Cáncer de Mama
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CÁNCER DE MAMA
TERÁPIAS ÓSEAS
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CA DE MAMA TEMPRANO: PREVENCIÓN DE FX
AUMENTO DE LA SLE CON TERAPIAS ADYUVANTES ÓSEAS
ENFERMEDAD METASTASICA
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Predictors of Fracture Risk
• BMD (DXA), femoral neck T-score– Serial monitoring should be done on the same
equipment with the same reference standards at the same site
• Age• Drugs• History/presence of vertebral fracture
– Best predictor of a subsequent fracture is an existing one
• Risk of falls• Vitamin D levels
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Tasa de Pérdida Ósea
1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223. 3. Maillefert JF, et al. J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306-3311.
Bo
ne
Lo
ss a
t 1
Yr
(%)
Naturally Occurring Bone Loss CTIBL
0
2
4
6
8
10
Normal Men[1]
Postmenopausal Women[1]
Al Therapy inPostmenopausal
Women[2]
ADT[3]
Al Therapy+ GnRH
Agonist inPremenopausal
Women[4]
Premature Menopause
Secondary toChemotherapy[5]
0.51.0
2.6
4.6
7.07.7
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Tamoxifen
LetrozoleAnastrozole
Fra
ctu
res
(%)
11.0
7.7
5.7
4.0
7.0
5.0
P < .0001
P < .001
0
2
4
6
8
10
12
14
P = .003
Exemestane
ATAC[1]
(68 mos)IES[2]
(58 mos)BIG 1-98[3]
(26 mos)
Riesgo de fx elevado de los IA esteroidales y noesteroidales vs Tamoxifeno
1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127. 3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757.
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Oral Bisphosphonate Impact on BMD in Patients With Breast Cancer
• Clodronate in breast cancer patients with chemotherapy-induced premature ovarian failureSaarto T, et al. J Clin Oncol. 1997;15:1341-1347.
• Risedronate reduces bone loss in women with chemotherapy-induced ovarian failureDelmas PD, et al. J Clin Oncol. 1997;15:955-962.
• Alendronate in GnRH agonist-induced premature menopause (patients without cancer)Ripps BA, et al. J Reprod Med. 2003;48:761-766.
• Monthly ibandronate and anastrozole-induced bone lossLester JE, et al. Clin Cancer Res. 2008;14:6336-6342.
• SABRE trial: study of anastrozole with risedronate Van Poznak C, et al. J Clin Oncol. 2010;28:967-975.
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Management of Bone Health Using BMD
T-Score: NCCN Task Force Report• T-score: > -1 (normal)
• T-score: -1.0 to -1.5
• T-score: -1.5 to -2.0
• T-score < -2.0 orFRAX 10-yr fracture risk: > 20% major fracture > 3% for hip fracture
• Repeat DXA every 2 yrs*
• Repeat DXA every 2 yrs*• Consider checking 25(OH) level
• Repeat DXA every 2 yrs*• Consider checking 25(OH) level• Consider pharmacologic
therapy• Repeat DXA every 2 yrs*• Consider checking 25(OH) level• Strongly consider
pharmacologic therapy
Gralow JR, et al. J Natl Compr Canc Netw. 2009;7:S1-S32.
*In selected cases, longer or shorter intervals may be considered. If a major change in patient risk factors or a major intervention occurs, then repeating DXA at 1 yr is reasonable.
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Key endpoints:Primary: BMD at 12 mosSecondary: BMD at 36 and 60 mos, disease recurrence, fractures, safety
Letrozole + immediate Zoledronic Acid 4 mg every 6 mos
Breast cancerstage I to IIIa(N = 1065)Postmenopausal or amenorrheic due to cancer treatmentER+ and/or PgR+
T-score ≥ -2.0
Letrozole +
Treatment duration: 5 yrs
RDelayed Zoledronic Acid
If 1 of the following occurs:BMD T-score < -2 Clinical fractureAsymptomatic fracture at 36 mos
Coleman R, et al. Ann Oncol. 2012. Oct 9.
ZO-FAST: A Phase III Study of the Use of Zoledronic Acid With Adjuvant Letrozole
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Coleman R, et al. Ann Oncol. 2012. Oct 9. [Epub ahead of print]
ZO-FAST (Primary Endpoint): Median Change in LS BMD With Zoledronic Acid
Immediate zoledronic acidDelayed zoledronic acid
P < .0001 for each
Ch
ang
e in
LS
(L
S-L
4) B
MD
(%
)
12 Mos 24 Mos 36 Mos 48 Mos 60 Mos-6
-4
-2
0
2
4
6
+4.3
-5.4
Δ 5.9 Δ 8.2 Δ 8.8 Δ 9.2 Δ 10.0
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Modalidades de tratamiento
Bifosfonatos orales
• Buena adherencia a sus meds
• Rechazan meds IV• No quieren o pueden ir a
la clínica• Menos costosos• Menos efectos 2os• < riesgo de osteonecrosis
o de fx subtrocantéricas
Bifosfonatos IV
• Mayor adherencia en pacientes conintolerancia GI (RGE) uotros síntomas.
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ABCSG-12: Phase III Study of Adjuvant Endocrine Therapy ± Zoledronic Acid
• Key endpoints– Primary: DFS at 5 yrs
– Secondary: recurrence-free survival, OS, BMD, safety
TAM 20 mg/day
ANA 1 mg/day
Treatment 3 yrs(median follow-up: 48 mos)
TAM + ZA 4 mg q6m
ANA + ZA 4 mg q6m
R
Long-term monitoring for 5 yrs for recurrence
and survival(DFS, OS)
3-yrBMD
5-yrBMD
Premenopausal patients with stage I/II breast cancer
(goserelin 3.6 mg/28 days)stratified by: ER+ and/or PgR+ Age Stage Grade Lymph nodes
(N = 1803)
Gnant M, et al. N Engl J Med. 2009;360:679-691.
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Gnant M, et al. Lancet Oncol. 2008;9:840-849.
ABCSG-12 Bone Substudy: Change in BMD at Yrs 3 and 5
10
5
0
-5
-10
-15
Per
cen
t C
han
ge
in L
S
BM
D (
g/c
m2 )
Fro
m B
asel
ine
Mos
Mos
No Zoledronic Acid
Tamoxifen Anastrozole
36 60
-9.0P < .0001
-4.5NS
-13.6P < .0001
-7.8P = .003
36 60
36 60 36 60
Zoledronic Acid
Tamoxifen Anastrozole
+1.0NS
+5.2P = .04
-0.1NS
+3.1NS
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*
*
*
Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882.
Denosumab in Patients With Breast Cancer Receiving Adjuvant AIs
Per
cen
t C
han
ge
in B
MD
Fro
m
Bas
elin
e at
LS
8
7
6
5
4
3
2
1
0
-1
-2
-31 3 6 12 24
Mos
5.5% difference at 12 mos
7.6% difference at 24 mos
*P < .0001 vs placebo
Placebo (n = 122)Denosumab 60 mg q6m (n = 123) *
*
Toxicity: no significant difference in AEs between denosumab and placebo arm
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Checklist for Bone Health in Patients With Breast Cancer
Item Description
Determine osteoporosis risk factors
•T-score < -1.5?•Older than 65 yrs?•Low BMI (< 20)?
Other factors
•Family history of hip fracture?•Personal history of fragility after 50 yrs of age?•Oral corticosteroid use of > 6 mos?•Smoking (current or past history)?•10-yr probability for hip fracture (by FRAX)?
Cancer treatment–related factors
•AIs?•Ovarian ablation?
Assays•DXA to assess BMD (every 2 yrs)•25(OH)D level•Serum calcium level
Treat the following with bone-directed therapy
•Hip or vertebral fracture•T-score < -2.0•10-yr probability for hip fracture ≥ 3%•10-yr probability of a major osteoporotic event ≥ 20%
Hadji P, et al. Ann Oncol. 2011;22:2546-2555. National Osteoporosis Foundation.
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T-score < -2.0Any 2 of the following risk factors
T-score < -1.5
Aged younger than 65 yrs
Low BMI (< 20)
Family history of hip fracture
Personal history of fragility fracture after 50 yrs of age
Oral corticosteroid use of > 6 mos
Smoking (current or history of)
T-score > -2.0, no risk factors
Monitor risk status and BMD q12m*
Monitor BMD on case by case basis for IV bisphosphonates;
q12-24m for oral bisphosphonates
ExerciseCalcium and vitamin D
supplements
*If ≥ 10% decrease in BMD (≥ 4% to 5% if osteopenic at baseline), investigate secondary causes and begin antiresorptive treatment. Use lowest T-score from 3 sites.
ExerciseTreatment including bisphosphonates,
denosumab,Calcium, and vitamin D
supplements
Guidance for Women With Breast Cancer Initiating AI Therapy: European
Guidelines
Hadji P, et al. Ann Oncol. 2011;22:2546-2555.
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¿AUMENTAR LA SOBREVIDALIBRE DE ENFERMEDAD?
Y/OSOBREVIDA GLOBAL?
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DFS
ABCSG-12 (84 Mos): Efficacy
100
80
60
40
20
0
DF
S (
%)
0 12 24 36 48 60 72 84 96 108
Mos Since RandomizationPatients at Risk, nNo ZAZA
903900
858862
833841
807822
758788
653674
521544
405419
191208
Events, n
Univariate Multiple CoxRegression
HR(95% CI)
P Value
HR(95% CI)
P Value
vs no ZA
vs no ZA
(Log-rank)
No ZA
132/903
0.72 (0.56-0.94)
.014 0.71(0.55-0.92)
.01198/900ZA
OS
100
80
60
40
20
0
DF
S (
%)
0 12 24 36 48 60 72 84 96 108
Mos Since RandomizationPatients at Risk, nNo ZAZA
903900
864868
856858
839849
811818
706708
576587
456454
215232
Events, n
Univariate Multiple CoxRegression
HR(95% CI)
P Value
HR(95% CI)
P Value
vs no ZA
vs no ZA
(Log-rank)
No ZA
49/903
0.63 (0.40-0.99)
.049 0.61(0.39-0.96)
.03333/900ZA
Gnant M, et al. SABCS 2011. Abstract S1-2.
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ZA treatment duration: 5 yrs
AZURE: Study DesignAccrual September 2003 - February 2006
Country Centers, n
Patients, n
United Kingdom
123 2710
Ireland 10 247
Australia 28 226
Spain 8 107
Portugal 1 32
Thailand 2 25
Taiwan 2 13
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
Standard therapy
Standard therapy +ZA 4 mg
Mos 6 30 60
3360 patients with stage II/III breast cancer
R
6 dosesq3-4w
8 dosesq3m
5 dosesq6m
Primary endpoint: DFS, with recurrence defined as date first suspected
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AZURE: DFS and IDFS
Patients at Risk, n 1681 1591 1465 1354 1241 580 83 1678 1583 1445 1344 1252 561 71
DFS
0
ZAControl
0
Patients at Risk, n1681 1578 1443 1337 1222 570 821678 1574 1426 1316 1221 544 68
IDFS
0
ZAControl
DFS IDFS
1 2 3 4 5 6 7
20
40
60
80
Yrs
Control (n = 1678)
Adjusted HR: 0.98 (95% CI: 0.85-1.13;P = .79)
Su
rviv
ing
(%
)
00
ZA (n = 1681)
0
100100
00 1 2 3 4 5 6 7
20
40
60
80
Yrs
Su
rviv
ing
(%
)
00
100
00
Control (n = 1678)
Adjusted HR: 0.98 (95% CI: 0.85-1.12;P = .73)
ZA (n = 1681)
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
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AZURE: IDFS and OS by Menopausal Status
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n A
live
and
in
vasi
ve D
isea
se F
ree
IDFS: Pre, Peri, and Unknown Menopausal Status
Adjusted HR: 1.15(95% CI: 0.97-1.36; P = .11)288 vs 256 events
Patients at Risk, nZA:
No ZA:1162 1088 996 919 829 393 57 0
1156 1092 995 920 853 388 47 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n A
live
OS: Pre, Peri, and Unknown Menopausal Status
Adjusted HR: 0.97(95% CI: 0.78-1.21; P = .81)161 vs 165 events
Patients at Risk, nZA:
No ZA:1162 1131 1078 1020 955 466 71 0
1156 1123 1076 1032 963 446 60 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n A
live
and
in
vasi
ve D
isea
se F
ree
IDFS: > 5 Yrs Postmenopausal
Adjusted HR: 0.75(95% CI: 0.59-0.96; P = .02)116 vs 147 events
Patients at Risk, nZA:
No ZA:519 490 447 418 393 177 25 0
522 482 431 396 368 156 21 0
0
Mos Since Randomization
1.0
6 12 18 24 30 36 42 48 54 60 66 72 78 84
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n A
live
OS: > 5 Yrs Postmenopausal
Adjusted HR: 0.74(95% CI: 0.55-0.98; P = .04)82 vs 111 events
Patients at Risk, nZA:
No ZA:519 502 482 448 422 190 29 0
522 509 475 441 401 177 26 0
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
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Typical ORMenopausal Group
Description
Total: -1% ± 7%Z = .13; P = .9
21 (heterogeneity) = 7.91; P = .005
Odds Reduction (± SD)
n = 1041263 events
n = 2318544 events
HR: 0.75 (95% CI: 0.59-0.96)
HR: 1.15 (95% CI: 0.97-1.36)
Pre + < 5 yrs post+ unknown status
> 5 yrs postmenopausal
High estrogen environment
Low estrogen environment
1.0 1.2 1.4 1.6 1.8 2.00.2 0.4 0.6 0.8
AZURE: Treatment Effect on IDFS by Menopausal Status
Coleman RE, et al. N Engl J Med. 2011;365:1396-1405.
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Niveles de Vit D 25 OHD > 30 ng/ml (suficientes) predicen beneficio del Ac Zoledrónico en las
tasas de recidiva a distancia en pacientes posmenopausicas
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Marshall H, et al. ASCO 2012. Abstract 502.
Adjuvant Zoledronic Acid in Early Breast Cancer: Expert Perspectives
• No benefit in overall unselected population• Significant benefit in postmenopausal women seen in
multiple studies– Effect of menopause on DFS driven by influences on
nonbone recurrence• Potential for harm in pre- and perimenopausal women• These subset analyses do not justify the routine use of
adjuvant zoledronic acid in postmenopausal women
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Letrozole + ZA 4 mg q6m
Letrozole + Delayed* ZA 4 mg q6m
*If 1 of the following occurs:BMD T-score < -2 SD Clinical fracture Asymptomatic fracture at 36 mos
Stage I-IIIa breast cancer Postmenopausal or
amenorrheic due to cancer treatment
ER+ and/or PgR+ T-score ≥ -2 SD
N = 1060
Treatment duration: 5 yrs
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: 5-yr Final Analysis
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*Censored patients at initiation of D-ZA (n = 144).
Time on Study (mos)
532533
518511
500491
488475
475463
376368
IM-ZAD-ZA
Patients at Risk, nTime on Study (mos)
532533
518459
500402
488376
475350
376267
IM-ZAD-ZA
Patients at Risk, n
ITT Population
100
90
80
70
60
50
40
30
20
10
0
DF
S (
%)
0 6 12 18 24 30 36 42 48 54 60 66
HR: 0.66; log-rank P value = .0375
IM-ZA 4 mg (42 events)D-ZA 4 mg (62 events)
Censored Analysis*
100
90
80
70
60
50
40
30
20
10
0D
FS
(%
)0 6 12 18 24 30 36 42 48 54 60 66
HR: 0.62; log-rank P value = .024
IM-ZA 4 mg (42 events)D-ZA 4 mg (53 events)
De Boer R, et al. SABCS 2011. Abstract S1-3.
27% of patients (n = 144) in the delayed arm initiated ZA on-study DFS HR: 0.46; P = .033
ZO-FAST: Final 5-yr DFS
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HR
ZO-FAST[1]
104 events
ABCSG-12[3]
230 events
0.2 0.4 0.6 0.8 1 1.2 1.4
N = 1803
1. De Boer R, et al. SABCS 2011. Abstract S1-3. 2. Coleman RE, et al. N Engl J Med. 2011;365:1396-1405. 3. Gnant M, et al. SABCS 2011. Abstract S1-2.
N = 1065
n = 1041AZURE - > 5 yrs postmenopausal[2]
263 events
P Value
.02
.0375
.011
0.75
0.66
0.71
ZA Studies: DFS Comparison
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NSABP B-34: Phase III Study of Adjuvant Clodronate in Breast Cancer
• Primary endpoint: DFS• Secondary endpoints: incidence of metastases, OS,
SREs, adverse events, and prognostic serum markers
Clodronate 1600 mg qd
Placebo
3323 patients withstage I-II breast cancer
receiving adjuvant standard therapy
Treatment duration: 3 yrs
R
Median follow-up: 8.4 yrsTwo thirds aged > 50 yrs; 25% N positive
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NSABP B-34: DFS
Paterson A, et al. SABCS 2011. Abstract S2-3.
Dis
ease
Fre
e (%
)
100
80
60
40
20
00 2 4 6 8
Yrs After Randomization
Treatment
Placebo
Clodronate
N
1656
1655
Events, n
312
286
HR: 0.91; P = .27
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NSABP B-34: Analysis of Specified Endpoints and Safety
• Adverse events comparable in clodronate and placebo arms– 1 case of ONJ observed in clodronate arm vs no cases in placebo
arm
Endpoint Events, n HR (95% CI) P Value
Clodronate(n = 1662)
Placebo (n = 1661)
DFS 286 312 0.913 (0.778-1.072) .266
OS 140 167 0.842 (0.672-1.054) .131
RFI 148 177 0.834 (0.671-1.038) .101
BMFI 61 80 0.765 (0.548-1.068) .114
NBMFI 78 105 0.743 (0.554-0.996) .046
Paterson A, et al. SABCS 2011. Abstract S2-3.
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NSABP B-34 Subset Analysis: DMFI, RFI, BMFI, and NBMFI in Patients ≥ 50
Yrs
Endpoint for Patients 50 Yrs of Age or Older
HR P Value
DMFI 0.62 .003
RFI 0.76 .05
BMFI 0.61 .024
NBMFI 0.63 .015
Paterson A, et al. SABCS 2011. Abstract S2-3.
DMFI: distant metastasis-free interval
RFI: relapse-free interval
BMFI: bone-metastasis-free interval
NBMFI: non-bone metastasis-free interval
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GAIN Trial: Study Design
Möbus V, et al. SABCS 2011. Abstract S2-4.
Arm A1: Arm B1:
Epirubicin150 mg/m2
q2w
Ibandronate50 mg PO QD 2 yrs
Paclitaxel225 mg/m2
q2w
Cyclophosphamide2000 mg/m2
q2w
Arm B2:Observation
Arm A2:Paclitaxel67.5 mg/m2 qwCapecitabine2000 mg/m2 Days 1-14 q3w
Epirubicin112.5 mg/m2
Cyclophosphamide600 mg/m2 q2w
PegfilgrastimCiprofloxacin
Darbepoetin alfa or Epoetin beta
CiprofloxacinPegfilgrastim
Darbepoetin alfa or Epoetin beta
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GAIN: DFS and OS (ITT)
1.0
0.8
0.6
0.4
0.2
0
Su
rviv
al P
rob
abil
ity
(%)
DFS (Mos)0 12 24 36 48 60
12
1996998
1814871
1590727
1057483
555264
210105
3-Yr DFSIbandronate: 87.6%Observation: 87.2%
Cox RegressionHR: 0.945 (95% CI: 0.768-1.16; P = .59)
Ibandronate Observation
Product-Limit Survival EstimatesWith Number of Patients at Risk
+ Censored1.0
0.8
0.6
0.4
0.2
0.0
OS (Mos)0 12 24 36 48 60
12
1996998
1836886
1653756
1121506
586277
219112
3-Yr OSIbandronate: 94.7%Observation: 94.1%
Cox RegressionHR: 1.04 (95% CI: 0.763-1.42; P = .80)
Product-Limit Survival EstimatesWith Number of Patients at Risk
+ Censored
Möbus V, et al. SABCS 2011. Abstract S2-4.
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GAIN: Subgroup AnalysesDFS for Ibandronate in Subgroups
HR0.5 1.0 1.5
Better With Ibandronate Worse With Ibandronate
pN1
pN2
pN3
ER and/or PgR positive
ER and PgR negative
Pre- and perimenopausal
Postmenopausal
< 60 yrs
≥ 60 yrs
HR: 1.04 (95% CI: 0.652-1.65; P = .877)
HR: 0.875 (95% CI: 0.599-1.28; P = .490)
HR: 0.951 (95% CI: 0.710-1.27; P = .734)
HR: 0.952 (95% CI: 0.736-1.23; P = .706)
HR: 0.856 (95% CI: 0.604-1.21; P = .383)
HR: 1.02 (95% CI: 0.756-1.37; P = .912)
HR: 0.897 (95% CI: 0.671-1.20; P = .462)
HR: 1.02 (95% CI: 0.807-1.30; P = .842)
HR: 0.746 (95% CI: 0.490-1.14; P = .172)
Möbus V, et al. SABCS 2011. Abstract S2-4.
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Variable Efficacy in an Unselected Population
*Analysis relates to bone metastasis-free survival.
1. Coleman RE, et al. N Engl J Med. 2011;365:1396-1405. 2. Gnant M, et al. SABCS 2011. Abstract S1-2.3. De Boer R, et al. SABCS 2011. Abstract S1-3. 4. Paterson A, et al. SABCS 2011. Abstract S2-3. 5. Powles T, et al. Breast Cancer Res. 2006;8:R13. 6. Mobus V, et al. SABCS 2011. Abstract S2-4.
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Consistent Efficacy in “Postmenopausal” Women
*Includes patients > 40 yrs on goserelin; no significant effect for patients < 40 yrs.†Analysis relates to OS. ‡≥ 60 yrs at study entry.
1. Coleman RE, et al. N Engl J Med. 2011;365:1396-1405. 2. Gnant M, et al. SABCS 2011. Abstract S1-2. 3. De Boer R, et al. SABCS 2011. Abstract S1-3. 4. Paterson A, et al. SABCS 2011. Abstract S2-3. 5. Powles T, et al. Breast Cancer Res. 2006;8:R13. 6. Mobus V, et al. SABCS 2011. Abstract S2-4.
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Conclusions
• Targeting the host environment may complement activity of direct anticancer treatments
• Adjuvant benefit from bone-targeted treatment appears to be dependent on a low reproductive hormone environment– Biologic mechanisms need further evaluation
• Inhibiting the vicious cycle may not always be beneficial• Adjuvant ZA should be considered in women with a low
estrogen environment– Prevent bone loss and fragility fracture– Potentially improve disease outcomes
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Shepherd LE, et al. ASCO 2012. Abstract 501. Used with permission.
Exemestane vs Anastrozole in Early Breast Cancer (MA.27): EFS Analysis
• EFS significantly improved with vs without osteoporosis therapy (HR: 0.70; P < .00001)
Patient-Reported Outcome, n (%)
Osteoporosis
Yes(n =
1294)
No(n =
6282)
Osteoporosis therapy (n = 2711)
1101 (85)
1610 (25.6)
No osteoporosis therapy (n = 4865)
193 (15)
4672 (74.4)
100
80
0Pat
ien
ts W
ith
ou
t E
ven
t (%
)
0 1 2 3 4 5 0
Yrs
P = .0003
Osteoporosis/no osteoporosis therapyOsteoporosis/osteoporosis therapyNo osteoporosis/no osteoporosis therapyNo osteoporosis/osteoporosis therapy
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FDA-Approved Antiosteoclast Agents for Reduction of SREs in MBC
• Both ASCO and NCCN recommend all 3 agents• No agent recommended over another
Agent Drug ClassRecommended Dose and
Schedule
Zoledronic acid
Bisphosphonate 4 mg IV q3-4w
Pamidronate Bisphosphonate 90 mg IV q3-4w
Denosumab RANKL-targeted MAb 120 mg SQ q4w
1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: breast cancer. v.1.2012.
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Denosumab vs Zoledronic Acid: Time to First On-Study SRE
Zoledronic acid 1020 829 676 584 498 427 296 191 94 29
Denosumab 1026 839 697 602 514 437 306 189 99 26
Patients at Risk, n
KM Estimate ofMedian Mos
DenosumabZoledronic acid
Not reached26.4
HR: 0.82 (95% CI: 0.71-0.95; P < .001 noninferiority; P = .01 superiority*)
Mos
0
1.00
Pro
po
rtio
n o
f S
ub
ject
s W
ith
ou
t S
RE
0 3 6 9 12 15 18 21 24 27 30
0.25
0.50
0.75
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
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40
20
0 Mo 12 Mo 18 At Time of Analysis
Denosumab (n = 1026)Zoledronic acid (n = 1020)
Per
cen
t o
f S
ub
ject
s W
ith
SR
Es
(95%
CI)
4.5%relative reduction
11.4%relative reduction
15.4%relative reduction
10
30
28.8%32.5% 32.9%38.9%25.4%26.6%
Stopeck A, et al. SABCS 2010. Abstract P6-14-01.
Denosumab vs Zoledronic Acid: Proportion Experiencing ≥ 1 SRE
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GRACIAS