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BREAST CANCER:A FOCUS ON BONE HEALTH INTEGRITYMohamed Abdulla M.D.Prof. of Clinical OncologyCairo University
KIOW – 1st WorkshopKhartoum – Corinthia Hotel31/10/2015
Speaker DisclosuresMember of Advisory Board, Consultant, and Speaker for:• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:
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. Pain2. Pathological Fracture3. Spinal cord compression4. Radiation therapy treatment5. 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
• 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.
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 80Patients With SREs (%)‡
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
No BM BM BM & SER0.00%
50.00%
100.00%
75.80%
8.30%2.50%
Impact of SER on 5 – Year OAS Among Breast Cancer Patients
No BM BM BM + SERMRR 10.5
14.4
Data from Saad F, et al. Cancer. 2007;110(8):1860-1867.
Hazard ratio0 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%
Riskincrease
1.29
< .0152% 1.52Prostate cancer
Breast cancer
Pathologic Fractures Negatively Affect Survival:
Cancer Related Bone Disease: The Old Dogma:
Palliative Radiation Therapy
> 15 Years Ago
Cancer Related Bone Disease: The New Insight:
Dynamic Structure
Bone Turnover
Res
orpt
ion Form
ation
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.
Normal Bone Physiology:
O.Blast O.BlastO.Blast
Bone Formation
O.Clast Precursor
Cells
RANKL
DifferentiatedO.Clast
Mature Multinucleated
O.Clast
Bone Resorption
H+ Enz
OPG
Rana et al. Hematol Oncol Clin N Am 27 (2013) 1261–1283 Ca++, Cytokines, NTX
Vit DPTH
PGE2IL1
E2
• 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..
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 Deprivation Associated Bone LossPremenopausal 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
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;
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.
Molecular Basis of Bone Metastases in Breast Cancer:
Bone Resorption Products.
Cancer Cell
O.Blast
RANKLO.Clast ++
Osteolytic Factors
Bone Resorption Osteolytic
Osteoblastic Factors
O.Blast++
New Bone Osteoblastic
Armstrong AP, et al. Prostate 2008; 68:92-104.
OsteoblasticOsteolytic
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
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=30105.7 months
RANK +, N=4758.9 months
N=77
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.
PPCaH+
Apoptosis
+
Targets to Avoid Bone Loss:1. Osteoclasts.
Bisphosphonates
2. RANKL.Denosumab
3. Tumor related osteolytic & Osteoblastic factorsInvestigational
Mechanistically Different
For Which Indication?
Adjuvant Treatment? Metastatic Treatment?
YES
Agent?Schedule?Duration?
Bone Directed Therapy in Breast Cancer:
Zoladronic Acid
Denosumab
Adjuvant Bisphosphonate Treatment:
The Lancet. Vol 386. 1353-61.October 3, 2015
Adjuvant Bisphosphonate Treatment:• Patients: 18206• Treatment: 2 – 5 years• Follow up: 5 – 6 years• First Recurrence: 3453• Subsequent Death: 2106
Reductions in RR PL.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 PL.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
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
Adjuvant Denosumab Treatment:
Slide 15
Adjuvant Denosumab Treatment:
Slide 19
Adjuvant Denosumab Treatment:
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)
RANDOMISATION
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;29:112532.
*Excluding breast and prostate.IV, intravenously; MM, multiple myeloma; Q4W, every 4 weeks; SC, subcutaneously.
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
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
Pat
ient
s w
ithou
t SR
E (%
)
DenosumabStudy month
00 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
100908070605040 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
302010
†Excluding breast and prostate. All data from primary analyses.MM, multiple myeloma; NS, not significant.
Denosumab prolonged time to first SREvs zoledronic acid regardless of SRE history
Pro
porti
on o
f pat
ient
s w
ithou
t on-
stud
y S
RE
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
0.06 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
DenosumabZoledronic 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
Denosumab significantly reduced the risk of multiple SREs vs zoledronic acid
18% risk reduction
Time to firstand 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
Cum
ulat
ive
mea
n nu
mbe
rof
SR
Es
per p
atie
nt
Study month
0.0
1.0
1.6
1.4
1.2
0.8
0.6
0.4
0.2
Total SREs1360
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
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 13
Med
ian
chan
ge fr
om b
asel
ine
(%)
BSAP uNTx
*
*
Integrated analysis
Cumulative incidence of ONJ
0.51.0
0.8
1.81.3
1.8
0
2
4
6
Month 012 Month 024 Month 036*
Pro
porti
on o
f pat
ient
s (%
) 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
Approved Indications for Bone Modifying Agents:
NCCN Task ForceReport: Bone Health in Cancer Care. August 2013/Vol 11 Supplement 3.
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)
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.
Thank you