Cochrane 2005
Aromatase Inhibitors: Aromatase Inhibitors: Review of adjuvant trials Review of adjuvant trials
and toxicityand toxicity
Treatment induced bone lossTreatment induced bone loss
Dr Richard de BoerDr Richard de BoerMedical Oncologist
Royal Melbourne/Western Hospitals
Cochrane 2005
OverviewOverview
Aromatase Inhibitors in Early Breast Cancer– Initial adjuvant therapy
– Switching from tamoxifen to AI
– “Extended Adjuvant” therapy
– Cancer treatment induced bone loss (CTIBL)
Cochrane 2005
OvarianSteroidogenesis
Granulosa
CorpusLuteum
Oestrogen Stimulation of Target Tissues inOestrogen Stimulation of Target Tissues inPre- and Postmenopausal WomenPre- and Postmenopausal Women
POSTmenopausal Women
Target Tissueseg,
BREASTBREAST TUMOR
ESTRONE
AROMATASE
AdiposeTissue
Breast
BreastTumor
PREmenopausalPREmenopausal Women Women
Adrenal Gland
ANDROSTENEDIONE
OESTRADIOLOESTRADIOL
AROMATASE
TamoxifenTamoxifenTamoxifen
GnRH GnRH agonistsagonists
AI'sAI's
Cochrane 2005
Trials of AI's in Adjuvant TherapyTrials of AI's in Adjuvant Therapy
PLACEBO
EXEMESTANE
LETROZOLE
ANASTROZOLE
TAMOXIFENATAC
ARNO
MA. 17
BIG 1.98
ICCG Study 96
NSABP B-33
TEAM EXE
Cochrane 2005
BIG 1.98: Adjuvant Letrozole TrialBIG 1.98: Adjuvant Letrozole TrialTrial DesignTrial Design
Tamoxifen
LetrozoleTamoxifen Letrozole
Letrozole Tamoxifen
RANDOMISE
0 2 5YEARS
A
B
C
D
2-Arm Option3/98 to 3/00
1835 pts
4-Arm Option9/99-5/036193 pts
Cochrane 2005Years from Randomisation0 2 3 4 51
0
10
5
15
20P
ropo
rtion
Fai
lure
(%)
L
T
BIG 1.98: Cumulative IncidenceBIG 1.98: Cumulative IncidenceBreast Cancer RelapseBreast Cancer Relapse
13.6%
10.2%8.1%
6.2%
5-year diff (L-T) = -3.4% (S.E. 1.2)P=0.0002
Cochrane 2005* Patients ≥1 fracture occurring before recurrence, including patients no longer on treatment
PrePre--specified adverse events (%)specified adverse events (%)
T
40.910.213.20.84.5
29.47.7
5.1
AI
35.75.43.50.22.8
35.611.0
1.3
Hot flushesVaginal bleedingVaginal dischargeEndometrial cancerVenous thromboembolic
Joint symptomsFractures
Hysterectomy
p-value
<0.0001<0.0001<0.00010.020.0004
<0.0001<0.0001
<0.0001
Cochrane 2005
A Randomised Trial of Exemestane after 2 to 3 A Randomised Trial of Exemestane after 2 to 3 Years of Tamoxifen in PM Women : Years of Tamoxifen in PM Women :
IntergroupIntergroup Exemestane StudyExemestane Study
ER+
Post-menopausal
2-3 yrs Tamoxifen
RANDOMISED
2-3 yrs Tamoxifen
2-3 yrs Exemestane
Yr after randomization
Yr after start Tamoxifen
Coombes RC et al. NEJM 2004:350;1081–92.
Cochrane 2005
IES Results: DiseaseIES Results: Disease--free Survivalfree Survival
Coombes RC et al. NEJM 2004:350;1081–92.
No. of Events/No. at Risk
Exemestane 0/2362 52/2168 60/1696 44/757 20/201
Tamoxifen 0/2380 78/2173 90/1682 76/730 18/185
Tamoxifen group
Exemestane group
0 1 2 3 4
75
50
25
100
Patie
nts
surv
ivin
g fr
ee o
f dis
ease
(%)
Years after randomisation
HR for recurrence or death:
0.68 (95% CI, 0.56–0.82) p<0.001,
Absolute DFS benefit - 4.7% (95% CI 2.6-6.8)
Cochrane 2005Saphner et al. J Clin Oncol. 1996;14:2738.
0
0.1
0.2
0.3
0 1 2 3 4 5 6 7 8 9 10 11 12
Rec
urre
nce
haza
rd ra
te
Years
ER– (n=1305)
ER+ (n=2257)
LongLong--Term Risk of Breast Cancer Term Risk of Breast Cancer Recurrence Remains High in ER+ PatientsRecurrence Remains High in ER+ Patients
Cochrane 2005
MA.17: MA.17: A Phase III Randomised, DoubleA Phase III Randomised, Double--Blind Study of Blind Study of Adjuvant Letrozole vs Placebo in PM Women Completing 5 Adjuvant Letrozole vs Placebo in PM Women Completing 5
Years of TamoxifenYears of Tamoxifen
* n=2575 (efficacy); 2154 (safety) in the letrozole arm.† n=2582 (efficacy); 2145 (safety) in the placebo arm.
Primary end point: DFSSecondary end points: OS/safety/QOL
Randomisation(Disease-free)
Tamoxifen
Placebo qd†
Letrozole 2.5 mg qd*
5 years early adjuvant 5 years extended adjuvant
Goss PE et al. NEJM 2003;349(19):1793–802.
Cochrane 2005
Overall SurvivalOverall Survival
Node-Positive Node-Negative
LetrozoleLetrozole Placebo
1171
1189
1144
1157
875
877
508
500
255
243
81
75
3
3
1292
1276
1265
1250
972
964
572
571
275
283
93
93
3
5
No. at risk(Letrozole) No. at risk(Placebo)
Months from randomization Months from randomization0 10 20 30 40 50 60 0 10 20 30 40 50 60
% S
urvi
ving
% S
urvi
ving
0
20
40
60
80
100
0
20
40
60
80
100
P P = 0.04= 0.04 P P = 0.24= 0.24
Cochrane 2005
Cancer TreatmentCancer Treatment--Induced Bone Induced Bone Loss (CTIBL)Loss (CTIBL)
in Breast Cancerin Breast Cancer
Cochrane 2005
Stromal cellStromalStromal cellcellMature osteoclastMature Mature osteoclastosteoclastMature osteoclastMature Mature osteoclastosteoclast
Oestrogen + Oestrogen -
PGE2IL-1TNF-α
RANKL
RANKL
Pre-B cellOsteoclastprogenitor
Oestrogen Depletion Oestrogen Depletion Accelerates Accelerates OsteoclastogenesisOsteoclastogenesis
Cochrane 2005
BIG 1.98: Bone FracturesBIG 1.98: Bone Fractures
1.44, p=0.0006Odds ratio, p-value (L:T)
1.5
(ATAC 1.5)
2.2
(ATAC 2.2)
Bone fracture rate (fracture/100 patient-years)
162 (4.1%)228 (5.8%)Patients w/ bone fracture
167247Bone fractures
39843965Patients
TamoxifenLetrozole
Cochrane 2005
BisphosphonatesBisphosphonates• 1st synthesised in Germany 1856• Bind to the bone matrix; Inhibit osteoclasts directly
Cochrane 2005
Zoledronic acidZoledronic acid increases BMD in increases BMD in postmenopausal women with reduced BMDpostmenopausal women with reduced BMD
Reid IR et al. N Engl J Med. 2002;346:653-661
Lumbar spine Femoral neck
12
Cha
nge
in B
MD
, %
0 3 6 9-1
7
3
5
1
Time, months
Zoledronic acid 4 mg
Placebo
0Time, months
3 6 9 12
Zoledronic acid 4 mg
Placebo
-1.5
0
1.5
3.0
Cochrane 2005
ZoZometameta--FFemaraemara AAdjuvant djuvant SSynergy ynergy TTrialrial
in in Patients with Breast CancerPatients with Breast Cancer
The The ZOZO--FAST studyFAST study
Cochrane 2005
• primary endpoint: lumbar BMD 12 m• secondary: hip BMD, fracture, bone
markers; DFS
Adjuvant BC• ER+ or PgR+• Postmenopausal
or recently postmenopausal
• T score > -2 SD Femara
RANDOMI SE
Femara + Immediate Zometa
Zometa: 4 mg IV q 6 mosFemara: 2.5 mg/day500mg of Ca and a multi-vit(400-800 IU of vitamin D)
Delayed Zometa:• BMD Tscore <-2 SD• Or clinical fracture• Or asymptomatic
fracture at 36 mos
Stratification
ZOZO--FAST ProgramFAST Program
Cochrane 2005
ZZ--FAST Trial (USA)FAST Trial (USA)
• Early results at SABCS Dec 2004– 6 month % change in BMD of Hip and LS
UpfrontZometa
DelayedZometa
Hip +1.02% -1.40%
Lumbar Spine +1.55% -1.78%
Cochrane 2005
CTIBL: ConclusionsCTIBL: Conclusions
• Treatment induced bone loss is a frequent and relevant problem in breast cancer pts.
• BMD loss during adjuvant treatment with AI's is approx. 3-5% per yr, and without specific treatment, the fracture rate is approx. 2% per year
• Bone loss can be identified early, and during treatment with AI's, yearly BMD measurements are recommended.
• Bisphosphonates can prevent bone loss and increase BMD.
Cochrane 2005
AI in EBC: ConclusionsAI in EBC: Conclusions
BUT– Increased arthralgias, osteoporosis, #s, ?lipid effects
• Robust evidence that aromatase inhibitors are effective as adjuvant or part of adjuvant treatment for PM hormone receptor +ve women
• Significant aromatase inhibitor advantages across all adjuvant studies compared with tamoxifen– Improvement in DFS– Reduction in contralateral breast cancer– Reduction in endometrial cancer and VTE
Cochrane 2005
Questions NOT Answered by Current AI Questions NOT Answered by Current AI Adjuvant TrialsAdjuvant Trials
• Optimal duration of AI treatment
• Optimal sequencing of endocrine therapy
• Which AI is the most effective and/or has least side effects?
• Best management of side effects
Cochrane 2005
Backup slidesBackup slides
Cochrane 2005
ATACATAC• 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
Cochrane 2005
ATAC: DiseaseATAC: Disease--free survivalfree survival(HR+ patients)(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
Cochrane 20051919
BIG 1.98: Adverse Events, Any GradeBIG 1.98: 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 flushesHyperchol*
JointMuscle
Vaginal bleedingBone fracture
CardiacThromboembolic
CVA/TIA
Percent of Patients
Letrozole
Tamoxifen
*Grade 1: 35.1% L, 17.3% T; Grade 2+: 8.4% L, 1.8% T
Cochrane 2005
BIG 1.98: Treatment FailuresBIG 1.98: Treatment Failures
0.017
0.155
0.077
0.288
0.005
0.842
0.092
0.034
0.003
9.6%8.1%Systemic Failures**
4.8%4.1%Deaths
10.7%8.8%First Failure Sites (DFS events)
0.9%1.4%Death without cancer event
2.0%1.7%Second (non breast) malignancy
5.8%4.4%Distant
0.3%0.3%Regional*
0.7%0.4%Contralateral Breast (invasive)
0.9%0.5%Local
Letrozole Tamoxifen P
* Regional includes axilla or internal mammary** SDFS ignores local and contralateral events
Thürlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511
Cochrane 2005
Bone mineral density in the proximal tibia
% change in B
MD
weeks
Sham
5
0
0 4 8 12 16 20 24
-5
-10
-15
-20
Let + Zom4.0 µg/kg
Let 1 mg/kg/d
OVX
Let + Zom 20 µg/kg
Gasser et al, San Antonio, 2002
Zoledronic acidZoledronic acid effectively inhibits effectively inhibits letrozoleletrozole--induced bone loss in ratsinduced bone loss in rats
Cochrane 2005
– Very rare adverse event (< 1 / 10,000 patients)
– No causal relationship between bisphosphonate use and osteonecrosis has been established
Osteonecrosis reported 4x more often in cancer patients than in the normal population
Multifactorial causes for osteonecrosis (trauma, infection, chemotherapy, radiotherapy, long-term glucocorticoid therapy)
OsteonecrosisOsteonecrosis of the Jaw in Cancer of the Jaw in Cancer Patients on Bisphosphonate TherapyPatients on Bisphosphonate Therapy
