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
A d ju s te d m e a n c h a n g e in BM D ( % )
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 f ra c tu re ( % )
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 f ra c tu re ( % )
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).
