Diapositiva 1

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CARCINOMA DELLA MAMMELLA
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UPDATE FROM AROMATASE INHIBITORS STUDIES AT
OCTOBER 2006 ANASTROZOLE (A), LETROZOLE (L),
EXEMESTANE (E)
DFS DDFS OS
UPFRONT vs TAM yes no
SWITCH yes yes A yes E no L not mature (2008)
EXTENDED ADJUVANT yes yes yes (MA.17)
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Whats really new in endocrine therapy in breast
cancer?
Jean-Philippe SPANO, MD, PhD GHPS, Paris, France
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The Aromatase Inhibitor Trials

• ATAC Tamoxifen vs Anastrozole vs Combined
  therapy
• MA17 Letrozole vs placebo after 5yr Tamoxifen
• IES Exemestane vs Tamoxifen after 2-3yr
  Tamoxifen
• ITA Anastrozole vs Tamoxifen after 2-3yr
  Tamoxifen
• ABCSG/ARNO ditto
• BIG 1-98 Letrozole vs Tamoxifen
• TEAM exemestane vs Tamoxifen

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AI Trials in Early Breast Cancer
Switch
Upfront
Extended
Years
0
2-3
5
10
Upfront Strategy
ATAC
combination
BIG 1-98

Point of Randomization
Switch Strategy
IES
ARNO/ABCSG8
Extended Strategy
MA-17
ABCSG-6A
Clemons et al. Cancer Treat Rev. 200430335-332.
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ATAC

• Recruitment July 1996 March 2000
• Median follow up 68 months (data cut 31st
  March 2004)
• 8 of patients remain on trial therapy

Tamoxifen (n3,116)
Surgery RT Chemo (20 )
Anastrozole (n3,125)
Arimidex Tamoxifen (n3,125)
Discontinued following initial analysis as no
efficacy or tolerability benefit compared with
tamoxifen arm

• 84 HR positive
• 61 Node negative

5 years
Reference
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Disease-free survivalCurves shown for HR
patients
HR 0.83 0.87
95 CI (0.730.94) (0.78-0.97)
p-value 0.005 0.01
A 424 575
T 497 651
25
HR
20
ITT
15
Patients ()
10
5
Absolute difference
1.6
2.6
2.5
3.3
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2540
2448
2355
2268
2014
830
T
2598
2516
2398
2304
2189
1932
774
Reference
DFS includes all deaths as a first event
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Overall Survival Curves shown for HR patients
25
p-value 0.7 0.7
HR 0.97 0.97
95 CI (0.831.14) (0.85-1.12)
A 296 411
T 301 420
20
HR
ITT
15
Patients ()
10
5
0
0
1
2
3
4
5
6
Follow-up time (years)
At risk
A
2618
2566
2505
2437
2377
2117
867
Includes non breast cancer deaths
Reference
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Efficacy Summary
Reference
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IES STUDY DESIGN
Coombes RC et al. N Engl J Med. 2004 350
1081-1092.
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Why This Study ?

• Patients with ER positive metastatic disease
  frequently respond to AIs after tamoxifen
• Tamoxifen pre-treatment can increase bone density
• Long-term tamoxifen can cause endometrial cancer
• Prior neo-adjuvant tamoxifen studies show that
  patients frequently relapse after 2-3 years

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IES EFFICACY ANALYSIS
NEJM SABCS 2004
DFS events 449 615
Deaths 199 339
Median Follow-up 30.6 months 37.4 months
Coombes RC et al. N Engl J Med. 2004 350
1081-1092.
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IES DEMOGRAPHICS 1
Exemestane Tamoxifen
Number of patients 2352 2372
Median age, n (range) 63.0 (38.0-96.0) 63.0 (31.0-90.0)
Nodal Status, n ( known)
Negative 1217 (54) 1228 (54)
Positive 1048 (46) 1038 (46)
Prior Chemotherapy, n ()
Yes 774 (33) 769 (32)
No 1578 (67) 1603 (68)
Of the 4742 subjects included in the NEJM
analysis, 2 were found to have duplicate PIDs and
16 subjects from one center were excluded from
all analyses because data were considered
unreliable.
Product Labeling
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IES DEMOGRAPHICS 2
Exemestane (n2352) Tamoxifen (n2372)
Receptor Status, n ()
ER PgR Positive 1331 (56.6) 1319 (55.6)
ER Positive PgR Negative/Unknown 677 (28.8) 692 (29.2)
ER and PgR Unknown 288 (12.2) 291 (12.3)
ER Negative 54 (2.3) 65 (2.7)

Median duration of Tamoxifen treatment (mths) at time of randomisation 28.5 28.4
US Product Labeling
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IES EVENTS CONTRIBUTING TO DFS
Exemestane Tamoxifen Total
Local recurrence only 43 56 99
Distant recurrence 150 208 358
Contralateral breast primary 12 26 38
Intercurrent deaths (without recurrence) 57 63 120
Total number of patients experiencing an event 262 353 615
Includes 1 ipsilateral breast cancer
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IES CAUSES OF DEATH
Exemestane Tamoxifen Total
Total number of deaths 152 187 339
Breast cancer deaths Inc. other COD in patients with recurrence/CLB 95 11 124 12 219 23
Intercurrent (without recurrence/CLB) Vascular Cardiac Other cancer Other Unknown 57 15 13 13 11 5 63 7 12 22 14 8 120 22 25 35 25 13
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IES DISEASE FREE SURVIVAL
Hazard Ratio 95 CI P value
Disease free survival 0.73 0.62-0.86 0.0001
Breast cancer free survival 0.70 0.58-0.83 0.00005
Time to contralateral breast cancer 0.50 0.26-0.97 0.04
CI denotes confidence interval
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IES DISEASE FREE SURVIVAL
100
(262 events)
Exemestane
Women surviving event-free ()
Tamoxifen
(353 events)
75
50
25
Hazard ratio0.73 (95 CI 0.62-0.86) Log-rank
test p0.0001
0
0
1
2
3
4
No. events/at risk
Years from randomisation
Exemestane
0 / 2352
57 / 2233
65 / 2081
75 / 1413
4124 / 661
Tamoxifen
0 / 2372
82 / 2243
105 / 2062
96 / 1359
4723 / 650
events occurring more than 4 years after
randomisation
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IES DISEASE FREE SURVIVALSubgroup Analysis
Data are hazard ratios (HR) and 95 confidence
intervals (CI)
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IES OVERALL SURVIVAL
Exemestane
(152 deaths)
100
Women alive ()
Tamoxifen
(187 deaths)
75

50
25
Hazard ratio0.83 (95 CI 0.67-1.02) Log-rank
test p 0.08
0
0
1
2
3
4
No. events/at risk
Years from randomisation
Exemestane
0 / 2352
18 / 2270
41 / 2137
41 / 1469
3715 / 690
Tamoxifen
0 / 2372
23 / 2300
53 / 2165
49 / 1465
4121 / 701
events occurring more than 4 years after
randomisation
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IES SAFETY PROFILE Musculoskeletal
Incidence Case Analysis Incidence Case Analysis Incidence Case Analysis
Events Any Grade Exemestane n () Tamoxifen n () P Treatment emergent P
Arthralgia 417 (19.8) 275 (13.1) lt0.001
Myalgia 50 (2.4) 32 (1.5) 0.004 NS
Arthritis / osteoarthritis 354 (16.8) 285 (13.5) 0.003 Osteo NS
Muscle cramp 64 (3.0) 107 (5.1) 0.001
Fractures Osteoporosis 80 (3.6) 175(8.3) 60 (2.6) 145(6.9) NS NS
Carpal tunnel 57 (2.7) 8 (0.4) lt0.001
Paraesthesiae 69 (3.3) 29 (1.4) lt0.001
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IES SAFETY PROFILE Cardiovascular /
Thrombo-embolic Disease
Incidence Case Analysis Incidence Case Analysis Incidence Case Analysis
Events Any Grade Exemestane n () Tamoxifen n () P Treatment emergent P
Thrombo-embolic disease 41 (1.9) 69 (3.3) lt0.001
Myocardial Infarction (MI) (Fatal Non Fatal) All MIs Age (mean) On treatment MIs 20 (0.9) 68.8 14 (0.7) 8 (0.4) 70.9 7 (0.3) NS (0.02) NS (0.13) NS
All patients with MI had ? 1 predisposing risk
factor

• Tamoxifen association with MI
• Meta-analysis Braithwaite et al, 2003 52,929
  patients.
• Suggestive of decrease in incidence of MI (HR
  0.74 (0.47-1.16))
• Decreases death from MI (HR 0.55 (0.36-0.87))

Reference
trend test NS No-significant (p ? 0.01),
0.001 ? p lt 0.01, p ? 0.001
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IES SAFETY PROFILE Gynaecological
Incidence Case Analysis Incidence Case Analysis Incidence Case Analysis
Events Any Grade Exemestane n () Tamoxifen n () P Treatment emergent P
Gynecological symptoms 301 (14.3) 376 (17.8) 0.002 Not done
Uterine Hyperplasia 19 (0.9) 39 (1.9) 0.008
Uterine Polyps 12 (0.6) 53 (2.5) lt0.001
Reference
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Preliminary Conclusions

• The proportion of patients with ET 5 mm was
  significantly reduced in the exemestane arm
• Switching to exemestane allows reversal of
  subclinical uterine abnormalities associated with
  tamoxifen
• Post-treatment scans should assess whether effect
  of exemestane is superior to simple T withdrawal

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IES SAFETY CONCLUSIONS

• No excess of intercurrent deaths
• Endocrine effects similar to tamoxifen
• Musculo-skeletal side effects more common
• Cardiovascular - more data required but serious
  events very rare
• Exemestane associated with a reduction in
  gynecological and thrombo-embolic side effects

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IES EFFICACY CONCLUSIONS

• Switching to exemestane reduces the risk of
• breast cancer recurrence or death (p0.0001)
• contralateral breast cancer (p0.04)
• Switching to exemestane appears to reduce the
  chances of dying (p0.08) but more follow-up is
  needed

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The ABCSG/ARNO Trial Switching at 2-3 years
Jakesz et al, 2005
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BIG 1-98 Design
R A N D O M I Z E
A
Tamoxifen
B
Letrozole
C
Tamoxifen
Letrozole
D
Letrozole
Tamoxifen
0
2
5
YEARS
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Primary Core Analysis
8028 Randomized
18 withdrew consent (no treatment / FU)
8010 Primary Core Analysis
4007 T
4003 L
versus
133 (1.66) ineligible cases included in primary
core analysis
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Follow-Up Time
Overall (median FU 35.5 mos.)
Primary core (median FU 25.8 mos.)
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STUDI HERCEPTIN ADIUVANTE MAMMELLA AGGIORNATO
MARZO 2006
Osservazione STUDIO HERA Qualsiasi CT RT
Tq3sett x 12 mesi Tq3sett per 24 mesi
Paclitaxel q3sett x 4 o qsett x 12 NSABP
B-31 AC x 4 Paclitaxel q3sett x 4
o qsett x 12 T qsett
Paclitaxel qsett x 12 INTERGROUP N9831 AC
x 4 Paclitaxel qsett x 12 T
qsett Paclitaxel qsett x 12 T
qsett
AC x 4 Docetaxel q3sett x 4 BCIRG 006 AC x
4 Docetaxel q3sett x 4 T qsett
Tq3sett Carboplatino docetaxel q3sett x 6
T qsett Tq3sett

q3sett alla dose di 6 mg/kg
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