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) BMD DXA (<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+) MA-17R 1918 (53%) B-42 3966 (42%) IDEAL 1824 (74%) DATA 1912 (67%) SOLE 4884 (99%) ABCSG16 3484 (31%) Duratio n ET/AI 10-15 5-10 5-10 2-10 7.5-10 2.5-10 5-9 3-6 5-10 5-10cont 7-10 2-10 DFS Benefit OS Benefit Y* N Y N N Y N N Y N N N N N? N N N New BC Benefit
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 B-42 5.4 4.8 IDEAL 14.7 13.2 DATA 60 54 SOLE 68 66 ABCSG1 6 13.1 10.5 54 52 11 10 12 10 15 14 14 9 5 2.8 10 8 10 9 6.3 4.7
ABCSG-18: study design Enrolled N = 3425* 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 Gnant M, et al. Lancet 2015;386:433 43 (and supplementary appendix). R A N D O M I S A T I O N Denosumab 60 mg SC Q6M n = 1711 Daily supplementation with calcium (500 mg) and vitamin D ( 400 IU) were recommended throughout study treatment Placebo SC Q6M n = 1709 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 *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.
ABCSG-18: outcomes Primary endpoint Time to first clinical fracture* Secondary endpoints 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) 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 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.
Adjusted mean change in BMD (%) ABCSG-18: denosumab significantly increased BMD in the lumbar spine, total hip and femoral neck vs placebo Lumbar spine Total hip Femoral neck Placebo Denosumab (n = 986) (n = 725) (n = 475) (n = 992) (n = 717) (n = 468) (n = 995) (n = 723) (n = 469) Months since randomisation P < 0.0001 at all bone sites and time points 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 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.
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Risk of fracture (%) Risk of fracture (%) ABCSG-18: denosumab significantly reduced the incidence of clinical fractures vs placebo regardless of baseline BMD Normal BMD (baseline T-score 1.0) Low BMD (baseline T-score < 1.0) 30 25 20 15 HR = 0.44 (95% CI: 0.31 0.64) P < 0.0001 Overall cumulative incidence of first clinical fractures Denosumab: n = 43/938 Placebo: n = 92/934 Placebo Denosumab 30 25 20 15 HR = 0.57 (95% CI: 0.40 0.82) P = 0.002 Overall cumulative incidence of first clinical fractures Denosumab: n = 49/773 Placebo: n = 84/775 10 10 5 5 0 Number at risk Placebo Denosumab 0 6 12 18 24 30 36 42 48 54 60 66 72 Months since randomisation 934 906 806 702 588 498 416 337 268 197 141 97 938 915 828 717 624 532 453 381 301 234 168 126 62 66 0 Number at risk Placebo Denosumab 0 6 12 18 24 30 36 42 48 54 60 66 72 Months since randomisation 775 754 664 563 481 423 369 300 245 187 134 773 750 660 580 494 433 370 307 248 198 137 88 95 50 50 Gnant M, et al. Lancet 2015;386:433 43 (and supplementary appendix). 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.