Transcript Slide 1

These slides were released by the speaker
for internal use by Novartis
Optimal treatment strategies
based on current data
Hope S Rugo
(UCSF Comprehensive Cancer Center, San Francisco, CA, USA)
AIs as the adjuvant therapy of choice
in postmenopausal HR+ early BC
 Recent guidelines based on current data recommend
that adjuvant endocrine therapy for postmenopausal
women with HR+ disease should include an AI
 ASCO Guidelines 2005
– ‘Optimal adjuvant hormonal therapy for a postmenopausal
woman with HR+ BC should include an AI either as initial
therapy or after treatment with tamoxifen’
Winer et al. J Clin Oncol 2005;23:619–29; Goldhirsch et al. Ann Oncol 2005;19:3817–27;
Rieber & Theriault J Natl Compr Canc Netw 2005;3:309–14
The ASCO guidelines – what's new?
 In postmenopausal women with HR+ disease
treatment options include
– 5 years of AI treatment
– sequential therapy consisting of tamoxifen
(for 2–3 or 5 years) followed by an AI for 2–3 years
 Patients intolerant of AIs should receive tamoxifen
 AIs are contraindicated in premenopausal and
perimenopausal women
Winer et al. J Clin Oncol 2005;23:1–11
The St Gallen guidelines – what's new?
 Basis for risk selection in adjuvant systemic Tx:
hormone responsiveness 
clinicopathological/molecular information
– First consideration for adjuvant Tx selection = hormone
responsiveness, not risk
 New classes of drugs in the adjuvant setting
– AIs, taxanes
 ATAC & BIG 1-98 support AIs as upfront therapy in
postmenopausal patients with HR+ BC
Goldhirsch et al. Ann Oncol 2005;16:1569–83
Senn & Thürlimann The Breast 2005;14:427–8
St Gallen treatment guidelines for
adjuvant therapy of early breast cancer
St Gallen 2005: endocrine responsiveness from a
biological continuum to ‘practical’ subgroups
 The 2005 St Gallen
guidelines redefine
risk categories
Endocrine
responsiveness
Absent
ER and PgR absent
Uncertain
ER and PgR low
and/or any of the
following
Certain
Both receptors
moderate to high
• PgR absent
No
• UPA/PAI-1 high
No
• HER-2 overexpressed
No
• ↑ proliferation
markers
No
 ER status no longer
sole determinant of
risk and treatment
response
Piccart M. Plenary lecture SABCS 2005
Advantages of tamoxifen
 Proven efficacy
 Mature and plentiful safety data
 Confers some protection against bone loss and
cardiovascular disease
Advantages of tamoxifen
 Proven efficacy
 Mature and plentiful safety data
 Confers some protection against bone loss and
cardiovascular disease
BUT no longer the most effective treatment
 Upfront AI improves DFS compared with tamoxifen
 Sequential tamoxifen followed by an AI improves DFS
compared with tamoxifen alone
 Survival data with adjuvant AIs at least equivalent
to tamoxifen
ATAC and Milan Institute database
New insights into natural history of EBC
 Biphasic recurrence curve with early peak at 1–2 years in ATAC trial
– Similar for relapses after surgery and no adjuvant therapy (Milan database)
Recurrences 
– Hypothetical interpretation
B
A
C
5
A: Induced angiogenesis (10 months)
B: Induced cell division at surgery
(18–40 months)
C: Steady stochastic transitions (natural
history, 60–200 months)
10
15
Follow-up (years)
20
 Hypothesis: surgery may stimulate development of metastatic disease
– An AI before or immediately after surgery might better counter that effect
Update of Baum J Clin Oncol 2005;23(16S):31s(abstract 612)
Change in hazard ratio with time
AI upfront or after initial tamoxifen?
Smoothed hazard ratio for recurrence
Start early or switch?
AI: Prevention of early distant relapses
should translate into mortality reduction
Annual HR for HR+
3.0
2.5
2.0
1.5
1.0
Anastrozole
Acquired tamoxifen resistance
developing at ~2–3 years?
0.5
Tamoxifen
0
0
1
2
3
4
5
6
Follow-up time (years)
Howell et al. Lancet 2005;365:1225–6
Buzdar & Cuzick Clin Cancer Res 2006;12(3 Suppl):1037s
Trials using AIs upfront
Randomization
TAMOXIFEN
5 years
ATAC*
5 years†
5 years
ANASTROZOLE
LETROZOLE
5 years
5 years
BIG 1-98*
EXEMESTANE
TEAM‡
2 years
3 years
2 years
3 years
2–3 years
2–3 years
5 years
*Registration trials; †Combination arm discontinued at first analysis; ‡ amended TEAM protocol
Switching and sequential therapy trials
Randomization
TAMOXIFEN
BIG 1-98*
ANASTROZOLE
LETROZOLE
5 years
5 years
TEAM‡
2 years
3 years
2 years
3 years
2–3 years
5 years
EXEMESTANE
IES
2–3 years
ARNO
2 years
ABCSG-8
ITA
2–3 years
2–3 years
3 years
3 years
2 years
2–3 years
2–3 years
3 years
3 years
2–3 years
2–3 years
*Registration trials; †Combination arm discontinued at first analysis; ‡TEAM protocol altered to affect switch to Exem after
2–3 years Tam; **ABCSG: randomization immediately after surgery, ARNO: randomization up to 2 years after surgery
Start AI upfront
Highest relapse rate years 2–3
ATAC
BIG 1-98
Randomization
Annual recurrence rate (%)
TEAM
16
12
8
N+
4
N–
0
0
2
4
6
8
10
Time (years)
Based on data from Saphner et al. J Clin Oncol 1996;14:2738–46
Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98: all endpoints
Comparison with ATAC
ATAC HR+
68 mo
-
33 mo
-
0.81
DFS
0.97
-
0.86
OS
0.93
-
0.73
Distant DFS
0.83
0.78
0.79
DFS (w/o 2nd malignancy)
0.84
-
0.73
Time to distant metastasis
0.74
0.73
0.72
Time to recurrence
0.5
Howell et al. Lancet 2005;365:60–2; Baum et al.
Lancet 2002;359:2131–9; Arimidex® PI 2005;
Thürlimann et al. N Engl J Med 2005;353:2747–57
0.75
Favors LET
1.0
1.33
2.0
Favors TAM
Hazard ratio (LET:TAM)
Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98 & ATAC* in comparison
Efficacy summary
 Risk of distant metastases
– significant  by 27% with letrozole in BIG 1-98
– no significant reduction with anastrozole in ATAC*
 Non-significant reduction in risk of death in both studies to date
–  by 14% with letrozole
–  by 3% with anastrozole
 Subgroup analyses
– BIG 1-98: letrozole showed a significant DFS advantage in
•
patients who received chemotherapy
•
patients with node+ disease
– ATAC: anastrozole showed a significant DFS advantage in
*HR+ population
•
Patients with node– disease
•
Patients who did not receive chemotherapy
Howell et al. Lancet 2005;365:60–62
Thürlimann et al. N Engl J Med 2005;353:2747–57
Letrozole is not licensed in all European countries for use in the early adjuvant setting
Distant recurrences are associated
with high risk of death
 All breast cancer recurrences associated with increased
risk of mortality
 Substantially higher risk of death in patients with distant
recurrences than with locoregional recurrences and new
contralateral breast cancers
 Distant metastases are more prevalent in high-risk N+ disease
than in N– disease
Lamerato et al. J Clin Oncol 2005;23(16S):62s(abstract 738)
Lawrence et al. Breast Cancer Res Treat 2005;94(Suppl 1):S211(abstract 5019)
Start AI after 2–3 years of tamoxifen
Randomization/analysis upfront or at switch
BIG 1-98
TEAM
IES, ABCSG/ARNO, ITA
Annual recurrence rate (%)
Randomization/
analysis
16
12
8
N+
4
N–
0
0
2
4
6
8
10
Time (years)
Based on data from Saphner et al. J Clin Oncol 1996;14:2738–46
Letrozole is not licensed in all European countries for use in the early adjuvant setting
DFS and OS benefits with AIs
(sequential and substitution trials)
ATAC1
BIG 1-982
IES3
ARNO/
ABSCG-84
ABCSG-85
5216
8010
4724
3224
2926
Follow-up (mo)
68
26
37.4
28
54*
Absolute DFS
benefit (%)
2.5 at 5 y
2.6 at 5 y
4.7 at 3 y5
3.1 at 3 y
1.5 at 5 y
Hazard ratio
0.83
0.81
0.68
0.60
0.76
p value
0.005
0.003
0.0001
0.0009
0.068
3
14
17
24**
7
0.7
0.16
0.08
0.16
0.71
No. patients
OS benefit (%)
p value
*Sequence **Analysis from switch
Suggests greater absolute reduction in risk of recurrence vs tamoxifen
with switch than achieved with upfront AI – but in a lower-risk population
1. ATAC Trialists’ Group Lancet 2005;365:60–2; 2. Thürlimann et al. N Engl J Med 2005;353:2747–57;
3. Coombes et al. N Engl J Med 2004;350:1081–92; 4. Jakesz et al. Lancet 2005;366:455–62;
5. Jakesz et al. Breast Cancer Res Treat.2005;94:(abstract 13)
Letrozole is not licensed in all European countries for use in the early adjuvant setting
Optimal timing of AI use in adjuvant
treatment of ER+ early breast cancer
Years lost to recurrence (%)
Model of the impact of the sequence of hormonal therapy on recurrence of
ER+ breast cancer (based on published data)
15
15
5 years Tam
5 years Tam + 5 years AI
2.5 years Tam + 2.5 years AI
5 years AI
10
10
5
5
0
0
0
2
4
6
8
10
Years
Risk of recurrence lowest with 5 years’ upfront AI therapy
Cuzick et al. Br J Cancer 2006;94:460–4
Is there a difference in AEs between
upfront and sequential AI use?
Adverse events in adjuvant AI trials
Upfront
Sequential
Extended adjuvant
AI vs tamoxifen
AI vs tamoxifen
Let vs placebo
 or =
=

Arthralgia



Thromboembolic


NR
Osteoporosis/
fracture

 or =

Gynecol. symptoms



Hypercholesterolemia


=
CV events


=
= (anastrozole)
=(exemestane)
=
Hot flushes
Quality of life
ATAC Trialists’ Group Cancer;98:1802-10; Thürlimann et al. N Engl J Med 2005;353:2747–57;
Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al. Lancet 2005;366:455–62;
Jakesz et al. Breast Cancer Res Treat 2005;94:(abstract 13)
NR: not reported; Slide adapted from: Review, Mouridsen, 2005
Letrozole is not licensed in all European countries for use in the early adjuvant setting
AE profiles are not significantly
different with upfront and sequential AI
• In all trials comparing an AI (sequential and upfront)
with tamoxifen
• Non-significant increase in CV events
• Tamoxifen has cardioprotective effects1,2
• Increase in hypercholesterolemia
• Lipid-lowering effect of tamoxifen (12–15%)3
• No evidence that 2–3 years of tamoxifen protects against
subsequent bone loss
• Pretreatment with tamoxifen may delay onset of fracture risk
1. EBCTCG Lancet 2005;365:1687–717; 2. Braithwaite et al. J Gen Intern Med
2003;18:937–47; 3. Herrington & Klein Womens Health Issue 2001:11:95–102
Are AIs cost-effective?
Cost-effectiveness in adjuvant treatment
 Cost of agent
 Cost of monitoring/managing/treating side effects
 Cost of treating relapsed disease
Cost-effectiveness ratios in oncology
Postmastectomy radiation therapy in EBC
Letrozole early adjuvant treatment vs tamoxifen
in postmenopausal women with HR+ EBC
Axillary node dissection in ER+ EBC
Pamidronate in MBC & bone lesions receiving CTx
FISH testing for HER2 in MBC
Ondansetron in cisplatin-induced emesis, 40 kg patient
Ondansetron in cisplatin-induced emesis, 70 kg patient
0
100
200
300
$ x 1000 / QALY
400
Lee et al. J Clin Oncol 2002;20:2713–25; Orr et al. Surgery 1999:126:568–76;
Hillner et al. J Clin Oncol 2000:18:72–9; Elkin et al. J Clin Oncol 2004;22:854–63;
Zbrozek et al. Am J Hosp Pharm 1994:51:155563
Are all AIs the same?
Are all AIs the same?
Inhibition of aromatase activity in vitro
IC50*
(nmol/L)
Letrozole
2.5
Relative
Potency
1800
Anastrozole
10
450
Exemestane
15
300
4500
1
Aminoglutethimide
Increasing
potency
Letrozole is the most potent third-generation AI in vitro
*In breast cancer homogenates
Miller et al. Endocr Relat Cancer 1999;6:187
Inhibition of whole-body aromatization
in 12 postmenopausal patients with BC
% Inhibition
Crossover 1
Crossover 2
92
92
94
94
96
96
98
98
100
100
Anastrozole Letrozole
Increasing
inhibition
Letrozole
Anastrozole
Anastrozole vs letrozole, p = 0.0022
Geisler et al. J Clin Oncol 2002;20:751–7
In adjuvant trials: upfront AI
 ATAC: 68 months’ median follow-up – 17% reduction
in recurrence risk (HR+ population)
 BIG 1-98: 26 months’ median follow-up – 19% reduction
in recurrence risk
• significant risk reduction in subgroups
(N+ disease, patients who had received adjuvant CT)
 In specific patient populations (e.g. higher-risk)
• benefit may depend on the AI used
ATAC Trialists’ Group. Lancet 2005;365:60–2; Thurlimann et al. N Engl J Med 2005;353:2747–57
Letrozole is not licensed in all European countries for use in the early adjuvant setting
Direct comparative trials
 MA.27
– Upfront for 5 years
– Anastrozole vs exemestane
– > 6800 postmenopausal HR+ early BC
– Nearing completion of accrual
 FACE
– Upfront for 5 years
– Anastrozole vs letrozole
– ~4000 N+ postmenopausal HR+ early BC
– Open to accrual, 19 patients to date
FACE trial: letrozole vs anastrozole
Early breast cancer
• ER+ and/or PgR+
• N+
• Postmenopausal
(FSH/LH/E2 levels)
• De novo adjuvant
therapy
R
A
N
D
O
M
I
Z
E
Letrozole 2.5 mg/day
Anastrozole 1 mg/day
 Primary endpoint
– DFS
 Secondary endpoints
– Safety
– Overall survival
– Time to distant metastasis
– Time to contralateral disease
Does PgR status or HER2/neu status
affect response to an AI?
Benefit with AIs vs tamoxifen
according to ER/PgR status
ER+/PgR+
ER+/PgR–
Study
AI
HR (95% CI)
HR(95% CI)
ATAC1
Anastrozole
0.84 (0.69–1.02)
p = 0.07
0.43 (0.31–0.61)*
p = 0.0001
BIG 1-982,3
Letrozole
0.84 (0.69–1.03)*
0.67 (0.51–0.88)†
0.83 (0.62-1.10)*
0.88 (0.55–1.41)†
*Local pathological assessment
†Central pathological assessment
1. Dowsett et al. J Clin Oncol. 2005;23:7512; 2. Update of Thürlimann et al. N Engl J Med 2005;353:2747–57;
3. Update of Viale et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S13(abstract 44);
Letrozole is not licensed in all European countries for use in the early adjuvant setting
BIG 1-98 DFS by central
pathological assessment
0.71
All patients (n = 4399)
0.67
ER+/PgR+ (n = 3330)
0.88
ER+/PgR– (n = 832)
0.5
0.75
Favors L
1.0
1.25
1.5
Favors T
Hazard ratio (L:T)
Viale et al. Breast Cancer Res Treat 2005;94(Suppl 1):S13(abstract 44)
BIG 1-98 DFS by central
pathological assessment
0.71
All patients (n = 4399)
0.72
ER+/HER2– (n = 3971)
0.68
ER+/HER2+ (n = 234)
0.5
0.75
1.0
Favors L
1.25
1.5
Favors T
Hazard ratio (L:T)
Viale et al. Breast Cancer Res Treat 2005;94(Suppl 1):S13(abstract 44)
PgR and HER2/neu status
 BIG 1-98 is only trial to perform central assessment
of ER and PgR status
 Letrozole achieved benefit in all patients with ER+ tumors
irrespective of PgR status, based on local and central
assessment
– In contrast, local assessment in ATAC showed a benefit in
only the ER+/PgR– subgroup
 Treatment decisions should not be based on PgR status
What do we do now and what are
we looking for in the future?
 Which patients should receive an AI upfront?
– Most postmenopausal women with early-stage, HR+ breast cancer
 Is there a population that can safely be treated with tamoxifen
followed by an AI?
– Women who are pre- or peri-menopausal
– Women intolerant of an AI
– Strongly ER/PR+ with low-grade, low-risk disease?
 The future
– Genomic analysis will help us to determine sensitivity and
resistance to hormone therapy
• May help to differentiate risk groups and appropriate endocrine
approach between different classes of drugs
• Will identify patients who can be safely treated with hormonal therapy