airoldi mario s.c. oncologia medica 2 città della salute e
TRANSCRIPT
La salute dell’osso nelle pazienti in trattamento
adiuvante
Airoldi Mario - S.C. Oncologia Medica 2
Città della Salute e della Scienza di Torino
BONE STRENGTH
• OSTEOPOROSIS SKELETAL DISORDER COMPROMISING BS LEADING TO INCREASED RISK OF FRACTURE
• BS HAS TWO COMPONENTS: MICROARCHITECTURE (QUALITY) , BONE DENSITY (QUANTITY)
• BMDDXA (<2.5 T SCORE=OSTEOPOROSIS)
FRAX ALGORITHM
understimates AI effect
-1.3% and -2.9% - AXELSEN
Outcomes Extended Duration AI beyond 5 yrs
N
(% N+)
Duratio
n
ET/AI
DFS
Benefit
OS
Benefit
New BC
Benefit
MA-17R 1918
(53%)
10-15
5-10
Y* N Y
B-42 3966
(42%)
5-10
2-10
N N Y
IDEAL 1824
(74%)
7.5-10
2.5-10
N N Y
DATA 1912
(67%)
5-9
3-6
N N N
SOLE 4884
(99%)
5-10
5-10cont
N N ?
ABCSG16 3484
(31%)
7-10
2-10
N N N
AEs Extended Duration AI beyond 5 yrs
Arthalgia
AI/Plc
Hot Flashes
AI/Plc
Vaginal
Dryness
AI/Plc
Cardio
vascular
AI/Plc
Fractures
AI/Plc
MA-17R
53
50
38
37
11
10
12
10
14
9
B-42
5.4
4.8
IDEAL 14.7
13.2
13.1
10.5
5
2.8
DATA 60
54
15
14
10
8
SOLE 68
66
54
52
10
9
ABCSG1
6
6.3
4.7
ABCSG-18: study design
Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).
*5 patients withdrew consent to use their data; †Defined as having undergone a bilateral oophorectomy, ≥ 60 years of age, or < 60 years of age
but with follicle-stimulating hormone and oestradiol levels in the postmenopausal range;
‡Oral BP treatment if taken for 3 years or longer continuously or if taken for between
3 months and 3 years unless the patient had a washout period of at least 1 year
before randomisation, or any use during the 3 months before randomisation.
IV, intravenous; ECOG, Eastern Cooperative Oncology Group; ER, oestrogen receptor; Q6M, every 6 months;
PR, progesterone receptor; SC, subcutaneous; SERM, selective oestrogen receptor modulator.
Enrolled
N = 3425*
Denosumab
60 mg SC Q6M
n = 1711
Placebo
SC Q6M
n = 1709
R
A
N
D
O
M
I
S
A
T
I
O
N
Daily supplementation with calcium (500 mg) and vitamin D (≥ 400 IU) were
recommended throughout study treatment
Key inclusion criteria
• Postmenopausal women†
• Histologically confirmed non-metastatic ER+
and/or PR+ adenocarcinoma of the breast
• Receiving or due to receive adjuvant non-steroidal
AI therapy
• ECOG performance score: 0 or 1
Key exclusion criteria
• AI therapy for > 24 months before trial inclusion
• Previous or concurrent treatment with SERMs
• Evidence of metastatic disease
• Ongoing or previous IV BPs; oral BPs‡
• Previous denosumab therapy
• Known history of: Paget’s disease, Cushing’s disease,
hyperprolactinaemia, hypercalcaemia, hypocalcaemia or other
active metabolic bone disease
• Major surgery or traumatic injury < 4 weeks before
randomisation
• Exploratory endpoints were: the percentage change in total lumbar spine, total hip and femoral
neck BMD from baseline to Months 12 and 24 (at preselected sites); the percentage change in
total lumbar spine, total hip and femoral neck BMD from baseline to Months 12, 24 and 36 (at all
participating clinical sites); new† and new or worsening vertebral fractures† at Months 12 and 24
• Safety endpoints were: incidence of treatment-emergent adverse events (TEAEs); clinically
significant changes in laboratory values; anti-denosumab antibody formation
ABCSG-18: outcomes
Gnant M, et al. Lancet 2015;386:433–43.
*Defined as clinically evident fractures with associated symptoms, except for those of the
skull, face, fingers, and toes, which are typically not associated with osteoporosis; †Morphometric fractures identified from study radiographs and
clinical vertebral fractures confirmed by radiographs.
Time to first
clinical fracture*
• Percentage change in total lumbar spine,
total hip and femoral neck BMD from baseline
to Month 36
• Incidence of new vertebral fractures† at Month 36
• Incidence of new or worsening of pre-existing
vertebral fractures† at Month 36
• Disease-free survival (DFS)
• Bone metastasis-free survival (BMFS)
• Overall survival (OS)
Primary endpoint Secondary endpoints
ABCSG-18: denosumab significantly increased BMD
in the lumbar spine, total hip and femoral neck
vs placebo
Gnant M, et al. Lancet 2015;386:433–43.
*Note: these data represent an exploratory endpoint of the study; †Note: these data represent a secondary endpoint of the study. Error bars are 95% CIs.
5.75% difference at Month 12*
8.28% difference at Month 24*
10.02% difference at Month 36†
3.86% difference at Month 12*
5.85% difference at Month 24*
7.92% difference at Month 36†
3.30% difference at Month 12*
5.19% difference at Month 24*
6.51% difference at Month 36†
(n = 992) (n = 717) (n = 468)
Lumbar spine Total hip Femoral neck
Placebo
Denosumab
Ad
jus
ted
me
an
ch
an
ge
in B
MD
(%
)
Months since randomisation
(n = 986) (n = 725) (n = 475) (n = 995) (n = 723) (n = 469)
P < 0.0001 at all bone sites and time points
Do not copy or distribute.
Placebo: n = 84/775
Denosumab: n = 49/773
72 66 60 54 48 42 36 30 24 18 12 6 0
0
5
10
15
20
25
30
Ris
k o
f fr
ac
ture
(%
)
Months since randomisation
50
50
88
95
134
137
187
198
245
248
300
307
369
370
423
433
481
494
563
580
664
660
754
750
775
773
Number at risk
Placebo
Denosumab
ABCSG-18: denosumab significantly reduced the
incidence of clinical fractures vs placebo regardless
of baseline BMD
Percentage risk of fracture based on Kaplan–Meier time-to-event analysis
within each treatment group at 6-month intervals. The HR and P value were
calculated from a Cox model including treatment groups as the independent
variable and stratified by the randomisation stratification factors.
HR = 0.44 (95% CI: 0.31–0.64)
P < 0.0001
Normal BMD
(baseline T-score ≥ –1.0)
Overall cumulative incidence of first clinical fractures
HR = 0.57 (95% CI: 0.40–0.82)
P = 0.002
Overall cumulative incidence of first clinical fractures
Low BMD
(baseline T-score < –1.0)
Placebo: n = 92/934
Denosumab: n = 43/938
72 66 60 54 48 42 36 30 24 18 12 6 0
0
5
10
15
20
25
30
Ris
k o
f fr
ac
ture
(%
)
Months since randomisation
62
66
97
126
141
168
197
234
268
301
337
381
416
453
498
532
588
624
702
717
806
828
906
915
934
938
Number at risk
Placebo
Denosumab
Placebo
Denosumab
Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).