Breast Cancer Risk of Recurrence and Impact on QOL Socioeconomic Burden Role of Aromatase Inhibitors Femara

1
Breast Cancer Risk of Recurrence and Impact on
QOLSocioeconomic BurdenRole of Aromatase
InhibitorsFemara Cost Effectiveness and
Outcomes

• December 2005

2
Table of Contents

• 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

3
Epidemiology of Breast Cancer
4
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.
200483(1)25. Sasser AC et al. Womens Health
Issues. 200515(3)97.
5
Global Incidence, Prevalence, and Mortality of
Breast Cancer
North America Incidence 229,631 5-Year
Prevalence 1,058,170 Mortality 48,239
Asia Incidence 384,985 5-Year Prevalence
1,346,220 Mortality152,587
Europe Incidence 360,749 5-Year Prevalence
1,488,759 Mortality 129,013
South America Incidence 75,907 5-Year
Prevalence 249,087 Mortality 24,681
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/.
6
Breast Cancer A Common Disease for Women In The
Developed World
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.
7
Breast Cancer in Europe

• Most common incident form of cancer and cause of
  cancer-related death among women

Excluding nonmelanoma skin cancer.
Boyle P, Ferlay J. Ann Oncol 200516(3)481.
8
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
Denmark Incidence 3,665 5-Year Prevalence
15,152 Mortality 1,359
France Incidence 35,725 5-Year
Prevalence156,539 Mortality 10,811
Italy Incidence 33,076 5-Year Prevalence
150,617 Mortality 11,031
Spain Incidence 15,528 5-Year Prevalence67,613 M
ortality 5,773
www.who.org. EUCAN. Available at
http//www-dep.iarc.fr/eucan/eucan.htm.
1998 estimates.
9
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

5-Year Survival Rates Mean 77
gt80
70
77
60-67
Sant M et al and the EUROCARE Working Group. Ann
Onc. 200314 (suppl 5)v61.
10
Cost of Breast Cancer in Europe

• Cumulative 10-year incidence-based cost is
  approximately 31,774 per postmenopausal breast
  cancer patient
• Costs were at their highest after diagnosis and
  before death

Cocquyt V et al. Ann Oncol. 2003141057.
11
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. 2003141057.
12
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.
13
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.
14
Most Frequently Diagnosed Cancer and 2nd
Leading Cause of Cancer-Related Death in the US
Deaths
US Women in 2005, times 1000
US Women in 2005, times 1000
Excluding skin cancers. Invasive breast
cancer.
American Cancer Society. Cancer Facts and Figures
2005.
15
Mortality Rate is Decreasing but Incidence Rate
is Increasing in the US
US Women per Year, times 100,000

• 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.
16
Survival Rates Correlate With Stage at Diagnosis
and Time Since Diagnosis
Survival Rate Declines Over Time

• 5-Year Survival Rate

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.
17
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 lt .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 lt .001

Average annual costs of illness across
different stages of the disease (onset,
treatment, management, remission, or all).
Brown ML et al. Med Care. 200240(8 suppl)IV
104. Lamerato A et al. SABCS, 2004. Abstract
2084. Radice D, Redaelli A. Pharmacoeconomics.
200321(6)383. Sasser AC et al. Womens Health
Issues 2005 May15(3)97. Rao S et al. Breast
Cancer Res Treat. 20048325. Arozullah AM et
al. J Supportive Oncol. 20042(3)271.
18
Impact of Breast Cancer on Quality of Life
19
QOL is Affected Most By Patients WithDistant
Metastases
Preferences for Breast Cancer Health States
Among Women With Early Breast Cancer
Better
Utility Value
Worse
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. 20047(6)641.
20
Available Therapies for Breast Cancer
21
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

22
Adjuvant Therapy Is a Well-Established Breast
Cancer Therapy Throughout the World
Localized
Locally advanced
100.0
80.0
60.0
Patients Receiving Adjuvant Therapy,
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.
23
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)

24
Hormonal Therapies for Breast Cancer

• Antiestrogens
• Tamoxifen
• Toremifene
• Fulvestrant
• Aromatase inhibitors
• Aminoglutethimide
• Fadrozole
• Anastrozole
• Letrozole
• Exemestane

• Progestins
• Megestrol acetate
• Medroxyprogesterone acetate
• Estrogens
• Estradiol
• Diethylstilbestrol (DES)
• Androgens
• Fluoxymesterone
• LHRH analogs
• Goserelin
• Leuprolide
• Buserelin

3rd generation
LHRH luteinizing hormone-releasing hormone.
25
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. 19983511451. BIG 1-98
Collaborative Group. Unpublished data. Fisher B
et al. J Natl Cancer Inst. 200193684.
26
No Benefit of Extending Tamoxifen Beyond 5 Years
NSABP B-14 Trial
DFS
OS
P 0.07
100
100
P 0.03
94
90
90
91
82
80
80
Patients Surviving,
78
Patients Surviving,
70
70
60
60
50
50
0
5
7
0
5
7
1
2
4
6
3
1
3
2
4
6
Years After 5-year Treatment With Tamoxifen
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. 200193684.
27
Risk for Breast Cancer Recurrence
28
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. 20053651687 Chaturvedi S et al.
Breast Cancer Res Treat. 200593(2)151. Kim KJ
et al. Jpn J Clin Oncol. 200535(3)126. Fisher B
et al. J Natl Cancer Inst. 199890(18)1371.
29
Recurrence During a 5-Year Period After
Chemotherapy Alone

• Incomplete Responders
• 32.6 metastases developed
• 4.5 metastases developed

• Complete Responders
• 17.3 metastases developed
• No local recurrence

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.
200593(2)151.
30
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. 200535(3)126.
31
Recurrence in the NSABP TrialTamoxifen 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.
199890(18)1371.
32
Probability of Recurrence After Tamoxifen

• After 5 years of tamoxifen
• Annual recurrence rate ratio 0.59
• Death rate ratio 0.66

Patients With Recurrence,
n 10,386 women 30 node positive.
Early Breast Cancer Trialists Collaborative
Group. Lancet. 20053651687.
33
Probability of Death After Tamoxifen

• Probability of death is 3-fold higher after 15
  years than after 5 years of completion of
  tamoxifen therapy

Breast Cancer Mortality Rate,
n 10,386 women 30 node positive.
Early Breast Cancer Trialists Collaborative
Group. Lancet. 20053651687.
34
Risk for Recurrence Remains High10 Years After
Adjuvant Treatment
Stage II
Stage III
Patients Who Are Relapse Free,
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.
20042323.
35
Risk for Recurrence is Higher for ER Tumors 5
Years Post Surgery
0.3
ER (n 2257)
ER (n 1305)
0.2
Recurrence Hazard Rate
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years Post Surgery
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. 1996142738.
36
Locoregional Recurrence Is Associated With
Substantial Risk for Distant Metastases
Patients With Distant Metastases,
Based on pooled results of 7 studies (n 1049).
Schmoor C et al. J Clin Oncol.
200018(8)1696. Kamby C, Sengelov L. Breast
Cancer Res Treat. 199745181. Borner M et al. J
Clin Oncol. 1994122071. Toonkel LM et al. Int
J Radiat Oncol Biol Phys. 1983933.
Moran, Haffty. Breast J 20028(2)81. Doyle et
al. Int J Radiat Oncol Biol Phys
200151(1)74. Haylock et al. Int J Radiat Oncol
Biol Phys 200046(2)355.
37
Most Recurrence Is Distant Metastasis
Recurrence During Tamoxifen Treatment
Contralateral (9-11)
Locoregional (16-28)
Distant Metastases (61-75)
The ATAC Trialists Group. Lancet
.20023592131. BIG 1-98 Collaborative Group.
Unpublished data.
38
Prognosis After Recurrence Remains Poor
5-Year Survival Rate,
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. 2004100(1)44.
39
Healthcare Utilization and Costs Associated With
Breast Cancer Recurrence
40
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.
41
Substantial Increases in Medical Care Costs
Post-recurrence Versus Pre-recurrence
Costs, US 1000
n 21
n 12
n 62
n 29
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.
42
Lifetime Cost Is Greatest Among Those
WithRecurrence With Distant Metastasis
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.
43
Metastatic Breast Cancer Results in Frequent
Hospitalizations and Visits
Mean, n
Per Month
Per Year
Rao S et al. Breast Cancer Res Treat. 20048325.
44
Cost of Metastatic Breast CancerIs Greatest in
Younger Patients
Lifetime Costs, US 1000
Age at Diagnosis of Metastatic Breast Cancer,
years
Berkowitz N et al. Value Health. 20003(1)23.
45
Medical Care Costs For Recurrent Metastatic
Breast Cancer
Total Median Cost per Patient 72,156
Berkowitz N et al. Value Health. 20003(1)23.
46
Beyond Tamoxifen

• 3rd-Generation Aromatase Inhibitors

47
FDA-Approved Indications
Tamoxifen Femara Arimidex Aromasin
Adjuvant therapy for early breast cancer v Filed v v
Extended adjuvant therapy for early breast cancer v
1st-Line for advanced breast cancer v v v
2nd-Line for advanced breast cancer v v v
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.
48
European-Approved Indications
Tamoxifen Femara Arimidex Aromasin
Adjuvant Therapy for Early Breast Cancer v Filed v v
Extended Adjuvant Therapy for Early Breast Cancer v
Neoadjuvant v (UK)
1st-Line for Advanced Breast Cancer v v v
2nd-Line for Advanced Breast Cancer v v v
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.
49
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.
50
Femara As an Extended Adjuvant Therapyin 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
200597(17)1262.
51
Femara is Superior to Tamoxifen1st-Line
Treatment of Advanced Breast Cancer

• Compared with tamoxifen, Femara
• Significantly increases
• Time to progression, P lt .0001
• Time to treatment failure, P lt .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. 2003212101.
52
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
199816(2)453. Chaudri HA et al. J Clin Oncol.
199917(12)3859 letter.
53
What is Cost-Effectiveness?
54
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
55
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)

56
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 (gt100,000 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

• Towse A, et al. Pharmacoeconomics. 200220(suppl
  3)95.
• Devlin N, Parkin D. Health Econ. 200413(5)437.
• Elkin EB et al. J Clin Oncol. 200422854.
• Zbrozek AS et al. Am J Hosp Pharm. 1994511555.

Earle CC et al. J Clin Oncol. 2000183302. Ubel
PA et al. Arch Intern Med. 20031631637. Hirth
RA et al. Med Decis Making. 200020(3)332.
57
Cost Effectiveness of Femara
58
Femara Is Cost-Effective as Adjuvant, Extended
Adjuvant, 1st-Line, and 2nd-Line Therapies
Adjuvant Therapy for Early Breast Cancer v Karnon J et al. ECCO, 2005. Abstract 341. Delea T et al. SABC, 2005. Abstract 2054.
Extended Adjuvant Therapy for Early Breast Cancer v Delea T et al. SABC, 2004. Abstract 1050. Karnon J et al. Pharmacoeconomics. In press.
1st-Line Therapy for Advanced Breast Cancer v Delea T et al. SABC, 2003. Abstract 542. Karnon J et al. Pharmacoeconomics. 200321(7)513. Karnon J et al. Ann Oncol. 2003141629. Dranat saris G et al. Am J Clin Oncol. 200326(3)289. Marchetti M et al. Clin Ther. 200426(9)1546. Okubo et al. Gan To Kagaku Ryoho. 200532(3)351.
2nd-Line Therapy for Advanced Breast Cancer v Dranitsaris G et al. Anticancer Drugs. 200011591.
59
Femara is Cost-Effective Compared With Tamoxifen
in the Early Adjuvant Setting (UK)
14,075 10,023
CostFemara CostTAM
4,052
13,643 per QALY gained



QALYFemara QALYTAM
0.3
12.79 12.49
Acceptable CE Ratio in UK 20-30,000
TAM tamoxifen.
Karnon J et al. ECCO 2005. Abstract 341.
60
Femara is Cost-Effective Compared With Tamoxifen
in the Early Adjuvant Setting (US)
63,990 54,964
9,026
CostFemara CostTAM
32,236 per QALY gained



QALYFemara QALYTAM
0.28
13.10 12.82
Acceptable CE Ratio in US ?50,000
Delea T et al. SABCS 2005. Abstract 2054.
61
Femara is Cost-Effective in the Extended
Adjuvant Setting (UK)
10,833 7,101
CostFemara CostPlacebo
3,732
10,338 per QALY gained



QALYFemara QALYPlacebo
0.36
13.66 13.30
Acceptable CE Ratio in UK 20-30,000
Karnon J et al. Pharmacoeconomics. In press.
62
Femara is Cost-Effective in the Extended
Adjuvant Setting (US)
32,561 23,761
CostFemara CostPlacebo
8,800
26,000 per QALY gained



QALYFemara QALYPlacebo
0.338
13.232 12.894
Acceptable CE Ratio in US ?50,000
Delea T et al. SABCS 2004. Abstract 1050.
63
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
EBV early-stage breast cancer FISH
fluorescent in situ hybridization MBC
metastatic breast cancer.
Lee JH et al. J Clin Oncol. 200220(11)2713.
Orr RK et al. Surgery. 1999126568. Hillner BE
et al. J Clin Oncol. 20001879. Elkin EB et al.
J Clin Oncol. 200422854. Zbrozek AS et al. Am J
Hosp Pharm. 1994511555.
64
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)

65
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)
66
Quality of Life AndAromatase Inhibitors
67
Femara Is Associated With Better QOL Than
Arimidex 2nd-Line Therapy
P .02
Worse
Better
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. 200326S40.
68
Patients Prefer Femara Over Arimidex
2nd-Line Therapy
P lt .01
Patient Preference for Treatment,
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. 200326S40.
69
QOL Does Not Diminish Over Time With Extended
Adjuvant Femara Treatment

• No change over time in SF-36 scores
• Small differences (lt 0.2 standard deviations P ?
  0.003) for
• Physical function domain (12 mo)
• Bodily pain domain (6 mo)
• Vitality domain (6 and 12 mo)

Physical Component Summary (Physical functioning,
role -physical, bodily pain, general health)
Mental Health Component Summary (Vitality, social
functioning, role-emotional, mental health)
10
100
Femara
8
Placebo
80
6
Mean Change in Score
Mean Change in Score
60
4
2
40
0
0
10
20
30
0
10
20
30
Months From randomization
Months From randomization
n 3612 women (1799 placebo 1813 letrozole).
Whelan TJ et al. J Clin Oncol. 200523(28)6931.
70
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

n 3612 women (1799 placebo 1813 letrozole).
Whelan TJ et al. J Clin Oncol. 200523(28)6931.
71
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 lt .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 lt .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 . 2005161458.
72
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.
199816(2)453.
73
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

74
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