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Effetto protettivo della terapia anti-riassorbitiva - Prof. F. Bertoldo

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Effetto protettivo della terapia anti-riassorbitiva sulla densità minerale ossea, sulle fratture e sulla sopravvivenza in corso di
blocco ormonale adiuvante nel carcinoma mammario non
metastatico: evidenze della letteratura - Prof. F. Bertoldo

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Effetto protettivo della terapia anti-riassorbitiva - Prof. F. Bertoldo

  1. 1. Francesco Bertoldo UOC Medicina Interna US Malattie del Metabolismo Osseo e Osteoncologia Dipartimento di Medicina Scuola di Medicina Università di Verona Effetto protettivo della terapia antiriassorbitiva sulla densità minerale ossea, sulle fratture e sulla sopravvivenza in corso di blocco ormonale adiuvante nel carcinoma mammario non metastatico: evidenze della letteratura
  2. 2. • Ai sensi dell’art. 3.3 sul conflitto di interessi, pag 17 del Regolamento Applicativo Stato-Regioni del 5/11/2009, dichiaro che negli ultimi 2 anni ho avuto rapporti diretti di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario: • Amgen • Abiogen • Astellas • Bayer • Chiesi • Lilly • Sandoz • Roche Conflitti di interesse
  3. 3. New metastasis BONE HEALTH CONCEPT IN CANCER PATIENTS (Age- VIT D levels- Hormonal Adj Therapy-Cancer) Fragility CTIBL Homing of CTC FRACTURE VISCERAL METASTASIS CTX NTX P1NP SDF-1 TGF b PDGF IGF-1 OP CTX NTX P1NP SDF-1 TGF b PDGF OP CTX NTX P1NP SDF-1 TGF b PDGF OP SRE NON METASTATIC PREMETASTATIC NICHE BONE MET. BONE Bertoldo F et al. edts:Bone Metastasis from Prostate Cancer ,Elsevier 2016 Bone Metastasis HIGH BONE TURNOVERRANK/RANKL PATHWAY
  4. 4. High Bone Turnover The “Bone Health” concept in Cancer Patients Bone Metastasis SRE Fracture Radiotherapy Spinal Compression Orth. Surg. Pain Fragility Fracture Bone Loss § Hormonal adjuvant therapy § Chemotherapy §High IL, TNFa serum levels §Age § Low vitamin D /high PTH levels Homing Cancer cell Pre-metastatic niche Bertoldo F 2006
  5. 5. 0 2 4 6 8 Normal men Late menop. women Early menop women Aromatase Inhibitor Bone Marrow transpl Androgen deprivation AI + GNrh agonist Ovarian failure due chemiother 1% 2 % 2.6% 3.3% 4.6% 7.0% 7.6% Lumbar spine BMD (% /year Bone Loss) 0.5% CANCER TREATMENT INDUCED BONE LOSS Rate of BMD Loss Rate of bone loss= bone turnover Hirbe A et al Clin Cancer Res 2006
  6. 6. 1.100 - 1.000 - 0.900 – 0.800 – 0.700 – 0.600 – 0.500 - 0.400 - 0.300 - 0.200 0.100 0.000- 30-50 50-60 60-70 >70 CTX(ng/ml) PREM. RANGE Naive Alendronato 70 mg Ac Zoledronico 5 mg Denosumab anni Bertoldo F et al LHRH +TAM Aromatase Inhibitors
  7. 7. 10 yrs Analysis of the ATAC Trial Lancet Oncol 2008 Yearly Fracture Rate 2.93% 1.90%
  8. 8. (primary end point)
  9. 9. 726660544842363024181260 0 5 10 15 20 25 30 Riskoffracture(%) 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 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 Osteopenia (baseline T-score < –1.0) 726660544842363024181260 0 5 10 15 20 25 30 Riskoffracture(%) 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 Adapted from Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).
  10. 10. NUOVA NOTA 79 G.U. 20/5/15 n 115
  11. 11. Zoledronic acid for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60- month results Coleman R et al Annals of Oncology 24: 398–405, 2013 UP –FRONT: at the start of aromatse inhibitors DELAYED: >3% BMD reduction, Fracture, BMD -2.5 T score
  12. 12. Shapiro L et al Zol 4 mg/ 3 mo. Arm A: UpFront Arm B : after 1 y of CIOF
  13. 13. NUOVA NOTA 79 G.U. 20/5/15 n 115
  14. 14. Linee Guida SIOMMMS Valore basale di 25(OH)D o presunto stato carenziale Dose iniziale di vitamina D Dose giornaliera di mantenimento <10 ng/ml o 25 nmol/l 600.000 2.000 10-20 ng/ml o 25- 50 nmol/l 400.000 1.000 20-30 ng/ml o 50-75 nmol/l 100.000 800 SUPPLEMENTAZIONE CON COLECALCIFEROLO Grado raccomandazione SIGN: B, positiva forte INIZIARE PRIMA DELLA TERAPIA CON ANTIRIASSORBITIVI
  15. 15. Effects of Antiresorptive therapy on BMD in BC Women treated with AI 0 1 2 3 4 5 Risedronate 35mg/w %frombaseline 4.4% 2.1% Ibandronate 150 mg/mo Zoledronate 4 mg 6 mo Denosumab 60 mg/6 mo 0.6 Hip 3% Spine Ellis JCO 2008, Gnant , Lancet 2015 6 3.5% 6.5% 1.% 4% Eidtman Ann Oncol 2010 Lester Clin Can Res 2008 Van Poznak JCO 2010 Greenspan SL 2015 2.3% 7.6% 4.6% Zoledronate 4 mg 6 mo (Prem BC)
  16. 16. J Clin Oncol 2008
  17. 17. Lester JE Clin Canc Res 2008
  18. 18. Zoledronic acid for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60- month results Coleman R et al Annals of Oncology 24: 398–405, 2013 UP –FRONT: at the start of aromatse inhibitors DELAYED: >3% BMD reduction, Fracture, BMD -2.5 T score
  19. 19. Ellis GK J Clin Oncol 2008 SPINE Femoral Neck Radius
  20. 20. Gnant M et al
  21. 21. (primary end point)
  22. 22. ABCSG-18: denosumab significantly reduced the incidence of new and new or worsening vertebral fractures at Month 36 vs placebo 0 1 2 3 4 5 6 7 8 9 10 Placebo Denosumab Proportionofpatients(%) Odds ratio = 0.53 (95% CI: 0.33–0.85) P = 0.009 Incidence of new vertebral fractures in vertebral analysis set (n = 1644) SC Q6M 60 mg SC Q6M 0 1 2 3 4 5 6 7 8 9 10 Placebo Denosumab Proportionofpatients(%) Odds ratio = 0.54 (95% CI: 0.34–0.84) P = 0.007 Incidence of new or worsening vertebral fractures in vertebral analysis set (n = 1644) SC Q6M 60 mg SC Q6M 6.1% (n = 49/809) 3.2% (n = 27/835) 6.8% (n = 55/809) 3.7% (n = 31/835) Elaborated from Gnant M, et al. Lancet 2015;386:433–43.
  23. 23. 726660544842363024181260 0 5 10 15 20 25 30 Riskoffracture(%) 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 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 Osteopenia (baseline T-score < –1.0) 726660544842363024181260 0 5 10 15 20 25 30 Riskoffracture(%) 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 Adapted from Gnant M, et al. Lancet 2015;386:433–43 (and supplementary appendix).
  24. 24. Gnant M et a lLancet 2015
  25. 25. Gnant M Lancet Oncol 2008 GnRH+
  26. 26. -2 -1 0 1 2 3 4 5 Denosumab Acido Zoledronico -1 -0,5 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 Denosumab Acido Zoledronico Bertoldo F et al Oncotarget 2016 (submitted) SWITCH OF BONE MODYFING AGENTs IN BC WITH AI Change%BMDSpineChange%BMDSpine PTS BP NAIVE PTS BP PAST USER p 0.57 vs baseline p 0.021 vs baseline 0 12 mo p 0.018 vs baseline p 0.034 vs baseline
  27. 27. 10 yrs Analysis of the ATAC Trial Lancet Oncol 2008 Yearly Fracture Rate 2.93% 1.90%
  28. 28. Vertebral Fractures Following Discontinuation of Denosumab: a Post-hoc Analysis of the Randomized Placebo-controlled FREEDOM Trial and its Extension. : 10.1002/jbmr.3337 . Cummings SR et al. J Bone Min Res 2017 Nov 4 doi The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants The odds (95% CI) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1-7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures. The vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1,
  29. 29. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Patients considered at high fracture risk should either continue denosumab therapy for up to 10years or be switched to an alternative treatment. For patients at low risk, a decision to discontinue denosumab could be made after 5years, but bisphosphonate therapy should be considered to reduce or prevent the rebound increase in bone turnover Optimal bisphosphonate regimen post-denosumab is currently unknown. continuation of denosumab can also be considered until results from ongoing trials become available.
  30. 30. B. Patient with NO FRACTURE RISK BEFORE Hornonal Adjuvant therapy (Primary Prevention). At suspension of AI, the DNB could be suspended without the need for other treatment. GUARANTEE FOLLOW UP ! Patient who has already osteoporosis (low BMD and / or fractures) before starting DNB Or Patients who develops a new fracture or at high risk factor during DNB At Suspension of AI ,treatment should continue (with DNB or others Antiresorptive Ag) A..GENERAL RULES: Always re-assess fracture risk at the end of the hormonal Adj therapy Ensure that it is suspended before suspending BPs or DNB. DENOSUMAB IN CTIBL: Personal opinion NO EBM
  31. 31. Grado di raccomandazione SIGN Raccomandazione clinica Forza della raccomandazione clinica B Per i pazienti in terapia ormonale adiuvante e con menopausa secondaria a chemioterapia va iniziata subito la terapia con inibitori del riassorbimento osseo Positiva Forte B Perr i pazienti in terapia ormonale adiuvante pazienti la terapia con farmaci antiriassorbitivi andrebbe protratta per tutta la durata delle terapia ormonale adiuvante Positiva Forte B Gli aminobisfosofonati orali ( alendronato, risedronato e ibandronato) e endovenosi ( ac zoledronico 5 mg / anno) prevengono la perdita di massa ossea.Il dato antifratturatvo è indiretto, dedotto da quanto avviene nell’osteoporosi postenopausale Positiva Debole A Il denosumab previene le fratture vertebrali cliniche e morfometriche nel maschio con cr della prostata in blocco androgenico e le fratture vertebrali e le non vertebrali nella donna con tumore della mammella in postmenopausa in terapia con inibitori della aromatasi Positiva forte B La supplementazione con calcio e vitamina D da sola non è in grado di prevenire o curare la CTIBL ma la loro associazione con farmaci antiriassorbitivi è fondamentale per l’effetto antifratturativo e per evitare l’ipocalcemia Positva forte LINEE GUIDA AIOM 2016- Guidelines for the diagnosis, prevention and management of osteoporosis. Rossini M, Adami S, Bertoldo F, Diacinti D, Gatti D, Giannini S, Giusti A, Malavolta N, Minisola S, Osella G, Pedrazzoni M, Sinigaglia L, Viapiana O, Isaia GC. Reumatismo. 2016 Jun 23;68(1):1-39
  32. 32. Risultati Survey salute dell’osso Nella Sua pratica clinica fa riferimento a qualche Linea Guida? 23 9,0% 9,0% 22,0% 13,0% 6,0% 78,0% 0% 20% 40% 60% 80% 100% a. AIOM b. SIOMMMS d. ESMO f. altro c. ASCO e. non faccio riferimento alle LG LG interne dell'Istituto per ora nessuna mi ha convinto appieno dovrei ma non sempre lo faccio SIO
  33. 33. Risultati Survey salute dell’osso Delle pazienti trattate con AIs o GnRH+TAM quante ne tratta con una terapia specifica per la salute dell'osso (in percentuale)? 10 64,2% Valore medio AI GnRH+TAM
  34. 34. Risultati Survey salute dell’osso Quando tratta con farmaci per la salute dell'osso il Suo obiettivo è: 21 % sul totale dei rispondenti 3% 2% d. migliorare la DFS a. aumentare la BMD 2% e. altro* 20% b. fermare il calo di BMD * Tutti i precedenti 74% c. ridurre il rischio di frattura
  35. 35. Risultati Survey salute dell’osso Fatto 100 le pazienti in terapia specifica per la salute dell'osso, sulla base di quale parametro ha iniziato la terapia per l'osso? 20 2,0 38,8 41,8 29,3 58,3 0 10 20 30 40 50 60 70 Valore medio, sul totale dei 29 rispondenti di cui uno risponde “tipo di trattamento ormonale intrapreso” a. BMD T.score <-2,5 b. BMD T.score <-1 c. precedenti fratture da fragilità d. rischio fratturativo DEFRA FRAX elevato e. altro 89 %
  36. 36. Risultati Survey salute dell’osso Fatto 100 le pazienti (sottoposte a terapia con AI o GNRH +TAM) in trattamento con una terapia specifica per la salute dell'osso, che percentuale di queste lei tratta con: 17 2,3 16,2 16,3 18,5 62,4 0 10 20 30 40 50 60 70 Valore medio, sul totale dei 31 rispondenti a. solo calcio e vit D b. bisfosfonati orali c. bisfosfonati EV d. denosumab e. altro
  37. 37. Risultati Survey salute dell’osso La presenza di una BMD ridotta o una frattura da fragilità presente alla diagnosi condiziona la mia scelta della terapia ormonale adiuvante? 24 % sul totale dei rispondenti 48% a. no scelgo indipendentemente 47% b. si, preferisco ad esempio tamoxifene agli inibitori aromatasi 5% c. altro dipende dalla valutazione endocrinologica del rischio fratturativo e dalla possibilità di terapie antiosteoporosi talvolta, in base al rischio biologico della neoplasia si, valutando rischi/benefici sulla malattia oncologica
  38. 38. High Bone Turnover The “Bone Health” concept in Cancer Patients Bone Metastasis SRE Fracture Radiotherapy Spinal Compression Orth. Surg. Pain Fragility Fracture Bone Loss § GnRH § Chemotherapy §Aromatase inhibitors §High IL, TNFa serum levels §Age § Low vitamin D /high PTH levels Homing cell metastatiche Pre metastic niche BP DNB BP DNB BP DNB BP DNB SURVIVAL by Bertoldo
  39. 39. Schnieder A Endocrinology 2005
  40. 40. Schnieder A Endocrinology 2005
  41. 41. Bone Lining cell Activated osteoblast Osteoclast VCAM-1 E-selectin N-cadherin VEGF IL-1 IL-6 IL-11 PGE Endothelial cell Sinusoid in bone metaphysis SDF-1 RANKL PRE-OC PTH TNFa IL-6 PRE-OC Receptors RANK CXCR4 BMP-R Ia,Ib,II ICAM-1 avb3, avb2 TGFb-RI-II Bertoldo F,Textbook of Osteoncology 2009 TGFb BMPs OPN BSP
  42. 42. Bone Lining cell Activated osteoblast Osteoclast VCAM-1 E-selectin N-cadherin VEGF IL-1 IL-6 IL-11 PGE Endothelial cell Sinusoid in bone metaphysis SDF-1 RANKL PTHrP TNFa PDGF VEGF Cancer Cell TGFb BMPs OPN BSP PTH TNFa IL-6 Cancer Cell Receptors RANK CXCR4 BMP-R Ia,Ib,II ICAM-1 avb3, avb2 TGFb-RI-II Bertoldo F, .Textbook of Osteoncology 2009
  43. 43. bone THE “PRE-METASTATIC NICHE” SDF1 Opn RANKL OB Hemat Stem Cell Periferal circulation Sinusoidal endothelial cells BoneMarrowniche cancer VEGF FGF IL6 IGF-1 MMP-2 MMP-9 SDF1 Opn Integrin VEGF FGF IL6 IGF-1 MMP-2 MMP-9 Boneniche HPC vegf+ VE GF FG F IL6 IGF -1 MMP- 2 MMP- 9 Mes Stem CellDTC Cancer Stem Cell POSTN Bertoldo F Textbook of Otseoncology 2009
  44. 44. Wang N J Bone Miner Res 2015
  45. 45. Wang N J Bone Miner Res 2015 Osteoblast ( green) PC cell line (red)
  46. 46. SDF-1 CXCR4 OPN Jagged 1 PTH/PTHrp R1 PTH/PTHrp Ratajczak MZ Leukemia 2010; Kollet Ot Nature 2006; Calvi LM Ann NY Acad Sci 2006 Wnt/bcatenin N cadherin b1 integrin NOTCH PTH/PTHrp RANNKL RANK MMP9 CATHEPSIN K BoneMarrowNicheEndostealniche BONE
  47. 47. Clodronate Improves Survival in BC Patients a. Bone metastases. Adapted from Powles T, et al. Breast Cancer Res. 2006;8(2):R13. Disease-freea survival Overall survival 0 1 2 3 4 5 Time, years 0.6 0.7 0.8 0.9 1.0 At 2 years HR = 0.546 (0.312, 0.954) P = .031 At 5 years HR = 0.692 (0.484, 0.990) P = .043 Placebo Clodronate Event-freesurvival Overallsurvival 0 1 2 3 4 5 6 7 8 9 10 11 Time, years Clodronate (n = 98/530) Placebo (n = 129/539) HR = 0.768 (0.591, 0.999) P = .048 1.0 0.8 0.6 0.4 0.2 0
  48. 48. Kremer R et al JNCI 2014 TIME TO BONE METASTASIS TIME TO CANCER SPECIFIC MORTALITY 21.6664 BC pt 10 yr follow up
  49. 49. L’importanza della stabilizzazione dei marcatori di turnover osseo durante il trattamento con acido zoledronico Coleman R. Crit Rev Oncol Hematol. 2011
  50. 50. DFS OS Coleman R et al Annals of Oncology 24: 398–405, 2013 Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results
  51. 51. ZOL 4 mg/6 mesi
  52. 52. AZURE Overall Patient Population: DFS and OS No. at risk: 1,681 1,591 1,465 1,354 1,243 580 83 1,678 1,583 1,445 1,344 1,252 561 71 DFS ZOL: CONT: 1 2 3 4 5 6 7 20 40 60 80 Time, years ZOL: N = 1,681 CTRL: N = 1,678 Adjusted HR = 0.98 95% CI = 0.85, 1.13; P = .79 100 0 0 1 2 3 4 5 6 7 20 40 60 80 100 Time, yearsNo. at risk: ZOL: CTRL: 1,681 1,633 1,560 1,468 1,380 656 100 1,678 1,632 1,551 1,473 1,364 623 86 0 0 Adjusted HR = 0.85 95% CI = 0.72, 1.01; P = .07 243 vs 276 deaths OS ZOL: N = 1,681 CTRL: N = 1,678 Abbreviations: CI, confidence interval; CTRL, control; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid. Coleman RE, et al. SABCS 2010, abstract S4-5. PatientsWithoutanEvent,% PatientsSurviving,%
  53. 53. AZURE Postmenopausala Subset: Improved OS and Reduced DFS Events 1 2 3 4 5 6 7 20 40 60 80 Time, years Zoledronic acid (n= 550) Control (n = 551) Adjusted HR = 0.71 P = .017 Overall Survival Ç 29% 0 0 100 PatientsSurviving,% n = 551 n = 550 DSF Events DFSEvents,n a Postmenopausal or > 60 years of age. Abbreviations: DFS, disease-free survival; OS, overall survival; ZOL, zoledronic acid. Left image reprinted from Coleman RE, et al. SABCS 2010, abstract S4-5; right image adapted from Coleman RE, et al. SABCS 2010, abstract S4-5. 68
  54. 54. Key endpoints: Primary: DFS Secondary: Incidence of metastases, OS, SREs, adverse events, and prognostic serum markers Accrual completed 2005. Abbreviations: BC, breast cancer; DFS, disease-free survival; OS, overall survival; R, randomisation; SRE, skeletal-related event. http://www.clinicaltrials.gov Identifier: NCT00009945. Clodronate 1,600 mg daily Placebo N = 3,400 BC, stage I/II/III on standard adjuvant therapy Treatment duration: 3 yr R NSABP B-34: Adjuvant Clodronate in BC (National Surgical Adjuvant Breast and Bowel Project protocol B-34
  55. 55. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial .Paterson AH et al the lancet.oncology DOI:10.1016/S1470-2045(12)70226-7 3323 pts, 1600 mg/day for 3 years, Primary end point: DFS
  56. 56. 1.100 - 1.000 - 0.900 – 0.800 – 0.700 – 0.600 – 0.500 - 0.400 - 0.300 - 0.200 0.100 0.000- 30-50 50-60 60-70 >70 CTX(ng/ml) PREM. RANGE Naive Alendronato 70 mg Ac Zoledronico 5 mg Denosumab anni Bertoldo F et al 2017 LHRH +TAM Aromatase Inhibitors
  57. 57. www.thelancet.com Published online July 24, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60908-4
  58. 58. Benefits on bone recurrences appear to be confined to postmenopausal/ older women Premenopausal Postmenopausal
  59. 59. Bone recurrence by bisphosphonate type
  60. 60. Enhances sensitivity to chemoterapy Yoldi G et al; Cancer Res 2016 PHYSIOPAT. 3
  61. 61. ABCSG-18: DFS by Tumor Size > 2 cm and Other Subgroups With Significant HR Gnant M, et al. SABCS 2015. Abstract S2-02. Reproduced with permission. Parameter Significant HR No AI prior to randomization 0.61 T-stage T2/T3/T4 0.66 Ductal invasive histology 0.79 ER+/PgR+ status 0.75 100 90 80 70 60 0 Disease-FreeSurvival(%) Mos Since Randomization 900 6 12 18 24 30 36 42 48 54 60 66 72 78 84 92.6% 87.0% 80.3% 88.9% 80.0% 69.8%.0163Placebo Denosumab Number of Events/Patients HR (95% CI) vs Placebo P value 83/467 58/479 0.663 (0.47-0.93)
  62. 62. • Primary endpoint: BMFS • Secondary endpoints: DFS, overall survival, distant recurrence-free survival, safety, patient-reported outcomes (pain, health utilities) • Exploratory: breast density, time to SREs, biomarkers D-CARE: study design N = 4500 5 years0 Key eligibility criteria • Stage II/III breast cancer • High risk risk of recurrence Standard (neo)adjuvant therapy + Denosumab 120 mg SC 6 doses Q4W then Q3M Standard (neo)adjuvant therapy + Placebo SC 6 doses Q4W then Q3M R A N D O M I S A T I O N Standard of care annual mammogram s, bone scans and CTs or MRIs of the chest and abdomen Goss P, et al. ASCO 2013 (Abstract TPS662 and poster); NCT01077154. Denosumab (120 mg Q4W) is currently not approved for prevention of bone metastases. Denosumab is investigational in that setting BMFS, bone metastasis-free survival.
  63. 63. NUOVA NOTA 79 G.U. 20/5/15 n 115
  64. 64. High Bone Turnover The “Bone Health” concept in Cancer Patients Bone Metastasis SRE Fracture Radiotherapy Spinal Compression Orth. Surg. Pain Fragility Fracture Bone Loss § GnRH § Chemotherapy §Aromatase inhibitors §High IL, TNFa serum levels §Age § Low vitamin D /high PTH levels Homing cell metastatiche Pre metastic niche BP DNB BP DNB BP DNB BP DNB SURVIVAL by Bertoldo BP DNB

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