Bone Protection and Improved Survival Professor Rob Coleman Weston Park Hospital Sheffield Cancer Research Centre University of Sheffield UK Trans Atlantique en Oncologie Paris November 20 th – 21 st November 2014
Uses of Bone Targeted Treatments in Cancer Patients Prevention of Prevention of Prevention of Prevention of Metastasis Metastasis Treatment Treatment Skeletal Skeletal Prevention Prevention Induced Bone Loss Induced Bone Loss Morbidity Morbidity
Lifetime Changes in Bone Mass Gain Consolidation Loss Men BMD Women Cancer Treatments Cancer Age
Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations 200 Bioavailable E2, pmol/l 160 120 80 40 0 Premenopausal Postmenopausal Normal Androgen Aromatase women women men Deprivation Inhibitor Therapy Therapy Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:3555-61
Normal and Cancer Treatment Related Bone Loss Rates Bone loss at I year 10 Naturally occurring CTIBL 7.7 bone loss 8 7.0 6 4.6 4 2.6 2.0 2 1.0 0.5 0 Normal Menopausal ADT 3 Premature men 1 Women menopause <55 1 secondary to chemotherapy 5 AI therapy in AI therapy Postmenopausal postmenopausal plus GnRH agonist in Women >55 1 women 2 premenopausal women 4 Kanis JA. Osteoporosis .1997:22-55. 1. Eastell R et al. J Bone Mineral Res. 2002. 2. Maillefert JF et al. J Urol . 1999;161:1219-1222. 3. Gnant M. San Antonio Breast Cancer Symposium, 2002. 4. Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311. 5.
Bone Loss With and Without Bone Protection Using Zoledronic Acid Ovarian Suppression Gnant et al. Lancet Oncology 2010
ESMO-Recommended Treatment Algorithm For Managing Bone Loss During Cancer Treatment Patient with cancer receiving chronic endocrine treatment known to T-score > -2.0 accelerate bone loss and no additional risk T-score < -2.0 factors Any 2 of the following risk factors: • Age >65 years Exercise • T-score < -1.5 Exercise Calcium and vitamin D • Smoking (current or history) Calcium and vitamin D Bisphosphonate • BMI < 20 therapy (zoledronic acid, • Family history of hip fracture alendronate, risedronate, • Personal history of fragility fracture ibandronate). >50 years Denosumab may be a • Oral glucocorticoid use for > 6 months potential treatment option Monitor risk and BMD at in some patients. 1–2 year intervals Monitor BMD every 2 years Check compliance with oral therapy Coleman RE, Body JJ, Aapro M, et al. Ann Oncol 2014 ; S3:iii124-iii137.
Uses of Bone Targeted Treatments in Cancer Patients Prevention of Prevention of Prevention of Prevention of Metastasis Metastasis Treatment Treatment Skeletal Skeletal Prevention Prevention Induced Bone Loss Induced Bone Loss Morbidity Morbidity
The Tumour Microenvironment At each level the tumour microenvironment consists of Ever increasing complexity – multiple, interactive components All of these interacting simultaneously in time and space Different cell types Macrophages, Immune cells Fibroblasts, Stromal cells Endothelial cells, Pericytes Bone marrow precursors Adipocytes, Osteoblasts, Tumour cells Osteoclasts Soluble factors Cytokines/Chemokines Hormones Local Growth factors microenvironment Angiogenic factors (The tumour) Enzymes Inhibitors Regional Extracellular matrix microenvironment (The breast) Proteins/peptides Proteoglycans Bound growth factors Distal Enzymes/Inhibitors microenvironment Physical properties (The skeleton) O 2 , pH, mechanical stiffness
Haematopoietic Stem Cell Niche Provides a Haven for Disseminated Tumour Cells CAR = CXCL-12 abundant reticular cells Kunisaki and Frenette, Nature Med. 2012;18,864-865.
Disseminated Tumour Cells Displace Haematopoietic Stem Cells From the Niche Forest et al. From Metastatic Cancer Clinical and Biological Perspectives Chapter 12; 2013
PTH Rapidly Increases Osteoblast Numbers Sacrifice Treat with PTH Inject tumour cells rhPTH(1-34) PTH 80ug/kg, 5 1 daily, days 1-5 Monitor tumour growth by in vivo imaging s.c. vehicle, 5 1 Control daily, days 1-5 Ob number/mm bone surface 30 Control Day 5: PTH PTH treated 20 animals have increased 10 number of osteoblasts 0 1 5 7 0 5 1 1 compared to y y y a a a y y D D D a a D D control Days post treatment start
Effects of Osteoblast Stimulation on Tumour Growth Increased tumour burden in animals treated Decreased number of circulating tumour with PTH – cells in PTH treated animals – More sites for tumour cells to settle? Increased numbers find a niche in bone? Number of skeletal tumours Circulating tumour cells/ml of blood Total number of skeletal tumours 10 25 PBS PTH 8 20 6 15 4 10 2 5 0 0 3 0 3 0 7 3 1 7 S H 1 1 2 2 3 4 4 B T P P Days post tumour cell injection Expansion of the osteoblast niche with PTH increases tumour burden H Brown, preliminary data
Breast Cancer Metastasis B) Tumour cell proliferation and bone A) Tumour cell colonisation of bone metastasis progression Tumour cells Environmental signals Re-circulation to Escape from Tumour cell home to the maintain tumour cell other metastatic quiescence proliferation HSC niche quiescence sites HSC Stimulation of bone resorption HSC niche Tumour cell Osteoblast Development of Hematopoietic Osteoclast stem cell (HSC) bone lesions Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.
Diapositive 14 54 CRC; 03/01/2014
Breast Cancer Metastasis Years Tumour cell proliferation and metastasis Tumour cell colonisation of bone progression Tumour cells Environmental signals Onward Escape from Tumour cell home to the maintain tumour cell Dissemination quiescence proliferation HSC niche quiescence HSC Stimulation of HSC niche bone resorption Tumour cell Osteoblast Hematopoietic Development of Osteoclast stem cell (HSC) bone lesions Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.
Bone Marrow Disseminated Tumour Cells (DTCs) Reduced With Adjuvant Bisphosphonates Rack et al 1 (N = 172) Aft et al 2 (N = 120) Solomayer et al 3 (N = 96) ZOL q 4 weekk (n = 31) vs ZOL q 3 weekly vs ZOL q 4 weeks (n = 44) vs no ZOL for 6 months (n = 141 no ZOL for 1 yr (w/Chx) no ZOL for 2 year (+ Adj Rx; n = 52) 30 P = .099 P = .009 70 70 P = .054 Patients With Persisting DTCs, % 25 Patients With Persisting DTCs, % Patients With Persisting DTCs, % 60 60 20 50 50 40 15 40 30 30 10 20 20 5 10 10 0 0 0 12 mo 6 mo 3 mo Abbreviations: Chx, chemotherapy; DTC, disseminated tumour cell; ZOL, zoledronic acid. 1. Rack B, et al. Anticancer Res. 2010;30(5):1807-1813; 2. Aft R, et al. Lancet Oncol . 2010;11(5):421-428.; 3. Solomayer EF, et al . Ann Oncol 2012; 23(9):2271-7.
Early Metastasis Prevention Studies: Clodronate Diel IJ, et al. Ann Oncol . 2008;19(12):2007-2011; Powles T, et al. Breast Cancer Res . 2006;8(2):R13; Saarto T, et al. Acta Oncol . 2004;43(7):650-656.
ABCSG-12: Efficacy Following Induced Menopause 84 month update DFS 100 80 Multiple Cox 60 DFS (%) Regression P value Events, HR (95% CI) n 40 132/903 No 0.71 .011 ZOL 20 (0.55-0.92) ZOL 98/900 0 0 12 24 36 48 60 72 84 96 108 Mos Since Randomization Pts at Risk, n 858 833 807 758 653 521 405 191 No ZOL 903 ZOL 900 862 841 822 788 674 544 419 208 Gnant M. et al. Ann Oncol, under revision 2014
AZURE: Study Design Accrual September 2003 - February 2006 Standard therapy Standard therapy 3,360 3,360 Breast Cancer Breast Cancer R Patients Patients Stage II/III Stage II/III Standard therapy + Standard therapy + Zoledronic acid 4 mg Zoledronic acid 4 mg Countries Centres Patients 6 doses 8 doses 5 doses 6 doses 8 doses 5 doses UK 123 2710 Q3-4 weeks Q 3 months Q 6 months Q3-4 weeks Q 3 months Q 6 months Eire 10 247 6 30 60 Months Australia 28 226 Spain 8 107 Zoledronic acid treatment duration 5 years Portugal 1 32 Thailand 2 25 Taiwan 2 13 Coleman et al. N Engl J Med 2011; 365:1396-1405
AZURE: No Effects on Overall Population DFS IDFS Adjusted HR 0.93 Adjusted HR 0.94 95% CI: 0.82-1.05, P=0.222 95% CI: 0.82-1.06, P=0.298 Control Control Zoledronic acid Zoledronic acid 0 No. at risk No. at Control risk ZOL Control ZOL Coleman et al Lancet Oncology 2014; 15(9):997-1006
AZURE: Delay in Bone Metastasis Bone metastasis as first recurrence Bone metastasis at any time Adjusted HR 0.78 Adjusted HR 0.81 95% CI: 0.63-0.96, P=0.020 95% CI: 0.68-0.97, P=0.022 Control Control Zoledronic acid Zoledronic acid Coleman et al Lancet Oncology 2014; 15(9):997-1006
AZURE: Benefits Identified in Postmenopausal Women Pre, peri and unknown >5 years post-menopausal menopausal status Adjusted HR 1.03 Adjusted HR 0.77 95% CI: 0.89-1.20 95% CI: 0.63-0.96 Control Control N = 1041 N = 2318 Zoledronic acid Zoledronic acid 347 events 702 events No. at No. at risk risk Control Control ZOL ZOL Menopausal Interaction: χ χ χ χ 2 1 =4.71; P=0.030 Coleman et al Lancet Oncology 2014; 15(9):997-1006
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