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CARCINOMA DELLA MAMMELLA. UPDATE FROM AROMATASE INHIBITORS STUDIES AT OCTOBER 2006 ANASTROZOLE (A), LETROZOLE (L), EXEMESTANE (E). What’s really new in endocrine therapy in breast cancer?. Jean-Philippe SPANO, MD, PhD GHPS, Paris, France. The Aromatase Inhibitor Trials. - PowerPoint PPT Presentation
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CARCINOMA DELLA MAMMELLA
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 yesE noL not mature (2008)
EXTENDED ADJUVANT yes yes yes (MA.17)
What’s really new in endocrine therapy What’s really new in endocrine therapy in breast cancer?in breast cancer?
Jean-Philippe SPANO, MD, PhDJean-Philippe SPANO, MD, PhDGHPS, Paris, FranceGHPS, Paris, France
The Aromatase Inhibitor TrialsThe Aromatase Inhibitor Trials
• ATAC: Tamoxifen ATAC: Tamoxifen vsvs Anastrozole Anastrozole vsvs Combined therapy Combined therapy
• MA17 : Letrozole MA17 : Letrozole vsvs placebo after 5yr Tamoxifen placebo after 5yr Tamoxifen
• IES : Exemestane IES : Exemestane vsvs Tamoxifen after 2-3yr Tamoxifen Tamoxifen after 2-3yr Tamoxifen
• ITA : Anastrozole ITA : Anastrozole vsvs Tamoxifen after 2-3yr Tamoxifen Tamoxifen after 2-3yr Tamoxifen
• ABCSG/ARNO : dittoABCSG/ARNO : ditto
• BIG 1-98 : Letrozole BIG 1-98 : Letrozole vsvs Tamoxifen Tamoxifen
• TEAM: exemestane vs TamoxifenTEAM: exemestane vs Tamoxifen
AI Trials in Early Breast CancerAI Trials in Early Breast CancerUpfrontUpfront ExtendedExtended00 55
ATACATAC
ARNOARNO/ABCSG8/ABCSG8
BIG 1-98BIG 1-98
MA-17MA-17
IESIES
ABCSG-6AABCSG-6A
TamoxifenTamoxifenAnastrozoleAnastrozoleLetrozoleLetrozolePlaceboPlaceboAromasinAromasin
Clemons et al. Cancer Treat Rev. 2004;30:335-332.Clemons et al. Cancer Treat Rev. 2004;30:335-332.
SwitchSwitchYears:Years: 2-32-3 1010
combinationcombination
Upfront StrategyUpfront Strategy
Switch StrategySwitch Strategy
Extended StrategyExtended Strategy
Point of Point of RandomizationRandomization
ATAC ATAC
• Recruitment July 1996 – March 2000• Median follow up 68 months (data cut 31st March 2004)• 8 % of patients remain on trial therapy
Arimidex + Tamoxifen (n=3,125)
Tamoxifen (n=3,116)
Surgery± RT
± Chemo (20 %) Anastrozole (n=3,125)
5 years
• 84 % HR positive• 61 % Node negative
Discontinued following initial analysis as no efficacy or
tolerability benefit compared with tamoxifen arm
Reference
Disease-free survivalDisease-free survivalCurves shown for HR+ patients Curves shown for HR+ patients
DFS includes all deaths as a first event
At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774
Follow-up time (years)
0
5
10
15
20
25
0 1 2 3 4 5 6
Absolute difference:1.6 % 2.6 % 2.5 % 3.3 %
Pat
ient
s (%
)
Anastrozole (A)Tamoxifen (T)
HR
0.83
0.87
HR+
95 % CI
(0.73–0.94)
(0.78-0.97)
p-value
0.005
0.01ITT
A
424
575
T
497
651
Reference
Overall SurvivalOverall Survival Curves shown for HR+ patients Curves shown for HR+ patients
At risk:A 2618 2566 2505 2437 2377 2117 867T 2598 2549 2502 2430 2333 2080 855
Follow-up time (years)
0
5
10
15
20
25
0 1 2 3 4 5 6
Includes non breast cancer deaths
Pat
ient
s (%
)
Anastrozole (A)Tamoxifen (T)
HR
0.97
0.97
HR+
95 % CI
(0.83–1.14)
(0.85-1.12)
p-value
0.7
0.7ITT
A
296
411
T
301
420
Reference
Efficacy SummaryEfficacy Summary
* Odds Ratio computed instead of Hazard Ratio
Disease-free survival
Time to recurrence
0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0
Time to distant recurrence
Overall survival
Time to breast cancer death
Contralateral breast cancer*
ITT populationHR+ population Anastrozole better Tamoxifen better
Hazard ratio (A : T) and 95 % CIReference
IES: STUDY DESIGNIES: STUDY DESIGN
Diagnosis of breast cancer & treatment for primary disease
RANDOMISE
2-3 yearstamoxifen
2-3 yearsexemestane
years from startof tamoxifen
0
2
3
5
years fromrandomisation
0
2-3
2 to 3 years tamoxifen
Patients followed up
Coombes RC et al. N Engl J Med. 2004 ; 350 : 1081-1092.
Why This Study ?Why This Study ?
• Patients with ER positive metastatic disease Patients with ER positive metastatic disease frequently respond to AI’s after tamoxifenfrequently respond to AI’s after tamoxifen
• Tamoxifen pre-treatment can increase bone densityTamoxifen pre-treatment can increase bone density
• Long-term tamoxifen can cause endometrial cancerLong-term tamoxifen can cause endometrial cancer
• Prior neo-adjuvant tamoxifen studies show that Prior neo-adjuvant tamoxifen studies show that patients frequently relapse after 2-3 yearspatients frequently relapse after 2-3 years
NEJMNEJM SABCS 2004SABCS 2004
DFS eventsDFS events 449449 615615
DeathsDeaths 199199 339339
Median Follow-upMedian Follow-up 30.6 months30.6 months 37.4 months37.4 months
IES: EFFICACY ANALYSISIES: EFFICACY ANALYSIS
Coombes RC et al. N Engl J Med. 2004 ; 350 : 1081-1092.
IES : EVENTS CONTRIBUTING TO DFSIES : EVENTS CONTRIBUTING TO DFS
ExemestaneExemestane TamoxifenTamoxifen TotalTotal
Local recurrence onlyLocal recurrence only†† 4343 5656 9999
Distant recurrenceDistant recurrence 150150 208208 358358
Contralateral breast primaryContralateral breast primary 1212 2626 3838
Intercurrent deaths (without Intercurrent deaths (without recurrence)recurrence)
5757 6363 120120
Total number of patients Total number of patients experiencing an eventexperiencing an event
262262 353353 615615
† Includes 1 ipsilateral breast cancer
IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVAL
Hazard RatioHazard Ratio 95 % CI*95 % CI* P valueP value
Disease free survivalDisease free survival 0.730.73 0.62-0.860.62-0.86 0.00010.0001
Breast cancer free Breast cancer free survivalsurvival
0.700.70 0.58-0.830.58-0.83 0.000050.00005
Time to contralateral Time to contralateral breast cancerbreast cancer
0.500.50 0.26-0.970.26-0.97 0.040.04
* CI denotes confidence interval
Women surviving event-free (%)
Years from randomisation0 1 2 3 4
0
25
50
75
100
No. events/at risk
Hazard ratio=0.73 (95% CI: 0.62-0.86)Log-rank test: p=0.0001
Exemestane
Tamoxifen
0 / 2352 57 / 2233 65 / 2081 75 / 1413 41+24† / 6610 / 2372 82 / 2243 105 / 2062 96 / 1359 47+23† / 650Tamoxifen
Exemestane
† events occurring more than 4 years after randomisation
IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVAL
(262 events)
(353 events)
IES : DISEASE FREE SURVIVALIES : DISEASE FREE SURVIVALSubgroup AnalysisSubgroup Analysis
Data are hazard ratios (HR) and 95% confidence intervals (CI)
Hazard Ratio (Log-Scale)
0.72 (0.62 – 0.85)p=0.00006
0.80 (0.54 – 1.18)
0.78 (0.59 – 1.04)
1.50 (0.71 – 3.15)0.55 (0.35 – 0.88)0.69 (0.48 – 1.01)0.75 (0.59 – 0.94)0.70 (0.58 – 0.83)
HR (95% CI)Subgroup (no. patients)Tamoxifen betterExemestane better
ER+/PgR- (740)ER+/PgR unk (629)
All ER+ (4019)
ER unk (586)
ER+/PgR+ (2650)
Nodes negative (2445)
1-3 Nodes positive (1429)4+ Nodes positive (657)
Previous CT (1531)No previous CT (3171)
All patients (4724) adjusted
0.4 0.6 0.8 1.0 1.2
ER- (119)
0.66 (0.50 – 0.86)0.68 (0.51 – 0.91)
0.68 (0.53 – 0.88)0.76 (0.62 – 0.94)
No. events/at risk
Women alive (%)
Years from randomisation0 1 2 3 4
0
25
50
75
100
Hazard ratio=0.83 (95 % CI : 0.67-1.02)Log-rank test : p = 0.08
Exemestane
Tamoxifen
18 / 2270 41 / 2137 41 / 1469 37+15† / 69023 / 2300 53 / 2165 49 / 1465 41+21† / 701
TamoxifenExemestane
† events occurring more than 4 years after randomisation
(152 deaths)
(187 deaths)
0 / 23520 / 2372
IES : OVERALL SURVIVALIES : OVERALL SURVIVAL
IES : SAFETY PROFILE : IES : SAFETY PROFILE : Musculoskeletal Musculoskeletal
Incidence Case AnalysisIncidence Case Analysis EventsEventsAny GradeAny Grade
ExemestaneExemestanen (%)n (%)
TamoxifenTamoxifenn (%)n (%) PP
Treatment Treatment emergentemergent
PPArthralgiaArthralgia 414177 ( (19.8)19.8) 272755 ( (13.1)13.1) <0.001+<0.001+ ****MyalgiaMyalgia 50 (50 (2.4)2.4) 32 (32 (1.5)1.5) 0.004+0.004+ NSNS
Arthritis / Arthritis / osteoarthritisosteoarthritis
353544 ( (16.8)16.8) 282855 ( (13.5)13.5) 0.000.0033 Osteo NSOsteo NS
Muscle crampMuscle cramp 64 (64 (3.0)3.0) 107 (107 (5.1)5.1) 0.001+0.001+ ****FracturesFracturesOsteoporosisOsteoporosis
80 (3.6)80 (3.6)175(8.3)175(8.3)
60 (2.6)60 (2.6)145(6.9)145(6.9)
NSNSNS NS
**
Carpal tunnelCarpal tunnel 5577 ( (2.7)2.7) 88 ( (0.4)0.4) <0.001<0.001 ****ParaesthesiaeParaesthesiae 6699 ( (3.3)3.3) 2929 ( (1.4)1.4) <<0.001+0.001+ ****
IES SAFETY PROFILE :IES SAFETY PROFILE :Cardiovascular / Thrombo-embolic DiseaseCardiovascular / Thrombo-embolic Disease
Incidence Case AnalysisIncidence Case Analysis
EventsEventsAny GradeAny Grade
ExemestaneExemestanen (%)n (%)
TamoxifenTamoxifenn (%)n (%)
PP Treatment Treatment emergent Pemergent P
Thrombo-embolic diseaseThrombo-embolic disease 4411 ( (1.9)1.9) 6699 ( (3.3)3.3) <<0.001+0.001+ **
Myocardial Infarction (MI)Myocardial Infarction (MI)(Fatal + Non Fatal) (Fatal + Non Fatal)
All MIsAll MIsAge (mean)Age (mean)
On treatment MIsOn treatment MIs
20 (20 (0.9)0.9)68.868.8
14 (0.7)14 (0.7)
88 ( (0.4)0.4)70.970.9
7 (0.3)7 (0.3)
NS (0.02)NS (0.02)
NS (0.13)NS (0.13) NSNS
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))
+ trend test ; NS = No-significant (p 0.01), * 0.001 p < 0.01, ** p 0.001 Reference
All patients with MI had 1 predisposing risk factor
IES : EFFICACY CONCLUSIONSIES : EFFICACY CONCLUSIONS
• Switching to exemestane reduces the risk of:Switching to exemestane reduces the risk of:– breast cancer recurrence or death (p=0.0001)breast cancer recurrence or death (p=0.0001)– contralateral breast cancer (p=0.04)contralateral breast cancer (p=0.04)
• Switching to exemestane appears to reduce the Switching to exemestane appears to reduce the chances of dying (p=0.08) but more follow-up is chances of dying (p=0.08) but more follow-up is neededneeded
The ABCSG/ARNO Trial : The ABCSG/ARNO Trial : Switching at 2-3 yearsSwitching at 2-3 years
Jakesz et al, 2005
BIG 1-98 DesignBIG 1-98 Design
Tamoxifen
Letrozole
Tamoxifen Letrozole
Letrozole Tamoxifen
RANDOMIZE
0 2 5YEARS
A
B
C
D
2-Arm Option3/98 to 3/001835 pts
4-Arm Option9/99-5/036193 pts
Primary Core AnalysisPrimary 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
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
STUDI HERCEPTIN ADIUVANTE MAMMELLA – AGGIORNATO MARZO 2006