Bone Protection and Improved Survival Professor Rob Coleman Weston - - PowerPoint PPT Presentation

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 20th – 21st November 2014

Uses of Bone Targeted Treatments in Cancer Patients

Metastasis Prevention Metastasis Prevention Prevention of Treatment Induced Bone Loss Prevention of Treatment Induced Bone Loss Prevention of Skeletal Morbidity Prevention of Skeletal Morbidity

Lifetime Changes in Bone Mass

BMD Age Gain Consolidation Loss Men Women

Cancer

Cancer Treatments

Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations

40 80 120 160 200

Bioavailable E2, pmol/l

Premenopausal women Postmenopausal women Normal men Androgen Deprivation Therapy

Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:3555-61

Aromatase Inhibitor Therapy

Normal and Cancer Treatment Related Bone Loss Rates

0.5 1.0 2.0 2.6 4.6 7.0 7.7 2 4 6 8 10 Bone loss at I year

Normal men1 AI therapy in postmenopausal women2 ADT3 AI therapy plus GnRH agonist in premenopausal women4 Menopausal Women <551 Postmenopausal Women >551 Premature menopause secondary to chemotherapy5

Naturally occurring bone loss CTIBL

1. Kanis JA. Osteoporosis.1997:22-55. 2. Eastell R et al. J Bone Mineral Res. 2002. 3. Maillefert JF et al. J Urol. 1999;161:1219-1222. 4. Gnant M. San Antonio Breast Cancer Symposium, 2002. 5. Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311.

Bone Loss With and Without Bone Protection Using Zoledronic Acid

Gnant et al. Lancet Oncology 2010

Ovarian Suppression

ESMO-Recommended Treatment Algorithm For Managing Bone Loss During Cancer Treatment

Patient with cancer receiving chronic endocrine treatment known to accelerate bone loss T-score > -2.0 and no additional risk factors 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

• ral therapy

Coleman RE, Body JJ, Aapro M, et al. Ann Oncol 2014; S3:iii124-iii137.

Uses of Bone Targeted Treatments in Cancer Patients

Metastasis Prevention Metastasis Prevention Prevention of Treatment Induced Bone Loss Prevention of Treatment Induced Bone Loss Prevention of Skeletal Morbidity Prevention of Skeletal Morbidity

Distal

microenvironment (The skeleton)

At each level the tumour microenvironment consists of multiple, interactive components

O2, pH, mechanical stiffness Macrophages, Immune cells Fibroblasts, Stromal cells Endothelial cells, Pericytes Bone marrow precursors Adipocytes, Osteoblasts, Osteoclasts Cytokines/Chemokines Hormones Growth factors Angiogenic factors Enzymes Inhibitors Proteins/peptides Proteoglycans Bound growth factors Enzymes/Inhibitors

Different cell types Soluble factors Extracellular matrix Physical properties

Regional

microenvironment (The breast)

Local

microenvironment (The tumour) Tumour cells

The Tumour Microenvironment

Ever increasing complexity – All of these interacting simultaneously in time and space

Kunisaki and Frenette, Nature Med. 2012;18,864-865. CAR = CXCL-12 abundant reticular cells

Haematopoietic Stem Cell Niche Provides a Haven for Disseminated Tumour Cells

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

5

rhPTH(1-34) 80ug/kg, daily, days 1-5

5

s.c. vehicle, daily, days 1-5

1 1

Inject tumour cells

Sacrifice Monitor tumour growth by in vivo imaging Days post treatment start Ob number/mm bone surface

D a y 1 D a y 5 D a y 7 D a y 1 D a y 1 5 10 20 30

Control PTH

Day 5: PTH treated animals have increased number of

• steoblasts

compared to control

Treat with PTH

PTH

Control

Effects of Osteoblast Stimulation on Tumour Growth

Increased tumour burden in animals treated with PTH – More sites for tumour cells to settle?

Number of skeletal tumours

Days post tumour cell injection Total number of skeletal tumours

3 1 1 3 2 2 7 3 3 4 1 4 7 2 4 6 8 10

PBS PTH Circulating tumour cells/ml of blood

P B S P T H 5 10 15 20 25

Decreased number of circulating tumour cells in PTH treated animals – Increased numbers find a niche in bone?

Expansion of the osteoblast niche with PTH increases tumour burden

H Brown, preliminary data

B) Tumour cell proliferation and bone metastasis progression

Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence HSC niche

HSC

Stimulation of bone resorption

A) Tumour cell colonisation of bone

Development of bone lesions Tumour cell proliferation

Tumour cell Hematopoietic stem cell (HSC) Osteoblast Osteoclast

Re-circulation to

• ther metastatic

sites

Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.

Breast Cancer Metastasis

Diapositive 14 54

CRC; 03/01/2014

Tumour cell proliferation and metastasis progression

Tumour cells home to the HSC niche Environmental signals maintain tumour cell quiescence Escape from quiescence HSC niche

HSC

Stimulation of bone resorption

Tumour cell colonisation of bone

Development of bone lesions Tumour cell proliferation

Tumour cell Hematopoietic stem cell (HSC) Osteoblast Osteoclast

Breast Cancer Metastasis

Onward Dissemination

Years

Coleman RE et al. The Breast 2013: 22 Suppl 2:S50-6.

Bone Marrow Disseminated Tumour Cells (DTCs) Reduced With Adjuvant Bisphosphonates

• 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.

Rack et al1 (N = 172) ZOL q 4 weekk (n = 31) vs no ZOL for 6 months (n = 141 6 mo 5 10 15 20 25 30 Patients With Persisting DTCs, % P = .099 Aft et al2 (N = 120) ZOL q 3 weekly vs no ZOL for 1 yr (w/Chx) 3 mo Patients With Persisting DTCs, % 10 20 30 40 50 60 70 P = .054 Solomayer et al3 (N = 96) ZOL q 4 weeks (n = 44) vs no ZOL for 2 year (+ Adj Rx; n = 52) 12 mo P = .009 Patients With Persisting DTCs, % 10 20 30 40 50 60 70

Abbreviations: Chx, chemotherapy; DTC, disseminated tumour cell; ZOL, zoledronic acid.

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.

DFS

ABCSG-12:

Efficacy Following Induced Menopause

100 80 60 40 20 DFS (%) 12 24 36 48 60 72 84 96 108 Mos Since Randomization

Pts at Risk, n No ZOL ZOL 903 900 858 862 833 841 807 822 758 788 653 674 521 544 405 419 191 208 Events, n Multiple Cox Regression HR (95% CI) P value No ZOL 132/903

0.71 (0.55-0.92) .011

98/900 ZOL

Gnant M. et al. Ann Oncol, under revision 2014

84 month update

AZURE: Study Design

Countries Centres Patients UK 123 2710 Eire 10 247 Australia 28 226 Spain 8 107 Portugal 1 32 Thailand 2 25 Taiwan 2 13

Standard therapy Standard therapy Standard therapy + Zoledronic acid 4 mg Standard therapy + Zoledronic acid 4 mg

3,360 Breast Cancer Patients

Stage II/III

3,360 Breast Cancer Patients

Stage II/III

Zoledronic acid treatment duration 5 years

Accrual September 2003 - February 2006

R

6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months 6 doses 8 doses 5 doses Q3-4 weeks Q 3 months Q 6 months

Months

6 30 60 Coleman et al. N Engl J Med 2011; 365:1396-1405

AZURE: No Effects on Overall Population

DFS IDFS

Adjusted HR 0.94 95% CI: 0.82-1.06, P=0.298 Adjusted HR 0.93 95% CI: 0.82-1.05, P=0.222

Control Zoledronic acid Control Zoledronic acid

• No. at risk

Control ZOL

• No. at

risk 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 95% CI: 0.63-0.96, P=0.020 Adjusted HR 0.81 95% CI: 0.68-0.97, P=0.022

Control Zoledronic acid Control Zoledronic acid Coleman et al Lancet Oncology 2014; 15(9):997-1006

AZURE: Benefits Identified in Postmenopausal Women

>5 years post-menopausal

Adjusted HR 1.03 95% CI: 0.89-1.20 Adjusted HR 0.77 95% CI: 0.63-0.96

Pre, peri and unknown menopausal status N = 1041 347 events N = 2318 702 events

Control Zoledronic acid Control Zoledronic acid

• No. at risk

Control ZOL

• No. at

risk Control ZOLMenopausal Interaction: χ

χ χ χ2

1 =4.71; P=0.030

Coleman et al Lancet Oncology 2014; 15(9):997-1006

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

Data Received and Included In Meta-analysis

Number trials Number patients Trials received Patients received Percent received

Lots of data with no major studies missing

Trials of <2 yrs clodronate

2 120 1 72 60%

Trials of ≥2 yrs clodronate

5 5054 4 4981 99%

<1year aminobisphosphonate 2

208 1 40 19%

≈1 year aminobisphosphonate 7

1088 3 448 41%

≤2 yrs aminobisphosphonate 10

3754 8 3614 96%

>2 yrs aminobisphosphonate 11

10739 9 9711 90%

All aminobisphosphonates

29 15894 20 13785 87%

All trials

36 21068 26 18766 89%

17

Diapositive 24 17 NATAN to be added

CRC; 24/11/2013

Recurrence Data: All Women

Recurrence Data: All Women

Reduction in bone recurrence is not a subset finding

Bone Recurrence by Menopausal Status

Premenopausal‡ Postmenopausal

‡ includes women aged < 45 if unknown

Heterogeneity between menopausal groups χ2

1 = 5.6 ; P=0.02

Bone Recurrence By Age

Breast Cancer Mortality By Menopausal Status

Premenopausal‡ Postmenopausal

‡ includes women aged < 45 if unknown

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

41

Diapositive 30 41 Probable back up slide

CRC; 24/11/2013

Incremental Benefits of Adjuvant Systemic Treatments

10 year risk reduction Study population Comparator Intervention 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

Bone Physiology Changes With Menopause

Wilson C et al. Cancer Treatment Reviews 2012; 38(7):877-89.

Smad2/3 Smad2/3

Increase Osteoclast Activity – Effects On Growth Of Disseminated Tumour Cells In Bone?

Day 0 Day 7 Day 56

Tumour Homing Tumour Homing Tumour progression

Inject breast cancer cells in 12-week old animals Cull Ovariectomy/ Sham ovariectomy

Increased growth

• f disseminated

tumour cells in bone following OVX compared to sham operation

PD Ottewell, Clinical Cancer Res 20; 292-2932, 2014

Inhibition Of Bone Resorption – Effects On OVX-induced Tumour Growth

Day 0 Day 7 Tumour Homing Tumour Homing

+/- weekly 100ug/kg Zoledronic acid

Cull Ovariectomy/ Sham ovariectomy Inject breast cancer cells (MDA-231) in 12-week old animals PD Ottewell, Clinical Cancer Res 20; 292-2932, 2014

Zol inhibits OVX- induced growth of disseminated tumour cells in bone

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=0.00001).

– 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

Coleman RE, Body JJ, Aapro M, et al. Ann Oncol 2014; S3:iii124-iii137; doi 10.1093/annonc/mdu103. ESMO, European Society for Molecular Oncology.

• 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

• n the topic of bone health for

the first time, supplement existing ESMO guidelines (e.g., palliative care)

ESMO Clinical Practice Guidelines: Bone Health in Cancer Patients

Acknowledgements

• Laboratory team
• Ingunn Holen
• Penny Ottewell
• Hannah Brown
• Faith Nutter
• Alison Evans
• Colby Eaton
• Peter Croucher
• Ning Wang
• Kimberley Reeves
• 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
• 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