chemoprevention in familial breast cancer: strategies to ... · fisher, b., et al. (1998)....

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.

http://www.cancer.gov/bcrisktool/

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



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



• 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



• 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



Cumulative Incidences of Invasive Uterine

Cancer and Thromboembolic Events.

Vogel V G et al. Cancer Prev Res 2010;3:696-706


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


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


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

[email protected]

301-435-0538

chemoprevention in familial breast cancer: strategies to ... · fisher, b., et al. (1998)....

Documents