Bone Protection and Improved Survival

Transcription

1 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

2 Uses of Bone Targeted Treatments in Cancer Patients Prevention of Treatment Induced Bone Loss Metastasis Prevention Prevention of Skeletal Morbidity

3 Lifetime Changes in Bone Mass Gain Consolidation Loss BMD Men Cancer Treatments Women Cancer Age

4 Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations 200 Bioavailable E2, pmol/l Premenopausal women Postmenopausal women Normal men Androgen Deprivation Therapy Aromatase Inhibitor Therapy Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:

5 Normal and Cancer Treatment Related Bone Loss Rates Bone loss at I year Normal men 1 Naturally occurring bone loss 1.0 Postmenopausal Women > Menopausal Women < Kanis JA. Osteoporosis.1997: Eastell R et al. J Bone Mineral Res Maillefert JF et al. J Urol. 1999;161: Gnant M. San Antonio Breast Cancer Symposium, Shapiro CL et al. J Clin Oncol. 2001;19: AI therapy in postmenopausal women ADT 3 CTIBL Premature menopause secondary to AI therapy chemotherapy 5 plus GnRH agonist in premenopausal women 4

6 Bone Loss With and Without Bone Protection Using Zoledronic Acid Ovarian Suppression Gnant et al. Lancet Oncology 2010

7 ESMO-Recommended Treatment Algorithm For Managing Bone Loss During Cancer Treatment T-score > -2.0 and no additional risk factors Patient with cancer receiving chronic endocrine treatment known to accelerate bone loss T-score < -2.0 Exercise Calcium and vitamin D Monitor risk and BMD at 1 2 year intervals Any 2 of the following risk factors: Age >65 years T-score < -1.5 Smoking (current or history) BMI < 20 Family history of hip fracture Personal history of fragility fracture >50 years Oral glucocorticoid use for > 6 months Exercise Calcium and vitamin D Bisphosphonate therapy (zoledronic acid, alendronate, risedronate, ibandronate). Denosumab may be a potential treatment option in some patients. Monitor BMD every 2 years Check compliance with oral therapy Coleman RE, Body JJ, Aapro M, et al. Ann Oncol 2014; S3:iii124-iii137.

8 Uses of Bone Targeted Treatments in Cancer Patients Prevention of Treatment Induced Bone Loss Metastasis Prevention Prevention of Skeletal Morbidity

9 The Tumour Microenvironment Ever increasing complexity All of these interacting simultaneously in time and space Tumour cells At each level the tumour microenvironment consists of multiple, interactive components Different cell types Macrophages, Immune cells Fibroblasts, Stromal cells Endothelial cells, Pericytes Bone marrow precursors Adipocytes, Osteoblasts, Osteoclasts Soluble factors Local microenvironment (The tumour) Regional microenvironment (The breast) Distal microenvironment (The skeleton) Cytokines/Chemokines Hormones Growth factors Angiogenic factors Enzymes Inhibitors Extracellular matrix Proteins/peptides Proteoglycans Bound growth factors Enzymes/Inhibitors Physical properties O 2, ph, mechanical stiffness

10 Haematopoietic Stem Cell Niche Provides a Haven for Disseminated Tumour Cells CAR = CXCL-12 abundant reticular cells Kunisaki and Frenette, Nature Med. 2012;18,

11 Disseminated Tumour Cells Displace Haematopoietic Stem Cells From the Niche Forest et al. From Metastatic Cancer Clinical and Biological Perspectives Chapter 12; 2013

12 PTH Rapidly Increases Osteoblast Numbers Treat with PTH Inject tumour cells Sacrifice rhpth(1-34) 80ug/kg, daily, days 1-5 s.c. vehicle, daily, days PTH Control 5 5 Monitor tumour growth by in vivo imaging Ob number/mm bone surface Day 1 Day 5 Day 7 Day 10 Days post treatment start Day 15 Control PTH Day 5: PTH treated animals have increased number of osteoblasts compared to control

13 Effects of Osteoblast Stimulation on Tumour Growth Increased tumourburden in animals treated with PTH More sites for tumour cells to settle? Decreased number of circulating tumour cells in PTH treated animals Increased numbers find a niche in bone? Number of skeletal tumours Total number of skeletal tumours Days post tumour cell injection PBS PTH Circulating tumour cells/ml of blood PBS PTH Expansion of the osteoblast niche with PTH increases tumour burden H Brown, preliminary data

14 Breast Cancer Metastasis A) Tumour cell colonisation of bone B) Tumour cell proliferation and bone metastasis progression Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence Tumour cell proliferation Re-circulation to other metastatic sites HSC Tumour cell HSC niche Hematopoietic stem cell (HSC) Osteoblast Osteoclast Stimulation of bone resorption Development of bone lesions Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.

15 Diapositive CRC; 03/01/2014

16 Breast Cancer Metastasis Years Tumour cell colonisation of bone Tumour cell proliferation and metastasis progression Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence Tumour cell proliferation Onward Dissemination HSC Tumour cell HSC niche Hematopoietic stem cell (HSC) Osteoblast Osteoclast Stimulation of bone resorption Development of bone lesions Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.

17 Bone Marrow Disseminated Tumour Cells (DTCs) Reduced With Adjuvant Bisphosphonates Rack et al 1 (N = 172) ZOL q 4 weekk (n = 31) vs no ZOL for 6 months (n = 141 Aft et al 2 (N = 120) ZOL q 3 weekly vs no ZOL for 1 yr (w/chx) Solomayer et al 3 (N = 96) ZOL q 4 weeks (n = 44) vs no ZOL for 2 year (+ Adj Rx; n = 52) Patients With Persisting DTCs, % P = mo Patients With Persisting DTCs, % P = mo Patients With Persisting DTCs, % P = mo Abbreviations: Chx, chemotherapy; DTC, disseminated tumour cell; ZOL, zoledronic acid. 1. Rack B, et al. Anticancer Res. 2010;30(5): ; 2. Aft R, et al. Lancet Oncol. 2010;11(5): ; 3. Solomayer EF, et al. Ann Oncol 2012; 23(9):

18 Early Metastasis Prevention Studies: Clodronate Diel IJ, et al. Ann Oncol. 2008;19(12): ; Powles T, et al. Breast Cancer Res. 2006;8(2):R13; Saarto T, et al. Acta Oncol. 2004;43(7):

19 ABCSG-12: Efficacy Following Induced Menopause 84 month update 100 DFS DFS (%) Events, n No 132/903 ZOL ZOL 98/900 Multiple Cox Regression HR (95% CI) 0.71 ( ) P value Mos Since Randomization Pts at Risk, n No ZOL ZOL Gnant M. et al. Ann Oncol, under revision 2014

20 AZURE: Study Design Accrual September February ,360 Breast Cancer Patients Stage II/III Countries Centres Patients UK Eire Australia Spain Portugal 1 32 Thailand 2 25 Taiwan 2 13 R Standard therapy Standard therapy + Zoledronic acid 4 mg 6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months Months Zoledronic acid treatment duration 5 years Coleman et al. N Engl J Med 2011; 365:

21 AZURE: No Effects on Overall Population DFS IDFS Adjusted HR % CI: , P=0.298 Adjusted HR % CI: , P=0.222 Control Zoledronic acid Control Zoledronic acid 0 No. at risk Control ZOL No. at risk Control ZOL Coleman et al Lancet Oncology 2014; 15(9):

22 AZURE: Delay in Bone Metastasis Bone metastasis as first recurrence Bone metastasis at any time Adjusted HR % CI: , P=0.020 Adjusted HR % CI: , P=0.022 Control Zoledronic acid Control Zoledronic acid Coleman et al Lancet Oncology 2014; 15(9):

23 AZURE: Benefits Identified in Postmenopausal Women Pre, peri and unknown menopausal status >5 years post-menopausal Adjusted HR % CI: Control Zoledronic acid N = events Adjusted HR % CI: Control Zoledronic acid N = events No. at No. at risk risk Control Control ZOL ZOLMenopausal Interaction: χ 2 1 =4.71; P=0.030 Coleman et al Lancet Oncology 2014; 15(9):

24 Hypotheses Emerging From Adjuvant Trials Bisphosphonates predominantly reduce distant metastases rather than either local recurrence or contralateral disease Effects likely to be largest on bone recurrence Bisphosphonates only improve disease outcome in women who have low levels of reproductive hormones Established natural menopause Induced menopause at start of treatment Possible adverse effects on non-bone recurrence in premenopausal women Individual patient meta-analysis of verified data on outcomes from all randomised trials that compared use of a bisphosphonate in the adjuvant setting (any type and schedule) versus no bisphosphonate or placebo Coleman RE SABCS 2013 Abs S4-07

25 Data Received and Included In Meta-analysis Number trials Number patients Trials received Patients received Percent received Trials of <2 yrs clodronate % Trials of 2 yrs clodronate % <1year aminobisphosphonate % 1 year aminobisphosphonate % 2 yrs aminobisphosphonate % >2 yrs aminobisphosphonate % All aminobisphosphonates % All trials % Lots of data with no major studies missing 17

26 Diapositive NATAN to be added CRC; 24/11/2013

27 Recurrence Data: All Women

28 Recurrence Data: All Women Reduction in bone recurrence is not a subset finding

29 Bone Recurrence by Menopausal Status Premenopausal Postmenopausal Heterogeneity between menopausal groups χ 2 1 = 5.6 ; P=0.02 includes women aged < 45 if unknown

30 Bone Recurrence By Age

31 Breast Cancer Mortality By Menopausal Status Premenopausal Postmenopausal includes women aged < 45 if unknown

32 41 Similar Effects on Bone Recurrence Irrespective of Type, Dose and Schedule Of Bisphosphonate

33 Diapositive Probable back up slide CRC; 24/11/2013

34 Incremental Benefits of Adjuvant Systemic Treatments Intervention Comparator Study population 10 year risk reduction Adjuvant tamoxifen Nil ER+ 31% Aromatase inhibitors Tamoxifen ER+ Postmenopausal 10% Adjuvant CMF Nil Most 12% Adjuvant anthracyclines CMF Most 14% Adjuvant taxanes Anthracyclines All high risk 16% Trastuzumab Nil Her2+ 25% Bisphosphonates Nil Postmenopausal 17% Potential saving of up to 1000 lives per year in the UK alone

35 Bone Physiology Changes With Menopause Smad2/3 Smad2/3 Wilson C et al. Cancer Treatment Reviews 2012; 38(7):

36 Increase Osteoclast Activity Effects On Growth Of Disseminated Tumour Cells In Bone? Inject breast cancer cells in 12-week old animals Day 0 Day 7 Day 56 Tumour Homing Tumour progression Ovariectomy/ Sham ovariectomy Cull Increased growth of disseminated tumourcells in bone following OVX compared to sham operation PD Ottewell, Clinical Cancer Res 20; , 2014

37 Inhibition Of Bone Resorption Effects On OVX-induced Tumour Growth Inject breast cancer cells (MDA-231) in 12-week old animals Day 0 Day 7 Tumour Homing +/- weekly 100ug/kg Zoledronic acid Ovariectomy/ Sham ovariectomy Cull Zol inhibits OVXinduced growth of disseminated tumour cells in bone PD Ottewell, Clinical Cancer Res 20; , 2014

38 Conclusions Clinicians need to be aware of the risk for CTIBL and institute a strategy for management The bone marrow microenvironment plays a central role in tumour dormancy and metastasis Adjuvant bisphosphonates reduce bone metastases and improve survival. Benefits in post-menopausal women are clearly of clinical relevance. Related to effects on the target organ (bone). 34% reduction in risk of bone recurrence (p= ). 17% reduction in risk of breast cancer death (p=0.004). Benefits appear to be a class effect. Insufficient randomised data for oral alendronate or risedronate

39 ESMO Clinical Practice Guidelines: Bone Health in Cancer Patients Clinicians treating cancer patients need to be aware of: Treatments to reduce skeletal morbidity in metastatic disease Strategies to minimise cancer treatment-induced skeletal damage ESMO guidelines provide a framework for maintaining bone health in patients with cancer These ESMO guidelines focus on the topic of bone health for the first time, supplement existing ESMO guidelines (e.g., palliative care) Coleman RE, Body JJ, Aapro M, et al. Ann Oncol 2014; S3:iii124-iii137; doi /annonc/mdu103. ESMO, European Society for Molecular Oncology.

40 Acknowledgements Clinical collaborators Helen Marshall Walter Gregory Richard Bell David Cameron David Dodwell Roger Burkinshaw Vicky Liversedge Janet Brown Matthew Winter Emma Rathbone Caroline Wilson Kash Purohit Sandra Gutcher Meta-analysis team Richard Gray Vaughan Evans Hon Pan Rosie Bradley Christina Davies Michael Gnant, Sandy Paterson Trevor Powles, Gunter von Minckwitz Kathy Pritchard Jonas Bergh, Judith Bliss, Julie Gralow, Stuart Anderson David Cameron Laboratory team Ingunn Holen Penny Ottewell Hannah Brown Faith Nutter Alison Evans Colby Eaton Peter Croucher Ning Wang Kimberley Reeves