This document summarizes information about bone health and integrity in the context of breast cancer. It discusses how breast cancer commonly spreads to bone, causing skeletal-related events like fractures. It notes that bone-targeted therapies like bisphosphonates and denosumab can help prevent these events by inhibiting bone resorption. Clinical trials show these drugs reduce the risk of skeletal complications when used adjuvantly or for metastatic breast cancer in bone. The document thus emphasizes the importance of bone health for breast cancer patients and the role of anti-resorptive therapies.

1. BREAST CANCER:
A FOCUS ON BONE
HEALTH INTEGRITY
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
KIOW – 1st Workshop
Khartoum – Corinthia Hotel
31/10/2015

2. Speaker Disclosures
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:

3. Cancer Related Bone Disease:
The Pessimist Layout:
• Cancer Related Bone Disease:
• Effect of Treatment.
• Effect of Metastases.
• Metastatic Breast Cancer  75% Bone Metastases.
• Improved Survival  more disease and therapy related events.
• SRE:
1. Pain
2. Pathological Fracture
3. Spinal cord compression
4. Radiation therapy treatment
5. Life threatening hypercalcemia
• Heavy Burden:
Medical, Psychological, Social and Economic.
Yong et al. Curr Opin Oncol 2014, 26:274 – 283
Loss of BMD
 QoL & Survival

4. • SRE require High Health Resource Utilization and
Cost.
• The cost is directly related to:
1. In- or out-patient care.
2. Surgical intervention (Fixation versus Decompression).
3. Radiation Therapy (yes or no).
4. Number of episodes of care (once or repeated).
• The Mean Costs in Observational Trials:
• US Data:
• USD 12469 in 2006 Dollars.
• Repeated SRE: USD 26384.
• One Type: USD 8484.
• European Data: Euro 1485 – 15267.
Cancer Related Bone Disease:
The Economic Burden:
Lage et al. Am J Manag Care 2008; 14:317–322.
Body et al. J Med Econ 2013; 16:539 – 546.

5. Incidence of Skeletal-Related Events:
Lung Cancer/Others†
Prostate Cancer*
Multiple Myeloma†
Breast Cancer*
Coleman RE. Oncologist. 2004;9(suppl 4):14-27.
*24 mos.
†21 mos.
‡Placebo arm of pamidronate or zoledronic acid randomized trials.
48
49
51
68
0 20 40 60 80
Patients With SREs (%)‡

6. Cancer Related Bone Disease:
The Pessimist Layout:
Danish National Patient Registry (1999-2007):
35912 Newly Diagnosed Breast Cancer Patients:
Cetin K, et al. BMJ Open 2015;5
75.80%
8.30%
2.50%
0.00%
50.00%
100.00%
No BM BM BM & SER
Impact of SER on 5 – Year OAS Among
Breast Cancer Patients
No BM BM BM + SER
MRR 10.5
14.4

7. Data from Saad F, et al. Cancer. 2007;110(8):1860-1867.
Hazard ratio
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
Decreased mortality Increased mortality
.04
P value
29%
Risk
increase
1.29
< .0152% 1.52
Prostate cancer
Breast cancer
Pathologic Fractures Negatively
Affect Survival:

8. Cancer Related Bone Disease:
The Old Dogma:
Palliative Radiation Therapy
> 15 Years Ago

9. Cancer Related Bone Disease:
The New Insight:
Dynamic Structure
Bone Turnover
Resorption
Formation
Total
Volume
of Bone
Time
Percent/Year
Bone Remodeling
Calcium
Homeostasis
Skeletal
Integrity
Parfitt AM. Bone. 2004; 35(1):1-3.
Fazzalari NL. Semin Cell Dev Biol. 2008; 19(5):467-72.

10. Normal Bone Physiology:
O.Blast O.BlastO.Blast
Bone Formation
O.Clast
Precursor
Cells
RANKL
Differentiated
O.Clast
Mature
Multinucleated
O.Clast
Bone Resorption
H+ En
z
OPG
Rana et al. Hematol Oncol Clin N Am 27 (2013) 1261–1283 Ca++, Cytokines, NTX
Vit D
PTH
PGE2
IL1
E2

11. • Estrogen + Osteoblast = Osteoprotegerin.
• Osteoprotegerin + RANKL =  RANK.
•  RANK  Arrest of Osteoclast Differentiation 
Apoptosis  NO BONE LOSS.
Normal Bone Physiology:
• Females:
• Premenopausal  Preservation of skeletal integrity.
• Postmenopausal & Endocrine Therapy (Breast Cancer) 
Osteoporosis.
• Males:
• Androgens –Aromatase Estrogen  Bone Preservation.
• Orchiectomy & ADT   Androgens  Estrogen  Bone Loss.
Boyle WJ, et al. Nature 2003; 423:337-42..

12. 1Kanis JA. In: Kanis JA, ed. Osteoporosis. London, 1997; 22-57; 2Eastell R, et al. J Bone Miner Res 2002; 17(suppl 1):S165;
3Lee WY, et al. J Clin Endocrinol Metab 2002; 87:329-35;4Maillefert JF, et al. J Urol 1999; 161:1219-22;
5Gnant M, et al. Breast Cancer Res Treat 2002; 76(suppl 1):S31, Abstract 12;6Shapiro CL, Manola J, Leboff M. J Clin Oncol 2001; 19:3306-
331..
Estrogen / Androgen DeprivationAssociated Bone Loss
Premenopausal women
Normal men1
Early menopausal women1
Late menopausal women1
AI therapy in post menopausal women2
Androgen deprivation therapy agonist4
AI therapy plus GnRH agonist5
Ovarian failure secondary to
chemotherapy6
AI, aromatase inhibitor;
GnRH, gonadotropin-releasing hormone;
BMD, bone mineral density.
Lumbar spine BMD loss at 1 year (%)
7.7%
7.0%
4.6%
2.6%
2.0%
1.0%
0.5%
0 2 4 6 8

13. Fractures with Adjuvant Aromatase
Inhibitors
Trial Mean F/U Fx w/AI Fx w/Tam
ATAC1 68 mo. 11% 7.7%
(p<0.0001)
BIG 1-982 51 mo. 8.6% 5.8%
(p<0.001)
IES3 55.7 mo. 7.0 4.9
(p=0.003)
1Forbes JF et al. Lancet Oncol. 2008;9(1):45-53; 2Crivellari D et al. J Clin Oncol. 2008;26(12):1972-9;
3Coombes RC et al. N Engl J Med. 2004;350(11):1081-92;

14. Molecular Basis of Bone Metastases in
Breast Cancer:
• Bone microenvironment is the ideal soil for cancer cells 
Enriched by resorption and growth factors.
• Tumor cell  Induce osteoclast bone destruction.
Mundy GR (ed). Cellular mechanisms of bone resorption. In: Bone Remodeling and Its Disorders. 2nd ed. London, England: Martin
Dunitz Ltd; 1999;23-25.

15. Molecular Basis of Bone Metastases in
Breast Cancer:
Bone Resorption
Products.
Cancer
Cell
O.Blast
RANKL
O.Clast
++
Osteolytic Factors
Bone Resorption
Osteolytic
Osteoblastic
Factors
O.Blast
++
New Bone
Osteoblastic
Armstrong AP, et al. Prostate 2008; 68:92-104.

16. RANKL Beyond its Bone Resorption
Effect:
Osteoblasts
RANKL
Bone matrix
Circulating Cancer cells
expressing RANK
RANKL may act as a
chemotactic factor which
attracts circulating cancer
cells expressing RANK to
migrate into the bone
Armstrong AP, et al. Prostate 2008; 68:92-104.
RANK

17. Daniele Santini, et al, PLoS One. 2011; 6(4): e19234
YES!!! RANK Expression in Primary Tumors
Associates with Bone Metastasis Occurrence in
Breast Cancer Patients:
RANK protein
expression was
associated with
accelerated bone
metastasis in a
multivariate analysis
(p=0.029).
RANK – N=30
105.7 months
RANK +, N=47
58.9 months
N=77

18. Bisphosphonates are Potent Inhibitors of
Osteoclastic Bone Resorption:
Clezardin P, et al (2005). Bisphosphonates and cancerinduced bone disease: beyond their antiresorptive activity. Cancer
Res 65, 4971–4974.
Lipton A (2008). Emerging role of bisphosphonates in the clinic—antitumor activity and prevention of metastasis to bone.
Cancer Treat Rev 34(suppl 1), S25–S30.
PPCa
H+
Apoptosis
+

19. Targets to Avoid Bone Loss:
1. Osteoclasts.
Bisphosphonates
2. RANKL.
Denosumab
3. Tumor related osteolytic & Osteoblastic factors
Investigational
Mechanistically
Different

20. For Which Indication?
Adjuvant Treatment? Metastatic Treatment?
YES
Agent?
Schedule?
Duration?
Bone Directed Therapy in Breast Cancer:
Zoladronic
Acid
Denosumab

21. Adjuvant Bisphosphonate Treatment:
The Lancet. Vol 386. 1353-61.October 3, 2015

22. Adjuvant Bisphosphonate Treatment:
• Patients: 18206
• Treatment: 2 – 5 years
• Follow up: 5 – 6 years
• First Recurrence: 3453
• Subsequent Death: 2106
Reductions in RR P
L.R. 0.94 0.08
D.R. 0.92 0.03
B.C. Mortality 0.91 0.04
Bone Recurrence 0.83 0.004
Entire Group of Patients:
Reductions in RR P
L.R. 0.86 0.002
D.R. 0.82 0.003
B.C. Mortality 0.82 0.002
Bone Recurrence 0.72 0.002
Postmenopausal Patients:Premenopausal Patients:
No Effect
The Lancet. Vol 386. 1353-61.October 3, 2015

23. Patients Characteristics Showing Benefit:
• Postmenopausal.
• Age > 50 years.
• ER –ve.
• G3.
• LNs 1 – 3.
• Treatment 2 Years.
• Cth –ve.
Adjuvant Bisphosphonate Treatment:
The Lancet. Vol 386. 1353-61.October 3, 2015

24. Adjuvant Denosumab Treatment:

25. Slide15
Adjuvant Denosumab Treatment:

26. Slide19
Adjuvant Denosumab Treatment:

27. Denosumab pivotal Phase III bone metastases
treatment trials: three trials of identical design in
different patient populations
Supplemental calcium and vitamin D
*Per protocol and Zometa® label, IV product dose adjusted for baseline
creatinine clearance and subsequent dose intervals determined by serum creatinine.
Denosumab 120 mg SC Q4W
+
Placebo IV Q4W*
Zoledronic acid 4 mg IV Q4W*
+
Placebo SC Q4W
Study 1361
Breast cancer
(N = 2049)
Study 1032
Prostate cancer
(N = 1904)
Study 2443
Other solid tumours*/MM
(N = 1779)
R
A
N
D
O
M
I
S
A
T
I
O
N
1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9;
2. Fizazi K, et al. Lancet 2011;377:813–22;
3. Henry DH, et al. J Clin Oncol 2011;29:112532.
*Excluding breast and prostate.
IV, intravenously; MM, multiple myeloma; Q4W, every 4 weeks; SC, subcutaneously.

28. 1. Lipton A, et al. Eur J Cancer 2012;48:3082–92;
2. Cleeland CS, et al. Ann Oncol 2010;21(Suppl 8):viii379[abstract 1248P and poster at ESMO 2010].
Integrated analysis endpoints: increased power
from high patient numbers
Time to first
on-study SRE
(non-inferiority)
• Time to first on-study SRE (superiority)
• Time to first and subsequent on-study SRE
(superiority, multiple-event analysis)
• Safety and tolerability
Primary1 Secondary1
• Overall survival, disease progression, individual SREs
and skeletal morbidity rate
• Pain prevention, pain palliation and analgesic use
• ONJ-related attributes
Exploratory1,2

29. 1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9;
2. Fizazi K, et al. Lancet 2011;377:813−22;
3. Henry DH, et al. J Clin Oncol 2011;29:1125−32.
Risk reduction in time to first SRE consistently
favoured denosumab across tumour types
PatientswithoutSRE(%)
Denosumab
Study month
0
0 3 6 9 12 15 18 21 24 27
Breast
cancer1
HR = 0.82 (95% CI, 0.71–0.95)
P = 0.01 (superiority)
Prostate
cancer2
HR = 0.82 (95% CI, 0.71–0.95)
P = 0.008 (superiority)
0 3 6 9 12 15 18 21 24 27
Other solid
tumours/MM3†
HR = 0.84 (95% CI, 0.71–0.98)
P = 0.0007 (non-inferiority)
P = 0.06 (NS for superiority)
0 3 6 9 12 15 18 21 24
100
90
80
70
60
50
40 26.4 months
Not yet reached
20.6 months
17.1 months 16.3 months
Zoledronic acid
18% risk
reduction
20.7 months
18% risk
reduction
16% risk
reduction
30
20
10
†Excluding breast and prostate. All data from primary analyses.
MM, multiple myeloma; NS, not significant.

30. Denosumab prolonged time to first SRE
vs zoledronic acid regardless of SRE history
Proportionofpatients
withouton-studySRE
Study month
HR = 0.84 (95% CI, 0.73–0.96)
P = 0.01
Prior SRE
0
1.0
0.8
0.6
0.4
0.2
0.0
6 12 18 24 30 0 6 12 18 24 30
HR = 0.82 (95% CI, 0.73–0.92)
P = 0.0006
No prior SRE
Study month
Denosumab
Zoledronic acid
1.0
0.8
0.6
0.4
0.2
0.0
Lipton A, et al. Eur J Cancer 2012;48:3082–92;
Lipton A, et al. Ann Oncol 2010;21(Suppl 8):viii379 [abstract 1249P and poster at ESMO 2010].
Integrated analysis

31. Denosumab significantly reduced the risk of
multiple SREs vs zoledronic acid
18% risk
reduction
Time to first
and subsequent SREs
RR = 0.82
(95% CI, 0.75–0.89)
P < 0.001 (superiority)
0 3 6 9 12 15 18 21 24 27 30 33 36
Cumulativemeannumber
ofSREsperpatient
Study month
0.0
1.0
1.6
1.4
1.2
0.8
0.6
0.4
0.2
Total SREs
1360
1628
Denosumab
Zoledronic acid
(N = 5723)
Lipton A, et al. Eur J Cancer 2012;48:3082–92.
Events occurring at least 21 days apart (multiple event analysis).
RR, rate ratio.
Significantly
fewer SREs with
denosumab
Integrated analysis

32. Lipton A, et al. Eur J Cancer 2012;48:3082–92.
BSAP, bone-specific alkaline phosphatase;
uNTx, urinary N-telopeptide corrected for serum creatinine.
*P < 0.001.
Significantly greater suppression of bone
turnover marker levels from baseline with
denosumab vs zoledronic acid at Week 13Medianchangefrombaseline(%) BSAP uNTx
*
*
Integrated analysis

33. Cumulative incidence of ONJ
0.5
1.0
0.8
1.8
1.3
1.8
0
2
4
6
Month 012 Month 024 Month 036*
Proportionofpatients(%)
Denosumab (n = 2814)
Zoledronic acid (n = 2836)
Saad F, et al. Ann Oncol 2012;23:1341–7.
No significant difference in ONJ rate between
denosumab and zoledronic acid
*P = 0.13
Denosumab
(n = 52)
1.8%
Zoledronic acid
(n = 37)
1.3%
Positively
adjudicated
for ONJ
(n = 89)
Potential ONJ
(n = 276)
All patients
(N = 5723)
Data are from the integrated analysis of three pivotal Phase III studies.
Proportions are % of all patients treated with zoledronic acid or denosumab.
Integrated analysis

34. Approved Indications for Bone Modifying
Agents:
NCCN Task ForceReport: Bone Health in Cancer Care. August 2013/Vol 11 Supplement 3.

35. Decreasing Risk of Osteoporosis:
Nonpharmacologic Interventions
• Calcium
• Vitamin D
• Increase physical activity (weight bearing, muscle
strengthening, balance)
• Prevent falls
• Eliminate tobacco, decrease caffeine
• Follow bone density studies (DEXA scans)

36. Take Home Message:
• Cancer related bone disease is common in breast cancer.
• Breast cancer is significantly associated SRE following
either AI treatment or bone metastases.
• Prevention of SRE is of up front priority in management.
• Understanding molecular events of normal bone
physiology was coupled with developing of effective bone
directed therapies.
• Blocking the osteoclast function through RANKL inhibitor
or direct inhibition is the target for prevention of bone
resorption.
• Further research is ongoing for better selection of
subgroups of patients who might benefit of bone directed
therapy is underway.

37. Thank you