0.54; 0.27-1.02
– Atypical hyperplasia RR 0.25; 0.10-0.52
OR Developing ER+ Invasive Breast Ca in
Tamoxifen Chemoprevention Trials
Cazzaniga, C. , Bonanni, B. Breast cancer chemoprevention: Old and new approaches, JBB, 2012; 985620 Cuzick et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet, 2003; 361:296-300.
OR Developing ER- Invasive Breast Ca in
Tamoxifen Chemoprevention Trials
Cazzaniga, C. , Bonanni, B. Breast cancer chemoprevention: Old and new approaches, JBB, 2012; 985620 Cuzick et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet, 2003; 361:296-300.
Major Adverse Events, Combined Outcomes
Event Tamoxifen versus
Control
Consensus
Relative Risk
Cancer Events
Endometrial cancer 53/22 2.4 (1.5-4.0; p=0.0005)
Thromboembolic Events
Venous thrombosis (excluding
superficial)
118/62
1.9 (1.4-2.6; p<0.0001)
Superficial thrombophlebitis 68/30
Cardiovascular Events
Myocardial infarction 47/41
Not Reported Cerebrovascular 96/93
CVA/stroke 59/39
TIA only 27/45
Cuzick, J., et al. (2003). Overview of the main outcomes in breast-cancer prevention trials. Lancet, 361, 296-300.
Major Adverse Events, cont
• NSABP P-1, elevation in major AE’s mostly ≥ 50
– Endometrial cancer RR 3.28; 95% CI, 1.87-6.03
• ≤49y, RR 1.42; 95% CI, 0.55-3.81
• ≥50y, RR 5.33; 95% CI, 2.47-13.17
– Pulmonary emboli RR 2.15; 95% CI, 1.08-4.51
• ≤49y, RR 2.01; 95% CI, 0.29-22.19
• ≥50y, RR 2.16; 95% CI, 1.02-4.89
– DVT RR 1.44; 95% CI, 0.9-2.30
• ≤49y, RR 1.34; 95% CI, 0.59-3.10
• ≥50y, RR 1.49; 95% CI, 0.84-2.68
Fisher, B., et al. (2005). Tamoxifen for the prevention of breast cancer: current status of the National Surgical
Adjuvant Breast and Bowel Project P-1 study. JNCI, 97, 1652-62
Other Adverse Events, NSABP P-1
Event Relative Risk (95% CI)
Fractures 0.68; 0.51-0.92
Cataracts 1.14; 1.01-1.29
Stroke 1.42; 0.97-2.08
All ischemic heart disease events 1.03; 0.79-1.36
Vaginal discharge 1.60; range not reported
Hot flashes 1.19; range not reported
Cold sweats 1.45; range not reported
Night sweats 1.22; range not reported
Clinically significant CES-D 0.93; range not reported
Day, R., et al. (1999). Health-related quality of life and Tamoxifen in breast cancer prevention: a report from the
National Surgical Adjuvant Breast and Bowel Project P-1 study. JCO, 17, 2659-2669
Fisher, B., et al. (1998). Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast
and Bowel Project P-1 study. JNCI, 90, 1371-1388
Fisher, B., et al. (2005). Tamoxifen for the prevention of breast cancer: current status of the National Surgical
Adjuvant Breast and Bowel Project P-1 study. JNCI, 97, 1652-1662
• No difference between placebo and Tamoxifen in SF-36
SERM: Raloxifene
• Estrogen agonistic effects on bone and lipids
• Estrogen antagonistic effects on endometrium and breast tissue
Trial Dates Population Randomized Ralox
Dose
Duration Median
FU (mo)
MORE* 1994-
98
Osteoporosis
PM
7705 60mg/
120mg
4 years 96
CORE (cont MORE)
1998-
2002
Osteoporosis
PM
4,011 MORE
rand cont
60mg Additional
4 years
96
RUTH 1998-
2000
Risk of CHD
PM
10,101 60mg 5 years 66.7
NSABP
P-2
1999-
2004
>1.66% 5 yr
LCIS, PM, >35
19,471 Ral 60mg/
Tam 20mg
5 years 81
Cummings SR, et al. (1999). The effect of raloxifene on risk of breast cancer in postmenopausal women: results from
the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA, 281, 2189-97.
Cuzick et al. (2003). Overview of the main outcomes in breast-cancer prevention trials. Lancet, 361, 296-300.
Martino, S. et al. (2004). Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal
osteoporotic women in a randomized trial of raloxifene. JNCI, 96, 1751-61
Vogel, V.G., et al. (2010). Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and
Raloxifene (STAR) P-2 Trial: Preventing breast cancer. CPR, 3, 696-706
Raloxifene Outcomes, NSABP P-2
Breast Cancer Relative Risk (95%CI)
Ralox vs Tam
All invasive breast cancer 1.24; 1.05-1.47
DCIS 1.22; 0.88-1.69
Vogel, V.G., et al. (2010). Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and
Raloxifene (STAR) P-2 Trial: Preventing breast cancer. CPR, 3, 696-706
• Benefit patients with histories of risk associated
lesions
– Lobular carcinoma in situ RR 1.13; 0.76-1.69
– Atypical hyperplasia RR 1.48; 1.06-2.09
Cumulative Incidences of Invasive and
Noninvasive Breast Cancer
Vogel V G et al. Cancer Prev Res 2010;3:696-706
©2010 by American Association for Cancer Research
NSABP P-2 Major Adverse Events
Event Relative Risk (95% CI)
Uterine Disease Events
Endometrial cancer 0.55; 0.36-0.83
Uterine hyperplasia 0.19; 0.12-0.29
Thromboembolic Events
Venous thrombosis
(excluding superficial)
0.75; 0.60-0.93
PE 0.80; 0.57-1.11
DVT 0.72; 0.54-0.95
Other Events
Cataracts 0.80; 0.72-0.89
Vogel, V.G., et al. (2010). Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and
Raloxifene (STAR) P-2 Trial: Preventing breast cancer. CPR, 3, 696-706
Cumulative Incidences of Invasive Uterine
Cancer and Thromboembolic Events.
Vogel V G et al. Cancer Prev Res 2010;3:696-706
©2010 by American Association for Cancer Research
Risk Of Breast Cancer From Pooled Estimates
Overall and for Each Treatment Separately
Cummings S R et al. JNCI J Natl Cancer Inst 2009;101:384-398
© The Author 2009. Published by Oxford University Press.
All invasive breast ca ER+ invasive breast ca
SERM: Lasofoxifene and Arzoxifene
• Both agents were found to reduce breast cancer events
– Lasofoxifene significantly reduced coronary events, strokes,
and fractures
• Development of lasofoxifene for breast cancer prevention has not
proceeded
– Arzoxifene reduced fractures but increased thromboembolic
events, hot flashes, muscle cramps, and GYN events
• Development of arzoxifene has been discontinued
Trial Dates Population Randomized Dose Duration Median
FU (mo)
PEARL 2001-
2007
Osteoporosis
PM
8,856 Lasox
0.50mg/
0.25mg
5 years 59.6
GENERA-
TIONS
2004-
2009
Osteoporosis or
low BMD, PM
9,354 Arzox 20mg 4 years 54.3
Sestak, I., Cuzick, J. Preventive therapy for breast cancer. COR, 2012; 14:568-573.
.
Pharmacogenomics:
Polymorphisms and Phenotype • UM-Ultrarapid Metabolizer
– Unusually high activity of a drug metabolizing enzyme (DME) or drug
transport protein (DTP)
– Limited response to recommended doses
• EM-Extensive Metabolizer
– Wild-type (normal activity) form of a DME or DTP
– Expected efficacy at recommended doses
• IM-Intermediate Metabolizer
– Reduced activity of a DME or DTP
– Some decreased efficacy at recommended doses
• PM-Poor Metabolizer
– Very low or no activity of a DME or DTP
– Increased toxicity
– Decreased efficacy at recommended doses
Katz et al. (2008). Defining drug disposition determinants: A pharmacogenetic–pharmacokinetic strategy. Nature Reviews Drug Discovery, 7, 293-305.
• Cases (591)/controls (1126) study from the NSABP P-1 and P-2 and breast cancer events
– Determine the impact of CYP2D6 genotype
– CYP2D6 inhibitor use
– Metabolizer status
• CYP2D6 genotype combined with CYP2D6 inhibitor use
• Treated with tamoxifen
– No association with CYP2D6 genotype, use of a potent CYP2D6
inhibitor, or CYP2D6 metabolizer status with breast cancer
occurrence
• Treated with raloxifene
– No association with CYP2D6 genotype, use of a potent CYP2D6
inhibitor, or CYP2D6 metabolizer status with breast cancer
occurrence.
Goetz et al. (2011). Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in women treated for breast
cancer chemoprevention: results from the NSABP P1 and P2 clinical trials. CCR 17(21):6944-6951
CYP2D6 and NSABP P-1 and P-2 Outcomes
AI: Exemestane
• Interferes with the adrenal enzyme aromatase, which is
responsible for estrogen production in postmenopausal
women
• Prevents estrogen synthesis
Trial Dates Population Randomized Dose Duration Median
FU (mo)
MAP.3 2004-
2010
>1.66% 5 yr
LCIS, PM
4,560 25mg 5 years 35
Dunn, B.K. et al. (2012). Exemestane: one part of the chemopreventive spectrum for ER postive breast cancer.
Breast, S0960-9776(13)00048-9
Goss, P.E.et al. (2011). Exemestane for breast cancer prevention in postmenopausal women. NEJM, 364, 1281-
2391.
Design of NCIC MAP.3 Trial
DeCensi A et al. Cancer Discovery 2012;2:25-40
©2012 by American Association for Cancer Research
Cumulative Incidence of Invasive Breast Cancer
Goss PE et al. N Engl J Med 2011;364:2381-2391.
AIs: New Primary Breast Cancer Events in
Contralateral Breast In Adjuvant Trials
DeCensi A et al. Cancer Discovery 2012;2:25-40
©2012 by American Association for Cancer Research
Primary Outcomes, MAP.3
Breast Cancer Hazard Ratio (95%CI)
All invasive breast cancer 0.35; 0.18–0.70
-ER negative 0.80; 0.21–2.98
-ER positive 0.27; 0.12–0.60
-PR negative 0.80; 0.21–2.98
-PR positive 0.26; 0.10–0.69
-Her2 negative 0.40; 0.19–0.82
DCIS 0.65; 0.28–1.51
All invasive and DCIS 0.47; 0.27–0.79
LCIS, AH 0.36; 0.11–1.12
Goss PE, et al. (2011). Exemestane for breast-cancer prevention in postmenopausal women. NEJM, 364, 2381–91
MAP.3 Major Adverse Events
Event Exemestane
N(%)
Placebo
N(%)
Pvalue
Hot Flashes 900 (40) 718 (32) <0.001
Fatigue 525 (23) 465 (21) 0.03
Vaginal dryness 352 (16) 343 (15) 0.68
Arthritis 247 (11) 196 (9) 0.01
Joint pain 665 (30) 606 (27) 0.04
Fractures 149 (6.7) 143 (6.4) 0.72
Osteoporosis 37 (1.7) 30 (1.3) 0.39
Cardiovascular
events
106 (4.7) 111 (4.9) 0.78
• Minor differences in health related quality of life as
measured by SF36 and MENQOL
– Vasomotor Goss PE, et al. (2011). Exemestane for breast-cancer prevention in postmenopausal women. NEJM, 364, 2381–91
Limitations
• Short follow-up
• Systematic bone assessments including
DEXA scans and fracture reporting was not
done
• Loose definition of “high risk,” especially
including all women ≥60 years of age, even
those with Gail model risk ≤1.66%
• Crossover to exemestane is being offered
to women on placebo diminishing follow-up
value DeCensi, A. et al. (2012). Exemestane for Breast Cancer Prevention: A Critical Shift? Cancer Discovery. 2, 25-
40
AI: Anastrozole
Trial Dates Population Randomized Tam/
Anas
Dose
Duration Median
FU (mo)
IBIS-II 2003-
2012
Prevention
PM
Increased risk:
-family hx,
-breast density,
-benign breast
disease
DCIS
Locally excised
ER or PR+
DCIS
Prevention
3864
DCIS
2980
Prev
Placebo/
Anas
1mg
DCIS
Tam
20mg/
Anas
1mg
5 years 35
http://www.ibis-trials.org/news/viewStory.php?storyId=186
http://www.breastinternationalgroup.org/Research/BIGClinicalTrials/BIG502IBISII.aspx
Cuzick, J., et al. (2008). IBIS II: a breast cancer prevention trial in postmenopausal women using the aromatase
inhibitor anastrozole. ERAT, 8, 1377-1335.
Systematic Review:
Uptake of Chemoprevention
• 13 studies (8 hypothetical, 4 actual, 1 both)
• Hypothetical decisions
– 9 studies
– Mean uptake rate, 24.7%; range 5.7-60.0%
• Actual decisions
– 5 studies
– Mean uptake rate, 14.8%; range 0.5%-51.2%
• One outlier study reported 51.2% uptake
– Abnormal biopsy and MD recommendation predicted use
• Mean of remaining 4 studies 5.7% Ropka, M.E., et al. (2010). Patient decisions about breast cancer chemoprevention: a systematic review and meta-
analysis. JCO, 28, 3090-5
Bober, S.L. et al. (2004). Decision-making about tamoxifen in women at high risk for breast cancer: clinical and
psychological factors. JCO, 22, 4951-7
Factors Associated with Uptake
• Increased uptake
– Perceived vulnerability to breast cancer
• 5 year Gail score associated in 1/3 studies
• Lower education level in 1/4 studies
• Reduced uptake
– Concern for adverse effects
– Studies enrolling only high risk subjects
– Education or decision support intervention
Ropka, M.E., et al. (2010). Patient decisions about breast cancer chemoprevention: a systematic review and meta-
analysis. JCO, 28, 3090-5
On the Horizon
• Same agents, new delivery methods/duration
• Biologic endpoints
• New agents
– Statins
– NSAIDS
– Bisphosphonates
– Metformin
– Retinoids/Rexinoids
– DHA (docosahexaenoic acid-omega 3FA)
– PARP Inhibitors
– Kinase Inhibitors
Conclusions
• Tamoxifen and Raloxifene FDA approved
– Prevent estrogen receptor positive breast cancer
• Tamoxifen
– Clear benefit, sustained benefit after treatment complete,
only option for premenopausal women
• Raloxifene
– Safety profile superior to tamoxifen, slightly lower efficacy, no
data yet available on sustained benefit
• Exemestane
– Promising but additional study still needed
• Breast cancer chemoprevention uptake rates low with
wide variation
Acknowledgement
• Barbara K. Dunn, MD, PhD
Medical Officer
National Cancer Institute,
Division of Cancer Prevention
Chemoprevention Agent Development Research
Group
Questions/Discussion
calzonek@mail.nih.gov
301-435-0538
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