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Breast Cancer
Risk of Recurrence and Impact on QOL
Socioeconomic Burden
Role of Aromatase Inhibitors
Femara – Cost Effectiveness and Outcomes
December 2005
For Internal Use Only
Table of Contents
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•
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•
•
•
•
•
•
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Epidemiology of Breast Cancer
Impact of Breast Cancer on Quality of Life
Available Therapies for Breast Cancer
Risk of Breast Cancer Recurrence
Healthcare Utilization and Costs Associated With Breast
Cancer Recurrence
Beyond Tamoxifen: 3rd-Generation Aromatase Inhibitors
What is “Cost-Effectiveness”?
Cost-Effectiveness of Femara®
Improved Quality of Life With Aromatase Inhibitors
Summary
Epidemiology of
Breast Cancer
For Internal Use Only
Epidemiology of Breast Cancer
• Highly prevalent throughout the world
• Incidence and mortality rates increase with age
• In the United States
–
–
–
–
–
Most frequently diagnosed cancer (excluding skin cancers)
2nd leading cancer-related cause of death, after lung cancer
Associated with high healthcare resource utilization
Poses substantial economic burden on society and patients
Prognosis and survival depend on stage at diagnosis
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.
American Cancer Society Facts and Figures 2005.
Barghout V et al. ECCO, 2005.
Rao S et al. Breast Cancer Res Treat. 2004;83(1):25.
Sasser AC et al. Womens Health Issues. 2005;15(3):97.
Global Incidence, Prevalence, and
Mortality of Breast Cancer
North America
Incidence: 229,631
5-Year Prevalence: 1,058,170
Mortality: 48,239
South America
Incidence: 75,907
5-Year Prevalence: 249,087
Mortality: 24,681
Europe
Incidence: 360,749
5-Year Prevalence: 1,488,759
Mortality: 129,013
Asia
Incidence: 384,985
5-Year Prevalence: 1,346,220
Mortality:152,587
Africa
Incidence: 65,196
5-Year Prevalence: 137,305
Mortality: 44,399
Australia/New Zealand
Incidence: 13,507
5-Year Prevalence: 55,987
Mortality: 3,338
www.who.org.
GLOBOCAN 2002 [online database]. Available at: http://www-dep.iarc.fr/.
Breast Cancer: A Common Disease for
Women In The Developed World
US
Incidence
Japan
Incidence
France
Incidence
Germany
Incidence
Italy
Incidence
Spain
Incidence
UK
Incidence
Local
105,451
Local
17,598
Local
16,025
Local
14,539
Local
11,101
Local
3,051
Local
13,236
Locally
advanced
86,806
Locally
advanced
13,739
Locally
advanced
24,755
Locally
advanced
26,204
Locally
advanced
21,851
Locally
advanced
11,996
Locally
advanced
20,936
Advanced
8,220
Advanced
1,929
Advanced
2,649
Advanced
14,539
Advanced
2,178
Advanced
842
Advanced
2,493
Local stage, stage I; locally advanced stage, stages II and III.
Breast Cancer: Changing Treatment Paradigms for Local and Locally Advanced Breast Cancer. DataMonitor [database online]. April 2005.
Breast Cancer in Europe
• Most common incident form of cancer and cause of
cancer-related death among women*
New Cases
27.4%
20%
13.3%
10%
6.0%
5.0%
0%
Breast
Colon and
rectum
Lung
Stomach
Percent of All Deaths Due to Cancers in 2004
Percent of All Cancers in 2004
30%
Deaths
30%
20%
17.4%
13.4%
9.8%
10%
7.6%
0%
Breast
Colon and
rectum
Lung
Stomach
* Excluding nonmelanoma skin cancer.
Boyle P, Ferlay J. Ann Oncol 2005;16(3):481.
Incidence, Prevalence, and Mortality of
Breast Cancer* in Select European Countries
United Kingdom
Incidence: 33,514
5-Year Prevalence: 129,521
Mortality: 13,198
Sweden
Incidence: 6,188
5-Year Prevalence: 26,929
Mortality: 1,549
Germany
Incidence: 48,098
5-Year Prevalence: 200,353
Mortality: 17,692
France
Incidence: 35,725
5-Year Prevalence:156,539
Mortality: 10,811
Spain
Incidence: 15,528
5-Year Prevalence:67,613
Mortality: 5,773
*1998 estimates.
Denmark
Incidence: 3,665
5-Year Prevalence: 15,152
Mortality: 1,359
Italy
Incidence: 33,076
5-Year Prevalence: 150,617
Mortality: 11,031
www.who.org.
EUCAN. Available at: http://www-dep.iarc.fr/eucan/eucan.htm.
Survival Rates for Breast Cancer in Europe
EUROCARE 3
• Registries covering
– All or part of 22 countries
– 42 types of cancer
• 1.8 million adults diagnosed with
cancer during 1990/1994 and
followed to the end of 1999
• n = 256,273 with breast cancer
SWITZERLAND
ANDORRA
5-Year Survival Rates
Mean: 77%
60-67%
~70%
~77%
>80%
Sant M et al and the EUROCARE Working Group. Ann Onc. 2003;14 (suppl 5):v61.
Cost of Breast Cancer in Europe
• Cumulative 10-year incidence-based cost is approximately €31,774
per postmenopausal breast cancer patient
Death
14%
Other Endocrine
4%
8%
Day clinic
5%
Tests
14%
Visits
1%
Hospital
30%
Chemo/radio/
surgery
24%
• Costs were at their highest after diagnosis and before death
Cocquyt V et al. Ann Oncol. 2003;14:1057.
Cost of Breast Cancer Treatment Is Highest
for Recurrence With Distant Metastases
Total 1-year Treatment Cost, €
Primary
Node-
Primary
Node+
Recurrence
Recurrence With
Metastatic Disease
6893
13,684
12,834
16,551
Cocquyt V et al. Ann Oncol. 2003;14:1057.
Breast Cancer in the United States
• Accounts for 1 in 3 cancers diagnosed in women in the US
• Age
– Incidence and mortality rates increase with age
– Median age (1998-2002) at diagnosis: 61 years
• Race
– After age 35, higher incidence in Caucasians vs African Americans
– Before age 35, higher incidence in African Americans vs Caucasians
– African Americans more likely to die of breast cancer at any age
*Excluding skin cancers.
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.
US Incidence, Mortality, and Prevalence*
• Incidence (2005)
– 211,240 new cases of invasive breast cancer
– 58,490 additional cases of in situ breast cancer
• Mortality (2005)
– 40,410 women
• Prevalence
– 2.3 million†
*
Figures are estimated.
†
Alive as of January 2002 with history of breast cancer.
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.
250
†
New Cases
Deaths
211
(32% of
total)
200
150
80
(12%)
100
74
(11%)
41
(6%)
50
US Women in 2005, times 1000
US Women in 2005, times 1000
Most Frequently Diagnosed Cancer* and
2nd Leading Cause of Cancer-Related Death in the US
250
200
150
100
73
(27% of
total)
40
(15%)
50
28
(10%)
16
(6%)
0
0
Breast
Lung
Colon and
rectum
Uterine
(corpus)
Lung
Breast
Colon and
rectum
Ovary
* Excluding
†
skin cancers.
Invasive breast cancer.
American Cancer Society. Cancer Facts and Figures 2005.
Mortality Rate is Decreasing but
Incidence Rate is Increasing in the US
US Women per Year, times 100,000
160
140
120
100
New Cases
Deaths
80
60
40
20
0
1980
1985
1990
1995
2000
Reasons for changes in mortality and incidence rates
Mortality
Because of increased awareness, earlier detection through screening, and better treatments
Incidence
• Changes in reproductive patterns that increase breast cancer risk (eg, delayed childbirth, having
fewer children)
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.
Survival Rates Correlate With Stage at
Diagnosis and Time Since Diagnosis
Survival Rate Declines Over Time*
120
100
100
98
81
80
60
40
26
20
Survival Rate, %
5-Year Survival Rate, %
5-Year Survival Rate*
88
80
80
71
63
60
40
20
0
0
Localized
Regional
Distant
Metastases
5
10
15
20
Years After Diagnosis
* Based on data from US women diagnosed between 1995-2001 and followed up through 2002.
American Cancer Society. 2004 Cancer Facts and Figures.
American Cancer Society. Breast Cancer Facts and Figures 2005-2006.
Costs of Breast Cancer in the US
• Medical costs
– $8.1 billion (in 2004 dollars) annually
• Total cost of care
– Approximately $74,500 per patient annually
• Average yearly cost to patients*
– Direct cost
• $13,925 versus $2,951 for those without breast cancer, P < .001
– Can be ≥2.5-fold higher for metastatic breast cancer patients
– Indirect costs
• $8,236 versus $2,292 for those without breast cancer, P < .001
* Average annual costs of illness across different stages of the disease (onset, treatment, management, remission, or all).
Brown ML et al. Med Care. 2002;40(8 suppl):IV 104.
Lamerato A et al. SABCS, 2004. Abstract 2084.
Radice D, Redaelli A. Pharmacoeconomics. 2003;21(6):383.
Sasser AC et al. Womens Health Issues 2005 May;15(3):97.
Rao S et al. Breast Cancer Res Treat. 2004;83:25.
Arozullah AM et al. J Supportive Oncol. 2004;2(3):271.
Impact of Breast Cancer on Quality
of Life
For Internal Use Only
QOL is Affected Most By Patients With
Distant Metastases
Preferences for Breast Cancer Health States
Among Women* With Early Breast Cancer
Better
1.0
0.97
0.77
Utility Value
0.8
0.64
0.6
0.4
0.29
0.2
Worse
0.0
Disease free
Locoregional
recurrence
Distant metastases
hormonal treatment
Distant metastases
chemotherapy
Utility values represent patient preferences for alternative health states based on chained standard-gamble technique:
1.0 = perfect health, 0 = death.
* n = 44; 55 to 70-year-old US women; history of stage I or II operable early breast cancer; and experience with
adjuvant hormonal therapy.
ISPOR 7th Annual European Congress. Abstracts. Sorensen et al. Value Health. 2004;7(6):641.
Available Therapies for Breast
Cancer
For Internal Use Only
Timing of Therapy
• Neoadjuvant therapy
– Treatment that occurs before surgery
• Adjuvant therapy
– Treatment occurring after surgery
• Extended adjuvant therapy
– Additional therapy that occurs after standard adjuvant therapy
• For example, when letrozole is given after 5 years of
adjuvant tamoxifen therapy
Adjuvant Therapy Is a Well-Established
Breast Cancer Therapy Throughout the World
Patients Receiving Adjuvant Therapy, %
Localized
Locally advanced
100.0
80.0
60.0
40.0
20.0
0.0
Total
US
Japan France Germany Italy
Spain
UK
Breast Cancer: Changing Treatment Paradigms for Local and Locally Advanced Breast Cancer. DataMonitor [database online]. April 2005.
Broad Categories of Therapy
• Local treatment
– Targets the breast and nearby lymph nodes without treating the
rest of the body
– Surgery
– Radiation
• Systemic therapy
–
–
–
–
–
Targets the entire body
Chemotherapy
Hormonal therapy
Targeted therapy
Others (eg, bisphosphonates)
Hormonal Therapies for Breast Cancer
•
•
Progestins
– Tamoxifen
– Medroxyprogesterone acetate
– Toremifene
– Fulvestrant
Estrogens
– Diethylstilbestrol (DES)
Androgens
– Fluoxymesterone
•
Antiestrogens
– Megestrol acetate
– Estradiol
•
•
LHRH analogs
– Goserelin
– Leuprolide
– Buserelin
LHRH = luteinizing hormone-releasing hormone.
•
Aromatase inhibitors
– Aminoglutethimide
– Fadrozole
– Anastrozole
– Letrozole
– Exemestane
3rd
generation
Tamoxifen
• Traditionally, standard of care for women with estrogen
receptor (ER)-positive early breast cancer
• Reduces risk for recurrence by 47% and mortality rate by
26% (versus controls not receiving tamoxifen)*
• Associated with increased risk for endometrial cancer,
thromboembolic events, vaginal bleeding, and hot
flashes
• Continuing tamoxifen therapy beyond 5 years provides
no additional benefit
– Reduces disease-free survival
– Progressively increases risk for endometrial cancer and
thrombolytic events
* Based on 10 years of follow-up of women with ER+ tumors who received adjuvant tamoxifen for 5 years.
Results reflect data collected and finalized from 1995-1996.
Early Breast Cancer Trialists Collaborative Group. Lancet. 1998;351:1451.
BIG 1-98 Collaborative Group. Unpublished data.
Fisher B et al. J Natl Cancer Inst. 2001;93:684.
No Benefit of Extending Tamoxifen Beyond 5 Years:
NSABP B-14 Trial*
P = 0.03
90
82%
80
78%
70
60
Placebo
Tamoxifen
50
100
Patients Surviving, %
Patients Surviving, %
100
DFS
OS
P = 0.07
94%
90
91%
80
70
60
Placebo
Tamoxifen
50
0 1 2 3 4 5 6 7
Years After 5-year
Treatment With
Tamoxifen
0 1 2 3 4 5 6 7
Years After 5-year
Treatment With
Tamoxifen
•After 5 years of adjuvant tamoxifen, patients were randomized to receive 5 more years of tamoxifen or placebo.
NSABP = National Surgical Adjuvant Breast and Bowel Project.
Fisher B et al. J Natl Cancer Inst. 2001;93:684.
Risk for Breast Cancer Recurrence
For Internal Use Only
Patients Are Always at Risk for Recurrence
• All breast cancer patients are at risk for recurrence, at
any stage of treatment
– After surgery
– After 5 years of treatment with tamoxifen
• More than 50% of all recurrences of breast cancer, and
most deaths, occurs after completion of 5 years of
tamoxifen
• Most recurrence is distant metastasis
• Prognosis after recurrence remains poor
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2005;365:1687
Chaturvedi S et al. Breast Cancer Res Treat. 2005;93(2):151.
Kim KJ et al. Jpn J Clin Oncol. 2005;35(3):126.
Fisher B et al. J Natl Cancer Inst. 1998;90(18):1371.
Recurrence During a 5-Year Period After
Chemotherapy Alone
Complete Responders
• 17.3%: metastases developed
• No local recurrence
Incomplete Responders
• 32.6%: metastases developed
• 4.5%: metastases developed
16.5%
83.5%
5-Year Overall Survival
88% for complete responders
versus
70% for incomplete responders, P = .036
N = 341 patients with breast cancer who were followed up for 5 years after primary (8 cycles, doxorubicin based) chemotherapy.
Chaturvedi S et al. Breast Cancer Res Treat. 2005;93(2):151.
Recurrence After Chemotherapy and
Surgery
• Recurrence
– Local relapse: 2.5%
– Regional relapse: 2.6%
– Distant metastasis: 7.1%
•
•
•
•
5-year overall survival: 95.3%
Local relapse-free survival: 97.2%
Distant metastasis-free survival: 91.3%
Disease-free survival: 88.5%
N = 611 patients with stages I and II breast cancers who received breast-conserving therapy (breast-conserving surgery
[lumpectomy or quadrantectomy] and whole breast irradiation) from October 1994 to December 2000 followed by axillary
lymph node dissection or sentinel lymph node biopsy in 608 cases (99.5%). Median follow-up period was 47 months.
Kim KJ et al. Jpn J Clin Oncol. 2005;35(3):126.
Recurrence in the NSABP Trial:
Tamoxifen versus Placebo
• 13,175 participants
– 6,599 received placebo
– 6,576 received tamoxifen
• Among those receiving placebo
– 244 invasive and noninvasive breast cancer occurrences
• 175 invasive
– Cumulative incidence rate through 69 months = 43.4/1000 women
• 69 noninvasive
– Cumulative incidence rate through 69 months = 15.9/1000 women
– Average annual rate = 2.68/1000 women
Fisher B et al. J Natl Cancer Inst. 1998;90(18):1371.
Probability of Recurrence After Tamoxifen
• After 5 years of tamoxifen
Patients With Recurrence, %
– Annual recurrence rate ratio = 0.59
– Death rate ratio = 0.66
50
45
40
35
30
25
20
15
10
5
0
38.3
45
33.2
26.5
Control
24.7
After ~5 Years
of Tamoxifen
15.1
0
n = 10,386 women; 30% node positive.
5
10
15
Years
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2005;365:1687.
Probability of Death After Tamoxifen
Breast Cancer Mortality Rate, %
• Probability of death is 3-fold higher after 15 years than after
5 years of completion of tamoxifen therapy
40
35
34.8
30
25.7
25.6
25
Control
20
15
After ~5 Years
of Tamoxifen
17.8
11.9
10
8.3
5
0
0
5
10
15
Years
n = 10,386 women; 30% node positive.
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 2005;365:1687.
Risk for Recurrence Remains High
10 Years After Adjuvant Treatment
Patients Who Are Relapse Free, %
Stage II
100
Stage III
94
90
86
84
84
74
80
77
71
60
RFS at 10 years
RFS at 15 years
40
20
0
ER-
ER+
ER-
ER+
n = 1407, treated with adjuvant systemic therapy and remained without recurrence 5 years after diagnosis.
RFS = relapse-free survival.
Hortobagyi GN et al. Proc Am Soc Clin Oncol. 2004;23:23.
Risk for Recurrence is Higher for ER+
Tumors 5 Years Post Surgery
Recurrence Hazard Rate
0.3
ER+ (n = 2257)
ER– (n = 1305)
0.2
0.1
0
0
1
2
3 4 5 6 7 8
Years Post Surgery
9
10 11 12
3,562 women entered the 7 completed and unblinded Eastern Cooperative Oncology Group-coordinated
studies of postoperative adjuvant therapy for breast cancer.
Saphner T et al. J Clin Oncol. 1996;14:2738.
Patients With Distant Metastases, %
Locoregional Recurrence Is Associated With
Substantial Risk for Distant Metastases
70
60
50
40
30
20
10
0
0
1
2
3
4
5
Years
6
7
8
9
10
Based on pooled results of 7 studies (n = 1049).
Moran, Haffty. Breast J 2002;8(2):81.
Doyle et al. Int J Radiat Oncol Biol Phys 2001;51(1):74.
Haylock et al. Int J Radiat Oncol Biol Phys 2000;46(2):355.
Schmoor C et al. J Clin Oncol. 2000;18(8):1696.
Kamby C, Sengelov L. Breast Cancer Res Treat. 1997;45:181.
Borner M et al. J Clin Oncol. 1994;12:2071.
Toonkel LM et al. Int J Radiat Oncol Biol Phys. 1983;9:33.
Most Recurrence Is Distant Metastasis
Recurrence During Tamoxifen Treatment
Contralateral
(9-11%)
Locoregional
(16-28%)
Distant Metastases
(61-75%)
The ATAC Trialists’ Group. Lancet .2002;359:2131.
BIG 1-98 Collaborative Group. Unpublished data.
Prognosis After Recurrence Remains Poor
5-Year Survival Rate, %
50
44
40
29
30
22
20
10
14
10
0
1974-1979
1980-1984
1985-1989
1990-1994
1995-2000
Year of Recurrence
5-year survival rates of individuals with recurrences within 5, 10, 15, and 20 years of treatment
Kaplan-Meier estimated 5-year survival in 834 women with breast cancer recurrence between November 1974 and
December 2000.
Giordano SH et al. Cancer. 2004;100(1):44.
Healthcare Utilization and Costs
Associated With Breast Cancer
Recurrence
For Internal Use Only
Breast Cancer Recurrence
• Results in substantial healthcare utilization and a high
economic burden
– Higher costs post-recurrence than pre-recurrence
– Higher costs for those with recurrence than for those without
recurrence
Lamerato A et al. SABCS 2004. Abstract 2084.
Substantial Increases in Medical Care Costs
Post-recurrence Versus Pre-recurrence
12 Months Pre-recurrence
60
12 Months Post-recurrence
52.3
Costs, $US 1000
50
39.6
40
30.5
30
25.1
20
10
5.7
5.6
6.8
6.2
0
Locoregional Contralateral
n = 21
n = 12
Distant
n = 29
Total
n = 62
Costs derived from charges using cost-to-charge ratio of 0.5 (2004 CMS Payment Impact File).
Lamerato A et al. SABCS 2004. Abstract 2084.
Lifetime Costs, $US 1000
Lifetime Cost Is Greatest Among Those With
Recurrence With Distant Metastasis
100
90
80
69
59
60
40
39
20
0
None
n = 1425
Contralateral
n = 31
Locoregional
n = 47
Distant
n = 113
Costs derived from charges using cost-to-charge ratio of 0.5 (2004 CMS Payment Impact File).
Charges adjusted for differences in age, comorbidities, hormone receptor status, type of treatment, and
duration of follow-up (median 44.5 mo).
Lamerato A et al. SABCS 2004. Abstract 2084.
Metastatic Breast Cancer Results in
Frequent Hospitalizations and Visits
3.0
Mean, n
2.0
2.1
1.9
1.7
Metastatic breast
cancer (n = 397)
Controls (n = 1191)
1.0
0.3
0.5
0.2
0.2
0.2
0.0
Hospitalizations
Per Year
MD Visits
Specialist
MD Visits
Generalist
Home Health Visits
Per Month
Rao S et al. Breast Cancer Res Treat. 2004;83:25.
Cost of Metastatic Breast Cancer
Is Greatest in Younger Patients
Lifetime Costs, $US 1000
120
101
100
80
61
60
57
52
43
40
20
0
<50
n = 9345
50-59
n = 12,919
60-69
n = 16,192
70-79
n = 17,451
80+
n = 14,576
Age at Diagnosis of Metastatic Breast Cancer, years
Berkowitz N et al. Value Health. 2000;3(1):23.
Medical Care Costs For
Recurrent Metastatic Breast Cancer
Total Median Cost per Patient = $72,156
Radiation Therapy
$11,713
16.2%
Hormonal Therapy
$1,307
1.8%
Professional
Services
$19,046
26.4%
Chemotherapy
$3,301
4.6%
Hospital
Admissions
$32,243
44.7%
Evaluation and
Management
Services
$4,546
6.3%
Berkowitz N et al. Value Health. 2000;3(1):23.
Beyond Tamoxifen
3rd-Generation Aromatase Inhibitors
For Internal Use Only
FDA-Approved Indications
Adjuvant therapy for
early breast cancer
Tamoxifen
Femara®
Arimidex®
Aromasin®
√
Filed
√
√*
√
Extended adjuvant
therapy for early breast
cancer
1st-Line for advanced
breast cancer
2nd-Line for advanced
breast cancer
√
√
√
√
√
√
* Adjuvant treatment of postmenopausal women with ER+ early breast cancer who have received 2 to 3 years of
tamoxifen and are switched to Aromasin for completion of a total of 5 consecutive years of adjuvant hormonal therapy.
European-Approved Indications
Adjuvant Therapy for
Early Breast Cancer
Tamoxifen
Femara®
Arimidex®
Aromasin®
√
Filed
√
√*
√
Extended Adjuvant
Therapy for Early
Breast Cancer
√ (UK)
Neoadjuvant
1st-Line for Advanced
Breast Cancer
2nd-Line for Advanced
Breast Cancer
√
√
√
√
√
√
* Adjuvant treatment of postmenopausal women with ER+ early breast cancer who have received 2 to 3 years of tamoxifen and
are switched to Aromasin for completion of a total of 5 consecutive years of adjuvant hormonal therapy.
Femara® is Superior to Tamoxifen:
Adjuvant Therapy in Early Breast Cancer
As an adjuvant therapy, Femara
• Significantly prolongs disease-free survival* compared
with tamoxifen
– Decreases the risk for recurrence by 19%, P = .003
• Demonstrates significant benefit in higher-risk patients
– 29% reduction in the risk for recurrence in node-positive patients
– 30% reduction in the risk for recurrence for chemotherapy
treated-patients
• Significantly improves distant disease-free survival rate
compared with tamoxifen
– Decreases risk for distant metastases by 27%, P = .0012
• Decreases mortality rate by 14%, P = NS
* Disease-free survival = the time from randomization to the first recurrence in local, regional, or distant sites; a new
invasive breast cancer in the contralateral breast; any second non-breast malignancy; or death from any cause.
NS = non significant.
BIG 1-98 Collaborative Group 2005. Unpublished data.
Femara® As an Extended Adjuvant Therapy
in Early Breast Cancer
As an extended adjuvant therapy, Femara
• Significantly improves disease-free survival* rate
compared with placebo, P = .00003
• Significantly improves distant disease-free survival
– Decreases risk for distant metastases by 40% compared with
placebo, P = .002
• Reduces risk for recurrence regardless of node status
• In node-positive patients, overall survival rate was
significantly improved compared with that of placebo,
P = .04
* Disease-free survival = time from randomization to earliest recurrence of primary disease (in the breast, chest wall,
nodal sites, or metastatic sites) or development of a new primary cancer in the contralateral breast.
Goss PE et al. J Natl Cancer Inst 2005;97(17):1262.
Femara® is Superior to Tamoxifen:
1st-Line Treatment of Advanced Breast Cancer
Compared with tamoxifen, Femara
• Significantly increases
– Time to progression, P < .0001
– Time to treatment failure, P < .0001
• Significantly improves
– Overall clinical benefit, P = .0004
– 1-Year survival rate, P = .004
– 2-Year survival rate, P = .02
• Improves overall survival rate
– An exploratory analysis of patients who did not cross over
showed improvement in survival rate for Femara
Mouridsen H et al. J Clin Oncol. 2003;21:2101.
Femara® is Superior to Megestrol Acetate:
2nd-Line Treatment of Advanced Breast Cancer
• Femara significantly
– Improves overall response
• P = .04 (Femara 2.5 mg vs megestrol acetate)
• P = .004 (Femara 0.5 mg vs megestrol acetate)
– Prolongs duration of objective response
• P = .02 (Femara 2.5 mg vs megestrol acetate at 33 months)
• P = .0009 (Femara 2.5 mg vs megestrol acetate at 51 months)
– Improves time to treatment failure (TTF)
Median TTF, months
P
Femara 2.5 mg
5.1
Megastrol acetate
3.9
.04
Femara 0.5 mg
3.2
.002
Dombernowsky P et al. J Clin Oncol 1998;16(2):453.
Chaudri HA et al. J Clin Oncol. 1999;17(12):3859 [letter].
What is “Cost-Effectiveness”?
For Internal Use Only
What is a Cost-Effectiveness Analysis?
• A tool used to aid decisions about which medical care should
be provided when resources are limited
• Goal is to determine whether expected benefits of an
intervention justify expected additional costs
• Requires consideration of 2 or more alternatives
• Typically involves uncertainty regarding outcomes and costs
• Cost-effectiveness (CE) expressed as a ratio
CostNew - CostOld
CE RatioNew vs Old =
EffectivenessNew - EffectivenessOld
What is a QALY and a Utility?
• QALY = quality-adjusted life-year
– A measure of health outcome that adjusts life expectancy, or
expected life-years (LYs), for the quality of life during those years
QALY = LY  utility
– QALYs provide a common unit for comparison of health outcomes
across different interventions or health problems
• Utilities are weights that represent patient preferences for
different health states
– Range from 0.0 (dead) to 1.0 (perfect health)
What is a “Cost-Effective” Intervention?
• CE ratio of $50,000 per QALY gained has long been
cited as the threshold for cost-effectiveness in the US
• Recent studies suggest threshold may be considerably
higher (>$100,000 per QALY)
– Many commonly used therapies have CE ratios greater than
$50,000 per QALY (eg, annual pap smears)
• CE ratio of ₤20,000 - ₤30,000 per QALY ($37,000 $55,000) is implied by NICE as an acceptable threshold
in the UK
• Many therapies have CE ratios above 100,000 per QALY
– eg, HER-2 testing and trastuzumab treatment for metastatic
breast cancer, ondansetron for cisplatin-induced emesis
Earle CC et al. J Clin Oncol. 2000;18:3302.
Ubel PA et al. Arch Intern Med. 2003;163:1637.
Hirth RA et al. Med Decis Making. 2000;20(3):332.
Towse A, et al. Pharmacoeconomics. 2002;20(suppl 3):95.
Devlin N, Parkin D. Health Econ. 2004;13(5):437.
Elkin EB et al. J Clin Oncol. 2004;22:854.
Zbrozek AS et al. Am J Hosp Pharm. 1994:51:1555.
Cost Effectiveness of Femara®
For Internal Use Only
Femara® Is Cost-Effective as Adjuvant, Extended
Adjuvant, 1st-Line, and 2nd-Line Therapies
Adjuvant Therapy for Early Breast Cancer
√
Karnon J et al. ECCO, 2005. Abstract 341.
Delea T et al. SABC, 2005. Abstract 2054.
Extended Adjuvant Therapy for Early Breast
Cancer
√
Delea T et al. SABC, 2004. Abstract 1050.
Karnon J et al. Pharmacoeconomics. In press.
1st-Line Therapy for Advanced Breast Cancer
√
Delea T et al. SABC, 2003. Abstract 542.
Karnon J et al. Pharmacoeconomics. 2003;21(7):513.
Karnon J et al. Ann Oncol. 2003;14:1629.
Dranat saris G et al. Am J Clin Oncol. 2003;26(3):289.
Marchetti M et al. Clin Ther. 2004;26(9):1546.
Okubo et al. Gan To Kagaku Ryoho. 2005;32(3):351.
2nd-Line Therapy for Advanced Breast Cancer
√
Dranitsaris G et al. Anticancer Drugs. 2000;11:591.
Femara® is Cost-Effective Compared With
Tamoxifen in the Early Adjuvant Setting (UK)
CostFemara – CostTAM
QALYFemara – QALYTAM
£14,075 – £10,023
=
12.79 – 12.49
£4,052
=
0.3
=
£13,643 per
QALY gained
Acceptable CE
Ratio in UK = £2030,000
TAM = tamoxifen.
Karnon J et al. ECCO 2005. Abstract 341.
Femara® is Cost-Effective Compared With
Tamoxifen in the Early Adjuvant Setting (US)
CostFemara – CostTAM
QALYFemara – QALYTAM
$63,990 – 54,964
=
13.10 – 12.82
$9,026
=
0.28
=
$32,236 per
QALY gained
Acceptable CE
Ratio in US
$50,000
Delea T et al. SABCS 2005. Abstract 2054.
Femara® is Cost-Effective in the
Extended Adjuvant Setting (UK)
CostFemara – CostPlacebo
QALYFemara – QALYPlacebo
£10,833 – £7,101
=
13.66 – 13.30
£3,732
=
0.36
=
£10,338 per
QALY gained
Acceptable CE
Ratio in UK = £2030,000
Karnon J et al. Pharmacoeconomics. In press.
Femara® is Cost-Effective in the
Extended Adjuvant Setting (US)
CostFemara – CostPlacebo
QALYFemara – QALYPlacebo
$32,561 – $23,761
=
13.232 – 12.894
$8,800
=
0.338
=
$26,000 per
QALY gained
Acceptable CE
Ratio in US
$50,000
Delea T et al. SABCS 2004. Abstract 1050.
Recent Cost Effectiveness Ratios
in Oncology
Postmastectomy radiation therapy in EBC
Early adjuvant treatment with Femara® vs tamoxifen in HR+
postmenopausal women with EBC
Axillary node dissection in ER+ EBC
Pamidronate in MBC and bone lesions receiving chemotherapy
FISH testing + trastuzumab in MBC
Ondansetron in cisplatin-induced emesis, 40-kg patient
Ondansetron in cisplatin-induced emesis, 70-kg patient
0
100
200
300
400
$000 / QALY
EBV = early-stage breast cancer; FISH = fluorescent in situ hybridization;
MBC = metastatic breast cancer.
Lee JH et al. J Clin Oncol. 2002;20(11):2713.
Orr RK et al. Surgery. 1999:126:568.
Hillner BE et al. J Clin Oncol. 2000:18:79.
Elkin EB et al. J Clin Oncol. 2004;22:854.
Zbrozek AS et al. Am J Hosp Pharm. 1994:51:1555.
Cost-Effectiveness Ratios for Early Adjuvant
Breast Cancer Therapies: US Perspective
Arimidex® vs tamoxifen
(Locker et al. SABCS, 2004)
Femara® vs tamoxifen
(Delea et al. SABCS, 2005)
Arimidex® vs tamoxifen
(Hillner et al. Cancer. 2004)
0
20
40
60
Cost ($000) per QALY
80
Cost-Effectiveness Ratios for Adjuvant
Breast Cancer Therapy: UK Perspective
Arimidex® vs tamoxifen
(Mansel et al. ESMO, 2004)
Femara® vs tamoxifen
(Karnon et al. ECCO, 2005)
Arimidex® vs tamoxifen
(Hillner et al. Cancer. 2004, converted from US$)
0
10
20
30
Cost (£000) / QALY
40
50
Quality of Life And
Aromatase Inhibitors
For Internal Use Only
Femara® Is Associated With Better QOL Than
Arimidex®: 2nd-Line Therapy
P = .02
Worse
50
45
48.5
43.4
QOL Score
40
35
30
25
20
15
Better
10
Femara
Arimidex
N = 72 women with asymptomatic or symptomatic controlled disease who had taken tamoxifen previously.
Crossover study in which patients took Femara (4 weeks) then Arimidex (4 weeks) or visa versa.
Thomas R. Am J Clin Oncol. 2003;26:S40.
Patient Preference
for Treatment, %
Patients Prefer* Femara® Over Arimidex®:
2nd-Line Therapy
100
90
80
70
60
50
40
30
20
10
0
P < .01
68
32
Femara
Anastrazole
* The reasons given for the treatment preference were adverse event-based, including nausea, hot flashes, and
abdominal symptoms with current therapy.
N = 72 women with asymptomatic or symptomatic controlled disease who had taken tamoxifen previously. Cross-over
study in which patients took Femara (4 weeks) then Arimidex® (4 weeks) or visa versa.
Thomas R. Am J Clin Oncol. 2003;26:S40.
QOL Does Not Diminish Over Time With
Extended Adjuvant Femara® Treatment
Physical Component Summary
Mental Health Component Summary
(Physical functioning, role -physical,
bodily pain, general health)
(Vitality, social functioning, role-emotional,
mental health)
10
8
6
4
2
0
0
10
20
30
Months From randomization
Mean Change in Score
Mean Change in Score
• No change over time in SF-36 scores
100
Femara®
Placebo
80
60
40
0
10
20
30
Months From randomization
– Small differences (< 0.2 standard deviations; P  0.003) for
• Physical function domain (12 mo)
• Bodily pain domain (6 mo)
• Vitality domain (6 and 12 mo)
n = 3612 women (1799 placebo; 1813 letrozole).
Whelan TJ et al. J Clin Oncol. 2005;23(28):6931.
QOL Does Not Diminish Over Time With
Extended Adjuvant Femara® Treatment
• No changes in MENQOL scores over time
– Slight differences in MENQOL vasomotor (6, 12, and 24 months)
and sexual function (12 and 24 months) domains in Femara
group reflecting consequences of estrogen depletion
MENQOL Sexual Domain
10
QOL score over time
QOL score over time
MENQOL Vasomotor Domain
8
6
4
2
0
0
10
20
30
Months From randomization
n = 3612 women (1799 placebo; 1813 letrozole).
10
Femara
Placebo
8
6
4
2
0
0
10
20
30
Months From randomization
Whelan TJ et al. J Clin Oncol. 2005;23(28):6931.
Quality-Adjusted Survival Favors Femara®:
Advanced 1st-Line Therapy
• Time without symptoms or toxicity
– Significantly longer with Femara (11.5 months) versus tamoxifen
(8.5 months; P < .001)
• Mean duration of disease progression
– Significantly shorter with Femara (11.5 months) versus tamoxifen
(12.7 months, P = .047)
• Quality-adjusted time without symptoms or toxicity
– Significant difference (2.5 months, P < .0001) in quality-adjusted
survival, favoring letrozole across all utility weights
Data from the P025 trial were reanalyzed taking into account the QOL of the patients using the Q-TWiST* (quality-adjusted
time without symptoms or toxicity) approach.
Irish W et al. Ann Oncol . 2005;16:1458.
Femara® Does Not Worsen Performance
Status: Advanced 2nd Line Therapy
• Megestrol treatment results in
– Significantly more patients experiencing a deterioration of WHO
performance status (55% vs 41% for Femara®, P = .01)
– Higher incidence of dyspnea, which was reflected in consistently
higher dyspnea in the QOL scale, than with Femara®
– Lower scores in physical functioning, which reflects the higher
levels of worsening of performance status, than Femara®
– No major differences in QOL compared with Femara®
WHO = World Health Organization.
Dombernowsky P et al. J Clin Oncol. 1998;16(2):453.
Femara® European Label Includes QOL
Results for Extended Adjuvant Therapy
• No significant differences were observed on global
physical and mental summary scores, suggesting that
overall, letrozole did not worsen QOL relative to placebo
• Treatment differences in favor of placebo were observed
in patients’ assessments particularly with the measures
of physical functioning, bodily pain, vitality, and sexual
and vasomotor items
• Although statistically significant, these differences were
not considered clinically relevant
Summary
• Breast cancer is a highly prevalent disease throughout the world
– Mortality rate is decreasing but incidence continues to rise
• Breast cancer poses a substantial economic burden on society and
patients in the US and Europe
• Breast cancer leads to a substantial decline in QOL
• All breast cancer patients are at risk for recurrence, at any stage of
treatment
– Prognosis after recurrence remains poor
• Femara® is approved (or approval has been requested) across all
categories of breast cancer treatment
• Femara® is cost-effective in the early adjuvant, extended adjuvant,
and advanced treatment settings from both the US and the UK
perspectives