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Cecilia NisticòCecilia NisticòDipartimento di Oncologia MedicaDipartimento di Oncologia Medica
Oncologia Medica COncologia Medica CDirettore: Prof. E. TerzoliDirettore: Prof. E. Terzoli
IRE - Istituto Nazionale TumoriIRE - Istituto Nazionale TumoriRegina ElenaRegina Elena
RomaRoma
Roma, 28 Novembre 2008
Endocrinoterapia adiuvante del
carcinoma nel 2008
Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella
Mediterranean Scholl of Oncology
Breast Cancer TreatmentBreast Cancer Treatment
• Final Outcomes:Final Outcomes:
• Adjuvant settingAdjuvant setting Treatment Goal:Treatment Goal: to Cureto Cure
• Advanced DiseaseAdvanced Disease Treatment Goal:Treatment Goal: to Careto Care
• Chemotherapy• Endocrine therapy
• Biologic targeted therapy
• Bisphosphonates–Organ specific therapy
Adjuvant Therapy- Early Breast Cancer -
Modified from Peto et al. Lancet 355:1822, 2000
Recent decrease in UK and USA breast cancer mortality at ages 35 69 years
Adj CTX
Adj HT
Screening
13%18%
12%15%
25%30%
!
Benefits from Adjuvant Systemic Therapy
• It is estimated that – Optimal chemotherapy would reduce annual odds of
recurrence by about 50%-60%
–Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70%
– Trastuzumab would reduce annual odds of recurrence by 45%-55%
– Zoledronic acid would reduce odds of recurrence by about 36%
• Reductions in odds of mortality are somewhat more modest because of competing causes of death
Benefits from Adjuvant Systemic Therapy
• Benefits of endocrine therapy are restricted to ER +/or PgR+ tumors– Can we predict response to individual endocrine
agents?
• Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70%
• Sequential administration of chemotherapy followed by endocrine therapy provides optimal benefit for the overall group– Can we identify patients in this group who do not
benefit from the addition of chemotherapy?
Davidson N, ASCO 2007
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality
EBCTCG. Lancet. 2005;365:1687-17.
Treatment Comparison
Breast Cancer Recurrence, %
Log Rank 2P
Breast Cancer Mortality, %
Log Rank 2P
Tamoxifen 5 yrs vs none, ER-positive women
11.8 < .00001 9.2 < .00001
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
EFFICACY OF ADJUVANT TAMEFFICACY OF ADJUVANT TAM5 YEARS, ER +/UNKNOWN5 YEARS, ER +/UNKNOWN
Relative reduction in odds of
AGE RECURRENCE DEATH
< 50 34%(+6%) 24%(+7%)
50-59 35%(+6%) 20%(+7%)
60-69 50%(+5%) 27%(+5%)
> 7038%(+18%)p=.00001
26%(+15%) p=.00001
EBCTCG, Lancet 2005;365:1687EBCTCG, Lancet 2005;365:1687-17-17
Polychemotherapy versus tamoxifen-treated ER+
disease, for entry age <50:
5-year probabilities of recurrence (ER+ includes
12% ER unknown)
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Lancet 2005; 365: 1687–1717
EBCTCG Overview (2005)
Davidson N, ASCO 2007
Davidson N, ASCO 2007
Davidson N, ASCO 2007
Davidson N, ASCO 2007
5 yrs
Davidson N, ASCO 2007
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality
EBCTCG. Lancet. 2005;365:1687-17.
Treatment Comparison
Breast Cancer Recurrence,
%
Log Rank 2P
Breast Cancer
Mortality, %
Log Rank 2P
Ovarian ablation or suppression vs none
4.3 .00001 3.2 .004
Meta-analysis of 194 randomized trials
Meta-analysis of 144,939 women
Treatment Comparison Breast Cancer Recurrence, %
Log Rank 2P Breast Cancer Mortality, %
Log Rank 2P
Ovarian ablation or suppression vs none
4.3 .00001 3.2 .004
EBCTCG. Lancet. 2005;365:1687-1717.
EBCTCG Overview (2005)
Ovarian function suppression (OFS) was accepted as an alternative where tamoxifen was contraindicated.
Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CMF.
J Clin Oncol 2005;23:5973-82
Retrospective subset analysis suggests that women younger than 40 years seemed to benefit from the addition of goserelin to CAF.
Vantaggio72/6465/5554/485/ 9 yrs DFS
< 40
PCAF-ZT
( % )
CAF-Z
( % )
CAF
( % )
Follow up
ASCO 1999/2003
Nessun Vantaggio
79/6973/6272/615/ 9 yrs DFS
40
Davidson N, ASCO 2007
1. TAM standard all pts2. TAM for 5 yrs3. Chemo + TAM better than whatever alone4. OS beneficial in youger pts continuing to
menstruate after chemo or TAM5. Optimal LHRH duration uncertain6. AIs in Meno after chemo: caution!7. No data of AIs + LHRH vs TAM (RCTs
ongoing)
AIs & TAM: mechanism of action
Placebo
Tamoxifen
Aromatase Inhibitors
Tamoxifen
Tamoxifen
Arom. Inhibitors
Aromatase InhibitorsR
R
Tamox. R
Hormonal Adjuvant Treatment Strategies in Early Breast
Cancer“Up-Front”
“Extended Switch”
“Early Switch”
2-3 years 3-2 years
5 years
10 years
StrategyStrategy RCTsRCTs PtsPts UpdateUpdateMedian Median
FU FU (mo.)(mo.)
AIAI
Efficacy [HR, Efficacy [HR, p]p]
DFS/EFSDFS/EFS OSOS
Up-FrontUp-FrontATACATAC 61866186 Lancet Lancet
20062006 6868 ANAANA 0.87 (0.01)0.87 (0.01) 0.85 (0.7)0.85 (0.7)
BIG-1-98BIG-1-98 49224922 JCO 2007JCO 2007 5151 LETLET 0.82 (0.007)0.82 (0.007) 0.91 (>0.05)0.91 (>0.05)
““Early” Early” SwitchSwitch
ITA-1ITA-1 380380 JCO 2001JCO 2001 6161 AGTAGT NR (0.6)NR (0.6) NR (0.005)NR (0.005)
ITA-2ITA-2 448448 Ann Oncol Ann Oncol 20062006 6464 ANAANA 0.57 (0.005)0.57 (0.005) 0.56 (0.1)0.56 (0.1)
IESIES 47424742 Lancet Lancet 20072007 5656 EXEEXE 0.76 (0.0001)0.76 (0.0001) 0.85 (0.08)0.85 (0.08)
ABCSG8/ABCSG8/ARNOARNO 32243224 Lancet Lancet
20052005 2828 ANAANA 0.60 (0.0009)0.60 (0.0009) NR (0.16)NR (0.16)
““Late” Late” SwitchSwitch
MA.17MA.17 51575157 JNCI 2005JNCI 2005 3030 LETLET 0.58 (0.001)0.58 (0.001) 0.82 (0.3)0.82 (0.3)
ABCSG 6aABCSG 6a 856856 JNCI 2007JNCI 2007 6060 ANAANA 0.64 (0.047)0.64 (0.047) NRNR
NSABP B-33NSABP B-33 15981598 SABCS SABCS 20062006 3030 EXEEXE 0.68 (0.07)0.68 (0.07) 1.20 (0.63)1.20 (0.63)
RCTs – AIs Adjuvant BCRCTs – AIs Adjuvant BC
Adjuvant Aromatase Adjuvant Aromatase InhibitorsInhibitors
StudyStudy therapytherapy f.u.f.u. HRHR Abs dAbs d
ATAC 03ATAC 03 upfrontupfront 44 0.820.82 3%3%
ITA 04ITA 04 switchswitch 33 0.360.36 5.3%5.3%
IES 04IES 04 switchswitch 2.72.7 0.680.68 4.7%4.7%
MA17 04MA17 04 extendedextended 2.52.5 0.580.58 5 %5 %
ARNO -ARNO -ABCSG 04 ABCSG 04
switchswitch 0.60.6 3%3%
BIG 05BIG 05 upfrontupfront 2.42.4 0.810.81 2.6%2.6%
Aromatase Inhibitors Aromatase Inhibitors Adjuvant Adjuvant Trials. Distant Trials. Distant metastasesmetastases
StudyStudy Reduction in Reduction in distant distant
metastasesmetastases
pp
ATAC ATAC Lancet 05Lancet 05 14%14% .01.01
BIG 1-98 BIG 1-98 NEJM 05NEJM 05 27%27% .0012.0012
IES IES NEJM 04NEJM 04 34%34% .0004.0004
ARNO/ABCSG ARNO/ABCSG Lancet Lancet 0505
39%39% .0067.0067
ITA ITA JCO 05JCO 05 51%51% .06.06
MA 17 MA 17 JNCI 05JNCI 05 40%40% .002.002
Patients (%)
Follow-up time (years)
20
25HR
0.74HR+
95% CI
(0.64–0.87)
p-value
0.0002
A
282
T
370
At risk:A 2618 2540 2448 2355 2268 2014 830T 2598 2516 2398 2304 2189 1932 774
ATAC: recurrences* before 2.5 ATAC: recurrences* before 2.5 years years (HR+ patients)(HR+ patients)
* Censoring non-BC deaths before recurrence
0
5
10
15
0 1 2 3 4 5 6
‘Arimidex’ (A)Tamoxifen (T)
Pre-defined adverse events*: Pre-defined adverse events*: ATACATACMedian follow-up 68 monthsMedian follow-up 68 months
Incidence (%)
Anastrozole
Tamoxifen
ATAC Trialists’ Group. Lancet 2005;365:60-62
Total fractures p<0.0001
Joint symptoms p<0.0001
Deep venous thromboembolic events p=0.02
Venous thromboembolic events p=0.0004
Ischemic cerebrovascular events p=0.03
Endometrial cancer p=0.02
Vaginal discharge p<0.0001
Vaginal bleeding p<0.0001
Hot flushes p<0.0001
0 10 20 30 40 50
* Other Pre-defined AE’s with NO significant differences seen between groups: Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue
*A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event reports
ATAC 100 mo.: SAEs: on and off treatment (Number – safety population)
Serious adverse event
On treatment
Anastrozole
Off treatment
Tamoxifen Anastrozole Tamoxifen
Treatment-related 153 284 49 57
Endometrial cancer 4 12 1 12
Myocardial infarction 34 33 26 28
Cerebrovascular accident 20 34 22 20
Fracture episodes* 375 234 146 143
†included as a non-predefined adverse event of interest
Predefined adverse eventsat any time on treatment or any severity
Hot flushesNausea and vomitingFatigue / tiredness (asthenia)Mood disturbancesMusculo-skeletal disordersVaginal bleedingVaginal dischargeIschaemic cardiovascular diseaseIschaemic cerebrovascular eventVenous thromboembolic eventsDeep venous thromboembolic eventsCataractsCarpal tunnel syndrome†
1102 (35.6)394 (12.7)578 (18.7)599 (19.4)
1104 (35.7)167 (5.4)110 (3.6)130 (4.2)64 (2.1)87 (2.8)48 (1.6)
189 (6.1) 79 (2.5)
1263 (40.8)358 (12.4)544 (17.6)555 (17.9)915 (29.6)319 (10.3)409 (13.2)106 (3.4)91 (2.9)141 (4.6)75 (2.4)218 (7.0)22 (0.7)
Anastrozole(N = 3092)
Tamoxifen(N = 3094)
Deaths according to treatment group (ITT population)
Cause of death
Total deaths
Deaths after recurrence
Deaths without recurrence
Cardiovascular
Cerebrovascular
Second primary non-breast cancer
Other
Anastrozole(n = 3125)
629 (20)
350 (11)
279 (9)
67 (2)
25 (1)
84 (3)
103 (3)
Tamoxifen(n = 3116)
624 (20)
382 (12)
242 (8)
66 (2)
29 (1)
60 (2)
87 (3)
No. patients (%)
Fracture episode rates throughout the study
29842976
At risk:AT
28592824
27452699
26402572
24962419
23062208
20772000
17131645
702659
Time since randomization (years)
Annual fracture episode rates (%)
Anastrozole (A)Tamoxifen (T)
0 1 2 3 4 5 6 7 8 90
2
3
4
1
ATAC 100: benefits continue and detrimental effects
decline after treatment cessation
Time to recurrence Fracture episode rates
Patients (%)
30
25
20
15
10
5
00 1 2 3 4 5 6 7 8 9
12.5%17.0%
21.8%
Follow-up time (years)
9.7%
2.8% 4.8%Absolutedifference
Tamoxifen (T)Anastrozole (A)
Time since randomisation (years)
Annual fracture episode rates (%)
Tamoxifen (T)Anastrozole (A)
0 1 2 3 4 5 6 7 8 90
2
3
4
1
BIG 1-98: cumulative incidence BIG 1-98: cumulative incidence of breast cancer relapseof breast cancer relapse
Proportionfailing(%)
Time since randomisation (years)
5-year difference (L-T) = -3.4% (SE 1.2)Cuminc p=0.0002
0 1 2 3 4 5
0
5
10
15
20
13.6%
10.2%
6.2%
8.1%
Letrozole (L)
Tamoxifen (T)
SE = standard error
Thürlimann B et al. The Breast 2005;14:S3, abs S4
BIG 1-98 DFS BIG 1-98 DFS by Local Pathological by Local Pathological AssessmentAssessment
Favors L Favors T
1.00.5 0.75 1.25 1.5
Hazard Ratio (L:T)
ER+ / PgR+ (n=5055)
ER+ / PgR- (n=1631)
0.84
0.83
All patients (n=8010)0.81
ER+ / PgR unk (n=1154)0.72
““Endometrial events” :Endometrial events” :Tamoxifen vs Aromatase Tamoxifen vs Aromatase InhibitorInhibitor
HysterectoHysterectomymy
EndometrialEndometrial
biopsiesbiopsies
ATACATAC 5% vs 1%5% vs 1%
BIG 1BIG 1 7.2% vs 7.2% vs 1.9%1.9%
Trial Design
Tamoxifen
RANDOMIZE
Exemestane
5162*
Tamoxifen
5294*
Post Treatment Follow-up
10335*
Diagnosis
2-3 years2-3 years study
treatment
Total 5 years endocrine therapy
Start of study
* Total women years
Results-event- and recurrence-free survival
Results-survival
Results-secondary outcomes
Cancer Treatment Reviews (2006) 32, 325– 332
TAM AIs
Aromatase Inhibitors: Aromatase Inhibitors: Tox IssuesTox Issues
1.1. Bone FracturesBone Fractures
2.2. Cardiovascular Cardiovascular DiseaseDisease
Bone Health: Bone Health: IssuesIssues
Protective Effects of TAMProtective Effects of TAM Steroidal vs Non-SteroidalSteroidal vs Non-Steroidal Predictive role of BMD on fracturePredictive role of BMD on fracture Other fracture risk factors:Other fracture risk factors:
Patient’ characteristicsPatient’ characteristics Bone turnoverBone turnover Steroid use (abuse?)Steroid use (abuse?)
What about bisphosphonates?What about bisphosphonates?
Fracture incidenceFracture incidence
Incidence of fracture reported in different adjuvant aromatase inhibitor trials
1. The earliest publications of the RCTs using AIs provided conflicting results about the supposed higher risk of ischaemic cardiovascular toxicity
2. The pathogenesis of cardiac damage induced by AIs is still definitively unclear, while some pathways seem to be involved1:• The reduction of circulating estradiol• The unbalanced lipid metabolism
CV Disease - CV Disease - BackgroundBackground
References: 1Howell JSBMB 2005
Lipid effectsLipid effects Increase of:Increase of:
ColestherolColestherol TGTG LpALpA LDL-CLDL-C
Decrease of:Decrease of: HDL-CHDL-C
PrimaryPrimary Cardiovascular Adverse Events Rate Cardiovascular Adverse Events Rate
(CVAE)(CVAE)
Grade 3-4 as defined by NCICGrade 3-4 as defined by NCIC
SecondarySecondary Thromboembolic Adverse Events Rate Thromboembolic Adverse Events Rate
(TEAE)(TEAE)
Cerebrovascular Adverse Events Rate Cerebrovascular Adverse Events Rate
(CBVAE) (CBVAE)
End-Points
In order to reduce heterogeneity across AIs, In order to reduce heterogeneity across AIs,
the analysis has been carried on the analysis has been carried on
considering:considering: all AIs (Overall analysis)all AIs (Overall analysis) only 3only 3rdrd generation AIs (CVAE-New) generation AIs (CVAE-New)Cuppone F, Cancer 2008
Selected RCTs
Cuppone F, Cancer 2008
Results – CVAE Rate(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results – CVAE Rate(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results - CVAE Rate-3rd Generation AIs(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Results - CVAE Rate-3rd Generation AIs(Cardiovascular Adverse Events)
Cuppone F, Cancer 2008
Cuppone F, Cancer 2008
Results – TEAE Rate(Thromboembolic Adverse Events)
Results – CBVAE Rate(Cerebrovascular Adverse Events)
Cuppone F, Cancer 2008
• Controversial ‘Motive’ (not clear background)
• Overestimated risk (0.5%) when AI vs TAM
• No difference AIs vs placebo
• Protective effect of TAM really ‘guilty’
‘Trial’ Verdict
…..free for lack of evidences
Cardio-protective effect of Cardio-protective effect of tamoxifen tamoxifen MetanalysisMetanalysis
32 trials comparing tamoxifen against a 32 trials comparing tamoxifen against a control group (metastatic, adjuvant, and control group (metastatic, adjuvant, and prevention settings) prevention settings) 12 reported on myocardial infarction death12 reported on myocardial infarction death
> 52,000 patients; 66% postmenopausal; > 52,000 patients; 66% postmenopausal; mean age 54.8 yrs; mean treatment mean age 54.8 yrs; mean treatment duration: 4.3 yrs; mean FU: 5.6 yrsduration: 4.3 yrs; mean FU: 5.6 yrs
Relative risk ratio for fatal MIs (tamoxifen / Relative risk ratio for fatal MIs (tamoxifen / control): 0.62 (95% CI: 0.41-0.93)control): 0.62 (95% CI: 0.41-0.93)
Risk ratio without the Scottish trial: 0.81 Risk ratio without the Scottish trial: 0.81 (95% CI: 0.48-1.37)(95% CI: 0.48-1.37)
Braithwaite et al JGIM 2003;18:937-47
Myocardial Infarction
Cognitive FunctionCognitive Function, , Fatigue and Menopausal Fatigue and Menopausal SymptomsSymptoms
HSCS*HSCS*
(impairment)(impairment)FACT-FFACT-F FACT-ESFACT-ES FACT-GFACT-G
Adjuvant Adjuvant CTCT
16%16% 3131 5858 7777
ControlControl 4%4% 4646 6464 9393
0.0080.008 0.00010.0001 0.00010.0001 0.00010.0001
* High Sensitivity Cognitive Screen
N Tchen, JCO 2005
LONG TERM TREATMENT WITH LONG TERM TREATMENT WITH A.I.A.I.
POTENTIALPOTENTIAL
BENEFITBENEFITPOTENTIAL POTENTIAL
RISKRISK
SUPERIOR EFFICACYSUPERIOR EFFICACY
LOSS SEVER LONG TERM EFFECTSLOSS SEVER LONG TERM EFFECTS Endometrial cancerEndometrial cancer ThromboembolismThromboembolism
FEWER HYSTERECTOMIESFEWER HYSTERECTOMIES
INCREASED FRACTURE RATEINCREASED FRACTURE RATE
TREATMENT-INDUCED BMD TREATMENT-INDUCED BMD LOSSLOSS
ARTHROMYALGIAARTHROMYALGIA
LIPID DISTURBANCESLIPID DISTURBANCES
COGNITIVE DISTURBANCESCOGNITIVE DISTURBANCES
VASOMOTOR SIDE EFFECTSVASOMOTOR SIDE EFFECTS
Tailoring the treatment on Tailoring the treatment on the basis of the clinical the basis of the clinical histories?histories?
Which patients should we deny the Which patients should we deny the advantage linked to AI treatment on advantage linked to AI treatment on the basis of their characteristics?the basis of their characteristics?