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Welcome and Introductions. Edith A. Perez, MD Director, Cancer Clinical Study Unit Mayo Clinic Jacksonville, Florida. The Early Use of Adjuvant Aromatase Inhibitors for Early Breast Cancer: New Contributions from the BIG 1-98 Letrozole Trial. John F. Forbes, MB, BS, MS, FRACS - PowerPoint PPT Presentation
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Edith A. Perez, MDDirector, Cancer Clinical Study Unit
Mayo ClinicJacksonville, Florida
Welcome and Introductions
John F. Forbes, MB, BS, MS, FRACSProfessor of Surgical Oncology
University of NewcastleDirector, Department of Surgical Oncology
Newcastle Mater Misericordiae HospitalNewcastle, Australia
The Early Use of Adjuvant Aromatase Inhibitors for Early Breast Cancer:
New Contributions from the BIG 1-98 Letrozole Trial
44
Outline
• Trial Design
• Statistical Analyses
• Population
• Efficacy Endpoints
• Subgroups
• Safety
• Conclusions
• Perspective
55
Argentina 123 New Zealand 157
Australia 667 Peru 51
Belgium 634 Poland 277
Brazil 17 Portugal 64
Canada 20 Russia 240
Chile 22 Slovenia 15
Czech Rep. 109 South Africa 187
Denmark 1396 Spain 70
France 1016 Sweden 64
Germany 113 Switzerland 611
Hungary 334 Turkey 54
Iceland 6 United Kingdom 401
Italy 1285 Uruguay 1
Netherlands 94 TOTAL 8028
BIG 1-98 Worldwide Collaborative8028 patients enrolled March 1998-May 2003
66
BIG 1-98 Design
Tamoxifen
Letrozole
Letrozole
Letrozole Tamoxifen
RANDOMIZE
0 2 5YEARS
A
B
C
D
• Compares Letrozole versus Tamoxifen• Letrozole: Arms B and D • Tamoxifen: Arms A and C• Excludes events and FU beyond switch for C & D
Tamoxifen
77
BIG 1-98
New since St. Gallen (January 2005)- Medical review of all cerebrovascular, cardiac,
unclear AEs (538 cases) and all deaths without prior cancer event (93 cases)
- Overall survival outcome by subgroups
- Identification of myalgia and arthralgia AEs
Still to come- Central review of ER, PgR, Her-2
- Update of safety and efficacy
- Results of sequential treatment comparisons
88
Primary Core Analysis
8028 Randomized
8010 Primary Core Analysis
4007 T4003 L versus
18 withdrew consent (no treatment / FU)
133 (1.66%) ineligible cases included in primary core analysis
Median Follow-Up=25.8 months
99
Patient/Tumor Characteristics
Letrozole Tamoxifen
Median age 61 61
Tumor size > 2 cm 36.5% 37.7%
Node positive 41.5% 41.2%
Chemotherapy given 25.3% 25.3%
ER+ / PgR+ 63.5% 62.7%
ER+ / PgR- 20.2% 20.5%
ER+ / PgR unk 14.5% 14.3%
Receptor positivity was a study requirement:99.8% of patients had receptor positive tumors
1010
Primary End Point: DFS
Time from randomization to first of: Invasive recurrence in
- Ipsilateral breast
- Chest wall
- Regional site (internal mammary/axilla)
- Distant site (including ipsi supraclavicular)
Contralateral breast (invasive)
Second (non breast) malignancy
Death without prior cancer event
1111
Secondary End Points
Overall survival (OS)
Systemic disease-free survival (SDFS)*
Distant disease-free survival (DDFS)**
Safety
* Excluding locoregional and contralateral events** Excluding locoregional and 2nd non-breast cancer
1212
T
0
20
40
60
80
100
0 1 2 3 4 5
Per
cen
t A
live
and
Dis
ease
-Fre
e
Years from Randomization
Disease-Free Survival
L
97.797.6
YearlyDFS %
95.193.4
90.589.0
86.884.6
84.081.4
No. at Risk
38923896
29642926
12611238
892866
40034007
567544
N HR (95% CI) p
8010 0.81 (.70-.93) 0.003
Events
779
1313
Years from Randomization
0 2 3 4 51
0
10
5
15
20
Pro
port
ion
Fa
ilure
(%
)
L
T
Cumulative IncidenceBreast Cancer Event
13.6%
10.2%
8.1%
6.2%
5-year diff (L-T) = -3.4% (S.E. 1.2)Cum incidence P=0.0002
1414
Treatment Failures
Letrozole Tamoxifen P
First Failure Sites (DFS events) 8.8% 10.7% 0.003
Local 0.5% 0.9% 0.034
Contralateral Breast (invasive) 0.4% 0.7% 0.092
Regional* 0.3% 0.3% 0.842
Distant 4.4% 5.8% 0.005
Second (non breast) malignancy 1.7% 2.0% 0.288
Death without cancer event 1.4% 0.9% 0.077
Deaths 4.1% 4.8% 0.155
Systemic Failures** 8.1% 9.6% 0.017
*Regional includes axilla or internal mammary**SDFS ignores local and contralateral events
1515
Deaths
Letrozole Tamoxifen
Patients 4003 4007
Deaths 166 192
Deaths following cancer event 111 154
Deaths w/o prior cancer event 55 38
- Cerebro-vascular accident 7 1
- Venous thromboembolic 2 2
- Cardiac 13 6
- Sudden death (cause unk) 10 10
- Other 23 19
1616
Protocol Endpoints
DFS
OS
SDFS
Favors L Favors T
0.81
0.86
0.83
1.00.5 0.75 1.33 2.0
Hazard Ratio (L:T)
1717
Other Endpoints
DFS
OS
SDFS
Time to recurrence
DFS (w/o 2nd malignancy)
Favors L Favors T
0.81
0.86
0.83
0.79
0.73
1.00.5 0.75 1.33 2.0
Hazard Ratio (L:T)
Time to distant recurrence
0.72
1818
Sub group Analyses
• Subgroup analyses should concentrate on:
differences from the average overall treatment
effect (via tests of heterogeneity or interaction)
• It is inappropriate to assess the effects of
treatment on a single subgroup by examination
of the 95% CI for that subgroup.
Cuzick J 1982; Lancet 2005 365:1308
1919
Sub group Analyses
Two types of error can occur
1. Attribution of an effect to a subgroup
when there is no overall effect and no evidence for heterogeneity (more common)
2. To claim a lack of effect in a subgroup
when the overall effect is significant
Cuzick J 1982; Lancet 2005 365: 1308
2020
Sub group Analyses
• Confidence intervals in subgroups are always wider than
those for the main effect because of smaller numbers.
• If the interval for a subgroup crosses the no effect point,
this is widely misinterpreted as a lack of effect in the
subgroup even when the overall effect is significant.
• The correct approach is to determine whether the effect
size for different subgroups varies significantly from the
main effect by a test for heterogeneity.
Cuzick J 1982; Lancet 2005 365: 1308
2121
Subgroups - DFS
Favors L Favors T
1.00.5 0.75 1.33 2.0
Hazard Ratio (L:T)
CT given (n=2024)
CT not given (n=5986)
0.70
0.85
N-positive (n=3311)
N-negative (n=4174)
0.71
0.99
ER+ / PgR+ (n=5055)*
ER+ / PgR- (n=1631)*
0.84
0.83
* Based on local assessment
2222
Subgroup - OS
0.76
0.90
Favors L Favors T
1.00.5 0.75 1.33 2.0
Hazard Ratio (L:T)
CT given (n=2024)
CT not given (n=5986)
0.82
0.88
N-positive (n=3311)
N-negative (n=4174)
1.00
0.79
ER+ / PgR+ (n=5055)*
ER+ / PgR- (n=1631)*
* Based on local assessment
2323
Summary of Efficacy
• Letrozole significantly decreased overall risk of recurrence (19% P=0.003)
• Letrozole significantly reduced the risk of distant metastases (27% P=0.0012)
• Letrozole was associated with a non significant decreased risk of death (14% P=0.16)
• The results are consistent with a similar effect in all subgroups examined
2424
Adverse Events, Any Grade
38.0
6.6
3.5
43.5
20.3
6.4
5.7
4.1
1.01.0
3.8
4.0
6.1
12.3
19.1
16.2
1.5
3.3
13.9
33.5
0 25 50
Night Sweats
Hot flushes
Hyperchol*
Joint
Muscle
Vaginal bleeding
Bone fracture
Cardiac
Thromboembolic
CVA/TIA
Percent of Patients
Letrozole
Tamoxifen
*Grade 1: 35.1% L, 17.3% T; Grade 2+: 8.5% L, 1.9% T Serial cholesterol levels are being reviewed.
2525
Cardiovascular Events, Grade 3-5
Letrozole Tamoxifen
Patients 3975 3988 P
CVA/TIA gr 3-5 1.0% 1.0% 1.0
Thromboembolic gr 3-5 0.8% 2.1% < 0.0001
Cardiac gr 3-5 2.1% 1.1% 0.0003
Ischemic heart disease gr 3-5 1.1% 0.6% 0.013
Cardiac failure gr 3-5 0.5% 0.1% 0.006
2626
Summary: Cardiovascular Events
• Compared with tamoxifen
- AIs reduce the risk of thromboembolic adverse events
- Adjuvant treatment with AIs has been associated with some increase in the
risk of CV events
• Current information is conflicting and insufficient to fully determine the
longer-term effect of AIs on CV health
• It is not possible at present to assign different cardiovascular risk profiles
to the individual AIs
• Further analyses of ongoing AI trials is required
2727
Bone Fractures
Letrozole Tamoxifen
Patients 3975 3988
Bone fractures 244 164
Patients w/ bone fracture 225 (5.7%) 159 (4.0%)
Bone fracture rate
(fracture/100 patient-years)
2.2 1.5
Risk ratio, p-value (L:T) 1.42 p=0.0006
2828
Endometrial Events
Letrozole Tamoxifen
Patients* 3089 3157
Endometrial biopsies (pts) 72 (2.3%) 288 (9.1%)
Invasive endometrial cancer 6 (0.2%) 15 (0.5%)
Invasive endometrial cancer
Risk ratio, p-value (L:T) 0.40, p=0.087
*Excludes 1717 patients with hysterectomy at baseline
2929
Perspective
Interpretation
Predictions
3030
RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+)
Lancet May 14 2005
HRAbs RRn
HRAbs RRn
0.5710.4
0.6413.7
0.7411.8
0.703.6
0.707.9
0.749.2
EBCTCG 2000 (2005)Recurrence
EBCTCG 2000 (2005)Mortality
11.7 HR 0.44
14.8
3131
Smoothed hazard rates for recurrence? Start Early or Switch
0.5
1.0
1.5
2.0
2.5
3.0
0 1 2 3 4 5 6
Follow-up time (years)
Anastrozole Tamoxifen
0
Letrozole: Prevention of early distant relapses Should translate into mortality reduction
? Acquired Tamoxifen resistance developing at ~ 2-3 years
AnnualHR HR+
%
3232
0
0.5
1
1.5
2
2.5
3
1 2 3 4 5 6
Years since randomization
Ann
ual r
ates
%
AnastrozoleTamoxifen
0
Fracture rates over time
Fracture rates per 1000 women years: Anastrozole 22.6; Tamoxifen 15.6; P1 control 18.4; WHI control 19.1
3333
Cross trial Comparisons
Cross trial (indirect) comparisons may be unreliable:
- Different end-point definitions
- Different populations
- Different treatments
- Non randomised comparisons
They should be interpreted with caution both for efficacy and side effects comparisons
But they may lead to new hypotheses
3434
Endpoint: ComparisonsBIG 1-98 and ATAC
Favors TAM
Hazard ratio (LET:TAM)
DFS
OS
SDFS
Time to recurrence
DFS (w/o 2nd malignancy)
0.81
0.86
0.83
0.79
0.73 Time to distant metastasis (DDFS)
0.72
Favors LET
1.00.5 0.75 1.33 2.0
ATAC HR+68 mo1 33 mo2
1. Lancet. Jan 7, 2005.2. Lancet. June 22, 2002.
0.97
0.84
0.73
0.83 0.78
-
-
0.74
-
-
-
-
3535
Subgroups: OS
0.76
0.90
0.82
0.88
1.00
0.79
Favors L Favors T
1.00.5 0.75 1.33 2.0
Hazard Ratio (L:T)
CT given (n=2024)
CT not given (n=5986)
N-positive (n=3311)
N-negative (n=4174)
ER+ / PgR+ (n=5055)*
ER+ / PgR- (n=1631)*
* Based on local assessment
3636
Retrospective analysis of time to recurrence for ER/PgR subgroups
At risk:A 451 435 417 400 390 347 124T 429 412 375 353 327 276 96
Follow-up time (years)
25
0
5
10
15
20
0 1 2 3 4 5 6
Anastrozole (A)Tamoxifen (T)
Pat
ient
s (%
)
Patient group HR+ ER+PgR+ ER+PgR-
Hazard ratio 0.79 0.84 0.43
ER+/PgR-
3939
Protective Effect of Tamoxifenon cholesterol?
1) http://www.nhlbi.nih.gov/about/framingham/index.html; 2) McDonald CC et al.: BMJ 1995;311:977–80; 3) Rutqvist LE et al.:J Natl Cancer Inst 1993;85:1398–406, 4) Bradbury BD et al, Cancer March 2005, 5) Reis SE et al.; J Natl Cancer Inst 2001, Vol 93, No 1, Jan 3:16-21
Cardiovascular risk substantially and progressively
increases in women age >65 (Framingham study)1
The cardio protective effect of tamoxifen has been
studied in several trials
–The data are conflicting, some studies showed a
cardio protective effect2-4, others did not5.
4040
RECURRENCE MORTALITY in trials of ~5 years of tamoxifen versus Not, ER+/unknown: 15-year outcome (life-table curve: 10386 women, all ages, 80% ER+, 30% N+)
Lancet May 14 2005
HRAbs RRn
HRAbs RRn
0.5710.4
0.6413.7
0.7411.8
0.703.6
0.707.9
0.749.2
EBCTCG 2000 (2005)Recurrence
EBCTCG 2000 (2005)Mortality
11.7 HR 0.44
14.8
Questions and Answers
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