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 1994:51:155563
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