1. Bisphosphonates in Cancer Management. “A Story of Success”
Mohamed Abdulla M.D.
Professor of Clinical Oncology
Cairo University
Good afternoon ladies and gentlemen I would like to thank the organizing committee especially Prof Kamal Hamad, Prof. Sedeek and all my colleagues in Khartoum Cancer Center for the generous hospitality and invitation to be here for the second time, also my appreciation to Novartis Oncology for inviting me for this talk about the integrated use of Bisphosphonates into routine daily oncologic practice and its positive influential impact upon patient’s quality of life as well as its specific anti-neoplastic effect. W: E:
Khartoum 04/12/2010

2. Agenda: Magnitude of The Problem; Skeletal Related Events.
Patho-physiology of Bone Metastases.
Bone Directed Therapy & Improvements in Quality of Life.
Anti-Tumor Effect.
Focus on Breast Cancer.
During the next few minutes we are going to explore the prevalence of skeletal affection due to involvement by malignant disease and as a result of specific cancer treatment, moving remember the basic fundamentals of how cancer cell can affect the normal bone homeostasis, then we will shift to the bone directed therapies and their impact upon improving quality of life, then we will have an overview of well established anti-tumor effect of Bisphosphonates and finally we will focus on bisphosphonates achievements in the management of breast cancer.

3. Prevalence of Skeletal Affection in Cancer Patients:
5-year world
prevalence, thousands1
Incidence of
bone metastases
in cancers2
Median survival,
months2-4
Myeloma
144
6 - 54
Renal
480 12
Melanoma
533 6
Bladder
1,000 40
6 - 9
Thyroid
475 60 48
Lung
1,394
6 - 7
Breast
3,860
Prostate
1,555
More lytic
More blastic
As we know skeletal metastases is a common event during disease evolution of most of malignant diseases with variable figures, The problem is quite apparent among patients with breast and prostate cancer as well as multiple myeloma and expected to be more obvious as these patients are going to entertain more prolonged survival as a result of improvements in adopted therapeutic strategies. It should be emphasized that myeloma patients have purely lytic lesions in contrast to breast and prostate cancer where lesions are predominantly sclerotic or osteoblastic.
1. Parkin DM, et al. Int J Cancer. 2001;94(2): ; 2. Coleman RE. Cancer Treat Rev. 2001;27(3): ; 3. Coleman RE. Cancer. 1997;80(8): ; 4. Zekri J, et al. Int J Oncol. 2001;19(2):

4. Bone Complications and Quality of Life:
Increased medical costs[1]
Impaired mobility[6]
Skeletal
complications
Diminished quality of life[2-4]
Negative impact on survival[5]
Skeletal complications either due to disease or therapy are usually coupled with dramatic scenario. The intro is usually impaired mobility with all of its associated complications, the body is diminished quality of life; both physically and emotionally and definitely the outro will be negative impact on survival. Also we should not forget the increased cost of care for these patients.
1. Groot MT, et al. Eur Urol. 2003;43: Weinfurt KP, et al. ESMO Abstract 662P. 3. Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S.

5. Pathologic Fractures Negatively Affect Survival:
Risk increase
P value
1.29
Prostate cancer
29%
.04
1.52
Breast cancer
52%
< .01
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Hazard ratio
Also, pathologic fracture as an important component of cancer related skeletal complications was proved to significantly increase mortality among breast and prostate cancer patients.
Decreased mortality
Increased mortality
Data from Saad F, et al. Cancer. 2007;110(8):

6. FDA Accepts Composite Endpoints to Evaluate Therapy Benefit:
Composite endpoints based on occurrence of skeletal-related events (SREs) defined as
Radiation to bone for bone pain or to treat or
prevent pathologic fractures or spinal cord compression
Pathologic fracture
Spinal cord compression
Surgery to bone
The FDA by the year 2003 accepted the terminology of skeletal related events to describe the most serious complications affecting bone due to cancer, It includes the need for palliative irradiation therapy, pathologic fractures, spinal cord compression and surgery to bone, and hence the efficacy of any proposed bone directed therapy should be evaluated in terms of preventing these events.
Johnson JR, et al. J Clin Oncol. 2003;21:

7. Patients With Bone Metastases Are at High Risk for Developing Skeletal-Related Events:
SREs
Placebo arms of large randomized studies
Any
Pathologic fracture
Radiation therapy
Surgical intervention
Spinal cord compression
Patients With SRE, %
Also we have to remember that data from placebo arms of large randomized trials indicated that 50 to 70% of patients with bone metastases are liable to develop skeletal related events and this was the triggering point to find a way to help these patients decades ago,
Breast1
24 Months
Prostate2
24 Months
Cancer Type
SRE, skeletal-related event.
1. Lipton A, et al. Cancer. 2000;88(5): ; 2. Saad F, et al. Eur Urol Suppl. 2007;6(11):

8. Bone as a Dynamic Structure: Normal Turnover:
When we look to the bone micro-environment, we will notice that it is a dynamic structure, where optimal bone health depends on a balanced cycle of bone turnover and remodelling. This homeostatic process involves a continuous process of interplay of bone matrix and mineral resorption (denoting osteoclastic activity) and reactive bone formation (indicating osteoblastic activity), and this interplay is necessary to maintain the integrity of the skeleton and plays an important role in calcium equilibrium.

9. Bone as a Dynamic Structure: Normal Turnover:
The annual turnover rate is 25% in cancellous bones & 2 – 3% in cortical bones.
The Process takes about 4 – 6 months.
1 osteoclast resorbs what 100 osteoblasts build.
And here we are going to stop and remember some of the basic informations about normal bone turnover

10. Types of Cancer Bone Disease:
Osteolytic
Breast and myeloma
Bone destruction mediated by osteoclasts
Also according to this interplay we have 2 types of cancer bone disease; osteolytic type as in breast and myeloma where bone destruction is mediated by osteoclasts and osteoblastic type as in prostate and breast cancer where bone formation is mediated by osteoblasts.
Osteoblastic
Prostate and breast
Bone formation mediated by osteoblasts

11. Normal interplay between Osteoclasts and Osteoblasts:
Destruction
RANK
RANK Ligand
In order to understand the normal interplay between osteoclasts and osteoblasts we have to be aware with 3 terms; RANK which is Receptor activator of nuclear factor kappa expressed on mature osteoclasts and precursors, RANK Ligand which is a cytokine expressed by osteoblasts, stromal cells and some tumor cells upon binding to receptors will lead to osteoclastic activation and Osteoprotegerin which is a natural antagonist of RANK Ligand and is secreted by bone lining cells, and we can imagine that over-expression of RANK and RANK Ligand is associated with more bone destruction while Osteoprotegerin synthesis is associated with more bone formation.
Formation
Osteoprotegerin

12. The Vicious Cycle of Bone Metastases: The Lytic Story:
PTHrP released by tumor cells
Tumor Cells
PTHrP
Osteoclastic resorption stimulated
BMP
PDGF
FGFs
IGFs
TGF-β
Peptides (eg, TGF-β) released by bone resorption
In metastatic disease with lytic lesions which is best demonstrated in breast cancer and myeloma, a parathyroid hormone related protein is released by tumor cells leading to stimulation of osteoclastic bone resorption with subsequent release of growth peptides to stimulate tumor cell proliferation with more and more release of parathyroid hormone related protein, more evident bone resorption and hence the vicious circle.
Tumor cell production of PTHrP increased
More bone resorption
Osteoclast
Tumor cell proliferation
Bone
Mundy GR, Yoneda T. N Engl J Med.1998;339:

13. The Vicious Cycle of Bone Metastases: The Sclerotic Story:
Tumor Cells
bFGFs
EGF
TGF-β
Proteases
ET-1, BMPs IGFs, OPG
In Metastatic Bone Disease with sclerotic lesions which is best demonstrated in Prostate and breast cancer, the osteoclastic activity is associated with release of many growth factors which in turn will stimulate tumor cell proliferation and excessive release of proteases. Such proteases are going to trigger osteoblasts to yield sclerotic metastases as well as the increased release of RANKL to activate osteoclasts and hence more and more bone destruction, What we have to realize is that we almost always have a lytic nature of disease behind sclerotic events.
RANKL
Osteoblasts
Sclerotic metastasis
Osteoclast
Bone
Mundy GR, Yoneda T. N Engl J Med.1998;339:

14. Specific Drug Directed Therapy
Principles of Management of Bone Metastases:
Specific Drug Directed Therapy
Over decades of oncologic practice, the management of skeletal metastases entailed the use of ionizing irradiation therapy to control pain as well as chemo-hormonal therapy in a trial to control the malignant growth and Orthopaedic procedures either to fix a pathological fracture or to relieve spinal cord compression. However in the past few years, a new class of pharmaceuticals was developed to specifically target osseous metastatic disease with a main goal is to lower skeletal related events.
External Beam
Radiation
Therapy
Radioactive
Isotopes

15. Ionizing External Beam Rth:
Used over a Century for Palliation of Bone Mets. Related Effects.
Bone Relief in The Majority of Patients.
Reducing The Rate of Bone Destruction.
6-12 Months of Pain Control.
Disadvantages:
Myelosuppression.
Dose to Surrounding Critical Structures.
As we all know radiation therapy is an effective tool in alleviating bony pains due to metastases, however with increasing survival duration, major radiation induced complications especially myelo-suppression and dose to nearby critical structures may limit its use.

16. Radioactive Isotopes:
Radio-nuclide
Carrier Ligand
Half Life (Days)
ß Energy (MeV)
Gamma Energy (MeV)
Max. Range mm
89St
Chloride
50.5
1.46 -
7.0
153Sm
EDTMP
1.9
0.81
0.103
2.5
186Re
HEDP
3.8
1.07
0.137
4.5
188Re
0.7
2.12
0.155
11.0
Also the use of radioactive isotopes although recommended by many authors, yet the expected treatment related pancytopenia is of major concern especially among patients expected to entertain prolonged survival.

17. Overall Structure of Bisphosphonates
PO3H2
R2 Chain
R1 Chain
Osteoclast C
Coming to Bisphosphonates which were used to reduce skeletal related events in clinic for more than 20 years, a long list of other agents are now under extensive investigation, of them the most recognized is Densomab with established clinical benefit. Bisphosphonates have a common central phosphate-carbon-phosphate backbone, which acts as the bone hook, making the Bisphosphonate bind avidly to the bone surface. The other end of the molecule, the R2 chain, affects bone cell function mainly the osteoclast activity/
PO3H2

18. Effect of Bisphosphonates on Vicious Cycle of Bone Destruction:
Decrease activity of osteoclasts
Tumor Cells
PTHrP
PTHrP
Reduction in release of peptides
BMP
PDGF
FGFs
IGFs
TGF-β
BMP
PDGF
FGFs
IGFs
TGF-β
Slowed tumor-cell growth
Reduced production of PTHrP
Upon binding of the Bisphosphonate to bone surface, it will inhibit the osteoclast activity leading to diminished release of growth factors and hence slow down tumor cell proliferation with decreased release of parathyroid hormone related protein ending by decreasing the bone destruction and hence broken vicious circle of bone destruction.
Decrease in bone resorption
Osteoclast
Bone
Mundy GR, Yoneda T. N Engl J Med. 1998;339:

19. Different Classes of Bisphosphonates:
Lung Cancer V ppt
4/14/2017 6:30 PM
Different Classes of Bisphosphonates:
Non-Nitrogen containing
1 Nitrogen containing
1 Nitrogen ring
2 Nitrogen ring
clodronate
pamidronate P O H N
risedronate
Zoledronic acid
etidronate
alendronate
Potency increases
Members of the first generation of bisphosphonates (etidronate and clodronate), introduced almost three decades ago, contain simple substituents (CH3, OH and Cl, respectively) and are relatively weak inhibitors of bone resorption
The subsequent development of nitrogen-containing bisphosphonates, which have an aliphatic side chain containing a single nitrogen atom, produced more potent compounds such as pamidronate, alendronate and ibandronate
Potency and therapeutic ratio could be further increased when the nitrogen atom was contained in a heterocyclic ring structure. The addition of a second nitrogen atom to the heterocyclic ring resulted in zoledronic acid, the most potent bisphosphonates known to date;
Bone affinity increases
ibandronate
tiludronate
1. Thurlimann B. Bisphosphonates in Clinical Oncology: Focus on Pamidronate. Heidelberg, Germany: Springer-Verlag Berlin; 1999:
2. Fleisch H. Bisphosphonates: Mechanisms of action. Endocr Rev. 1998;1:80-100 19

20.  Skeletal-related events*
Bisphosphonate Therapy: Potential Mechanisms for Improved Outcomes:
Bisphosphonates
 Skeletal-related events*
Anticancer effects
 Therapy options (preservation of function)
 Mortality associated with skeletal-related events
Anticancer effects in bone microenvironment
Effects on cancer cells (alone or with
chemotherapy)
The use of Bisphosphonate therapy is not only associated with reduction in the skeletal related events, but with anticancer effects as well, either in the bone micro-environment itself and on cancer cells with or without chemotherapy leading to improved disease outcome in terms of prolongation of progression free as well as overall survival.
Improved disease outcomes
Delayed disease progression
Prolonged survival
*Zoledronic acid has demonstrated efficacy in preventing bone loss in women with hormone-sensitive early breast cancer receiving endocrine therapy.

21. Zoledronic Acid and Risk of SREs in Multiple Tumor Types:
Risk Reduction
P Value
41%
.019
Breast
Prostate
36%
.002
Solid tumors
31%
.003
Lung cancer
32%
.016
The clinical benefit of using zoledronic acid in significantly reducing the risk of developing Skeletal Related Events was clearly demonstrated in many tumor types including Breast, prostate, lung and renal cancer as well as other solid tumors.
RCC
58%
.010
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Relative Risk of SRE
In favor of ZOL
In favor of placebo
Kohno N, et al. J Clin Oncol. 2005;23: Saad F, et al. J Natl Cancer Inst. 2004;96: Rosen LS, et al. Cancer. 2004;100: Lipton A, et al. Cancer. 2003;98:

22. Zoledronic Acid more than just an anti-osteoclast !!
I think we agree that Zoledronic acid is the standard of care in the management of secondary malignant bone disease, but we have not to think of it as just an anti-osteoclast, based on the molecular data of its inhibitory effect on Farsynl dipyrophosphate enzyme or FPP which plays a key role in cell mediated signal transduction.
Main mode of action is inhibition of FPP synthase enzyme
which plays a key role in cell mediated signal transduction

23. Preclinical Anticancer Activity With Bone-Targeted Therapies
ZOL
IBN
PAM
CLO
ALN
RIS
DEN
Prevention
Angiogenesis 
()
Apoptosis
Proliferation
Invasion
Adherence
Migration
Activity
Inhibition of tumor growth
Synergy with chemotherapy
Immunomodulation
Moreover, Zoledronic acid among all bone-targeted therapies, is the only one to show activity against nearly all active molecular steps encountered during the process of disease evolution as angiogenesis, apoptosis, proliferation and so on as well as its use is associated with inhibition of tumor growth and synergy with chemotherapy.
denotes activity; () to be confirmed.
ZOL, zoledronic acid; IBN, ibandronate; PAM, pamidronate; CLO, clodronate; ALN, alendronate; RIS, risedronate; DEN, denosumab.

24. HOW? Direct antitumor effect Indirect antitumor effect
Primary tumor
Angiogenesis
Invasion
Inhibits angiogenesis
Decreases matrix invasion
Synergy with anticancer drugs
Induces tumor cell apoptosis
Stimulates immune surveillance
Metastasis to bone occurs via a multi-step process, and inhibition of any of these steps could prevent metastasis to bone1
The primary malignant neoplasm promotes new blood vessel formation (angiogenesis)
Cancer cells must then invade the blood vessels, wherein they form multi-celled aggregates
Aggregates of tumor cells form emboli that lodge in capillary beds in bone
Cancer cells can adhere to vascular epithelial cells to escape the blood vessels and must extravasate through the extracellular matrices to enter the bone microenvironment
As cancer cells enter the bone, they are exposed to factors in the bone microenvironment, such as growth factors released from the bone matrix during osteolysis, which may promote tumor growth
Zoledronic acid can inhibit multiple steps in the metastatic process and has demonstrated direct and indirect antitumor activities in preclinical assays2
Reference
Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):
Lipton A. Emerging role of bisphosphonates in the clinic-Antitumor activity and prevention of metastasis to bone. Cancer Treat Rev May 15. [Epub ahead of print]
Decreases adhesion to bone
Metastases
Micrometastases
Adhesion & extravasation
Arrest in distant capillary
Adapted from Mundy GR, et al. Nature Reviews Cancer. 2002;2:

25.  = European registration.  = Global registration.
Bisphosphonate Indications:
Indication
HCM
Breast cancer
Multiple myeloma
Prostate cancer
Other solid tumors
Clodronate 
Pamidronate
Zoledronic acid
Ibandronate
And based on its efficacy, zoledronic acid had gained a global agreement to be used in malignant hypercalcemia as well as secondary malignant bone affection in breast and prostate cancer as well as multiple myeloma and other solid tumors.
 = European registration.  = Global registration.

26. A focus on Breast Cancer
Zoledronic Acid
A focus on Breast Cancer
Coming to special focus on breast cancer.

27. SRE Risk Reduction in BC: Results From an Independent Meta-analysis:
P value
0.59
ZOL 4 mg % .001
(Kohno 2005)
PAM 90 mg 23% < .001
(Aredia study 18 and 19)
0.77
0.82
Ibandronate 6 mg 18% .04
(Body 2003)
0.86
Ibandronate 50 mg 14% .08
(Body 2004)
A meta-analysis of 21 studies in metastatic breast cancer had proven the activity of all bisphosphonates in skeletal related events risk reduction when compared to placebo or no bisphosphonates. The only placebo-controlled zoledronic acid trial was conducted in Japan and showed a 41% reduction in the risk of a skeletal-related events, a result that appears to outperform all other agents used to date. .
Oral clodronate 1,600 mg
(Kristensen 1999) 31%
(Paterson 1993) 17%
(Tubiana-Hulin 2001) 8%
0.69
0.83
.03 (pooled)
0.92
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Cochrane database comparing placebo-controlled trials in breast cancer setting.
ZOL, zoledronic acid; PAM, pamidronate.
Adapted from Pavlakis N, et al. Cochrane Database Syst Rev. 2005:CDC

28. Zoledronic Acid Reduced All Types of SREs at 1 Year in Patients With Bone Metastases From BC:
Zoledronic acid 4 mg (n = 114)
Placebo (n = 113)
And such risk reduction was evident for all components of skeletal related events.
SRE, skeletal-related event; BC, breast cancer; SCC, spinal cord compression; HCM, hypercalcemia of malignancy.
Adapted from Kohno N, et al. J Clin Oncol. 2005;23(15):

29. In favor of pamidronate In favor of zoledronic acid
Breast Cancer—Benefits of ZOL Are Beyond Those of PAM and Continue After the Onset of SREs:
ZOL reduced the risk of experiencing any SRE on study or after the first SRE by ~30% vs PAMa in a large, double-blind, phase III trial
Risk reduction
P value
All SREs (n = 766)
.015
0.711
29%
0.690
Excluding first SRE
31%
.045
Also in a large double blind phase III trial by Zheng, Zoledronic Acid was significantly associated with higher risk reduction of developing Skeletal related events by 30% when compared to Pamidronate. The most interesting finding is the continued benefit even after the occurrence of the first skeletal related event.
0.2
0.4
0.6
0.8 1
1.2
1.4
1.6
1.8 2
Relative risk
In favor of pamidronate
In favor of zoledronic acid
a As determined by Andersen-Gill multiple event analysis. ZOL, zoledronic acid (4 mg q 3-4 wks); PAM, pamidronate (90 mg q 3-4 wks); SRE, skeletal-related event.
Adapted from Zheng M, et al. Poster presented at: 9th International Conference on Primary Therapy of Early Breast Cancer; January 26-29, 2005; St. Gallen, Switzerland. Poster 104.

30. BPI Mean Change From Baseline
Zoledronic Acid Significantly Reduces Mean Composite Brief Pain Inventory (BPI) Score:
ZOL 4 mg q 4 wk
Placebo
Increased pain
*P < .05
BPI Mean Change From Baseline * *
Decreased pain * * * * * * * * * * *
Also Zoledronic acid consistently reduced Brief Pain Inventory scores from baseline when compared to placebo group throughout the same study. 2 2 2 4 8 12 16 20 24 28 32 36 40 44 48 52
Time on Study, Weeks
Patients continued to receive chemotherapy or standard treatment for breast cancer. IV, intravenous.
1. Lipton A, et al. Cancer. 2000;88(5): ; 2. Body J-J, et al. Ann Oncol. 2003;14(9): Reprinted from Kohno N, et al. J Clin Oncol. 2005;23(15):

31. ZOL Significantly Improves Most Quality-of-Life Measures in Patients With Bone Metastases From BC:* * * *
Again Zoledronic Acid Significantly Improves Most Quality-of-Life Measures in Breast Cancer Patients With Bone Metastases
Graph depicts overall mean change from baseline quality-of-life scores reported at final visit after 9 infusions. ZOL, zoledronic acid; BC, breast cancer; EORTC QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire.
*P < 0.05 compared with baseline values.
Reprinted from Wardley A, et al. Br J Cancer. 2005;92(10):

32. Adjuvant Zoledronic Acid in Breast Cancer.
Now it is the time to more focus on the anti-tumor effect of zoledronic acid and its role in the adjuvant sitting of breast cancer.

33. Cell viability (% control) after 4 days of treatment
Zoledronic Acid: An Anti-Tumor Potential:
Reduces the viability of human breast cancer cells in vitro1
zoledronic acid
pamidronate
clodronate
100
Cell viability (% control) after 4 days of treatment 50
Based on pre-clinical data, zoledronic acid was proved to be more powerful inhibitor of human breast cancer viability in vitro when compared to pamidronate or chlodronate. 1 10
100
1000
Bisphosphonate concentration (µM)
* These points have reached statistical significance.
1. Senaratne SG, et al. Br J Cancer

34. Ovarian Suppression Plus TAM or ANA +/- ZA: ABCSG-12 Trial Design:
Accrual
1,803 premenopausal breast cancer patients
Endocrine-responsive (ER and/or PR positive)
Stage I & II, <10 positive nodes
No chemotherapy except neoadjuvant
Treatment duration: 3 years
Tamoxifen
20 mg/d
Tamoxifen 20 mg/d +
Zoledronic acid 4 mg Q6Mos
Anastrozole 1 mg/d
Recently, high-profile results from the ABCSG 12 trial were published in the New England Journal of Medicine. This study accrued 1803 premenopausal patients who were all endocrine responsive and had a relatively good prognosis. Only 5% of patients had received neoadjuvant chemotherapy. Following treatment with goserelin, patients were randomized to tamoxifen alone, anastrozole alone, or either agent with zoledronic acid. This design provided the opportunity to compare the benefits of tamoxifen vs anastrozole, as well as the effects of zoledronic acid on both bone and disease‑related outcomes
Anastrozole 1 mg/d +
Zoledronic acid 4 mg Q6Mos
Surgery
(+RT)
Goserelin
3.6 mg Q28D
Randomize
1:1:1:1
Gnant M, et al. ASCO Abstract LBA4.

35. ABCSG-12: Zoledronic Acid Significantly Improves DFS vs Endocrine Therapy Alone:
Zoledronic acid vs no zoledronic acid 90
Death without prior recurrence 2
100 90 80 70 60 50 40 30 20 10 12 24 36 48 72 84 80
Secondary malignancy
ZOL 10
Contralateral breast cancer 70
No ZOL
Distant recurrence 10
Locoregional recurrence 60 50 9
Disease-free survival, %
First event per patient (n)
HR = 0.64
P = .01 6 40 41
Addition of Zoledronic Acid significantly improved disease free survival as compared to endocrinal therapy alone after a median follow up of 48 months. Moreover its use was associated with improvement in the rate of loco-regional, contra-lateral as well as distant recurrences, and hence supported the use of adjuvant zoledronic acid among premenopausal patients with endocrine responsive breast cancer.
Median follow-up = 48 mo 30 29 20 10 12 10
Time since randomization (mo)
No ZOL
ZOL
(n = 904)
(n = 899)
Gnant M, et al. N Engl J Med. 2009;360(7):

36. Z-FAST, ZO-FAST, EZO-FAST: Zoledronic Acid + Letrozole Adjuvant Synergy Trials:
Key endpoints
Primary: bone mineral density
Secondary: bone markers; fractures; and time to recurrence/relapse
Treatment duration 5 yrs
Patients with stage I-IIIa breast cancer, who are:
Postmenopausal or amenorrheic due to cancer treatment
ER+ and/or PgR+
T-score ≥ -2 SD
(N = 2195)
Letrozole +
Zoledronic acid 4 mg every 6 mos
Are there other data to support the adjuvant use of bisphosphonates in breast cancer? The suite of bone protection studies known as Z-FAST, ZO-FAST, and EZO-FAST randomized more than 2100 postmenopausal women with early breast cancer to either letrozole plus concurrent zoledronic acid to prevent bone loss or to letrozole followed by zoledronic acid delayed until development of a clinical fracture or a decline in the bone mineral density T score to less than -2 standard deviations.
Letrozole + delayed* zoledronic acid 4 mg every 6 mos
*Zoledronic acid started when 1 of the following occurs:
BMD T score < -2 SD, clinical fracture, or asymptomatic fracture at 36 mos

37. Risk of DFS events decreased by 41% at 36 mo Disease-Free Survival
ZO-FAST: Upfront Zoledronic Acid Significantly Decreased the Risk of DFS Events:
Risk of DFS events decreased by 41% at 36 mo
Disease-Free Survival
(n = 532)
Disease Recurrencea
Patients (n) 10 20 30 40 50
Delayed ZOL
Upfront ZOL
Lymph node
Distant
Local 3 5 2
100 80
Upfront ZOL
Delayed ZOL 60
HR = 0.588
P = .0314
DFS (%) 40
Where results favoured the use of upfront Zoledronic acid in terms of improving disease free survival at 36 months follow up as well as lowering the risk of disease recurrence.. 20 5 10 15 20 25 30 35
Time (mo)
aMultiple sites of metastases may be reported for the same patient. Sites of distant metastases include bone, brain, liver, lung, skin, and lymph node.
Adapted from Eidtmann H, et al . Presented at SABC Symposium, Dec 10-14, Abstract 44.

38. Safety Profiles of Adjuvant Zoledronic Acid + Endocrine Therapy:
Adjuvant ZOL in premenopausal and postmenopausal women
ZO-FAST / Z-FAST / E-ZO-FAST1 48 / 61 / 36 mo
ABCSG-122
48 mo
Patients, n (%)
Upfront + LET (n = 1079)
Delayed + LET (n = 1104)
+ TAM
(n = 449)
+ ANA
(n = 450)
Arthralgia
503 (47)
625 (57)
65 (15)
150 (33)
Myalgia
157 (15)
146 (13)
None reported
Pyrexia
129 (12)
34 (3)
34 (8)
46 (10)
Bone pain
162 (15)
104 (9)
132 (29)
185 (41)
Hot flashes
332 (31)
372 (34)
27 (6)
25 (6)
Renal adverse events (grade 3 or above)
4 (0.3)
3 (0.3)
0 (0)
Atrial fibrillation
2 (0.2)
6 (0.5)
ONJa
5 (0.4)
Addition of zoledronic acid to endocrine therapy was not associated with grave co-morbid events . Also osteo-necrosis of the jaw was reported only among 5 patients received upfront zoledronic acid in addition to Letrozole with negligible incidence among more than 3000 patients received the drug.
aOverall incidence of ONJ (osteonecrosis of the jaw) in the total population (N = 3082) = 0.16%.
1. Coleman R, et al. Presented at San Antonio Breast Cancer Symposium, Dec 13-16, Abstract 4082.
2. Gnant M, et al. N Engl J Med 2009;360(7):

39. ZOL Reduced Residual Cancer Burden in 3 Clinical Trials in Early Breast Cancer:
Rack et al.1 (N = 172) ZOL q 4 wk vs no ZOL for 6 mo
Aft et al.2 (N = 120) ZOL q 3 wk vs no ZOL for 1 yr (w/Chx)
Lin et al.3,4 (N = 45) ZOL q 4 wk (vs BL)
for 2 yr
ZOL  DTC clearance
ZOL keeps patients DTC-free
ZOL consistently  DTCs over time 30 80
P = .01 90
1 yr
P = .0018 25 70 80 70 60 20 60
3 mo 50
Patients with persisting DTCs, % 15 50
Residual BC cells may remain in the bone marrow after first-line therapy, and these cells are a potential source of recurrent disease
ZOL reduces the number of residual BC cells (termed disseminated tumor cells [DTCs]) and prolongs time without such cells especially when used for 2 years.
Patients with  DTCs, % 40
Patients with persisting DTCs, % 40 10 30 30 20 20 5 10 10
6 mo
DCT-free at BL
Overall
1 year
2 years
DTC = Disseminated tumor cells; BL = Baseline; ZOL = Zoledronic acid. 1. Rack BK, et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 511; 2. Aft R, et al. Presented at: ASCO Abstract 1021; 3. Lin A, et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 510; 4. Lin A, et al. Presented at: ASCO Abstract 559.

40. Adjusted Median RITS (mm) Patients achieving pCR (%)
Neoadjuvant AZURE: Exploratory Analysis of Residual Invasive Tumor Size (RITS) and pCR:
CT alone 50 30
CT + ZOL 45
 43% 25 40
P = 0.005 35 20
Adjusted Median RITS (mm) 30
 ~2 fold 25
Patients achieving pCR (%) 15 20 10
Also, adding zoledronic acid to neoadjuvant chemotherapy is associated with significant lowering of the residual invasive tumor size as well as improvement in the attained rate of pathological CR. The neoadjuvant AZURE trial. published this year in the British Journal of Cancer. 15
27.4 10
15.5
11.7 5 5
6.9 CT
CT + ZOL CT
CT + ZOL
Multivariate analysis N = RITS, residual invasive tumor size; CT, chemotherapy; ZOL, zoledronic acid; pCR, pathologic complete response
Coleman R, et al. British Journal of Cancer; 2010: March (e-pub: doi: /sj.bjc )

41. Zoledronic Acid Dosing Rationale in Breast Cancer:
ADJUVANT
Early Late
METASTATIC
Description
Early stage (BC I–III) ABCSG-12 trial1 E/Z/ZO-FAST trials2
Later stage (BC II/III) AZURE trial3
Metastatic BC Trial 010, 15014,5
Tumor burden
Low
Moderate
Very high
Key clinical issue with skeleton
Potential site for harboring tumor cells and seeding metastatic disease
Ongoing, active destruction of skeletal integrity through tumor cell–mediated, osteoclast bone resorption
Treatment goal with zoledronic acid
Prevent metastases, improve DFS / RFS
Stop cycle of bone destruction. Significantly reduce the risk of skeletal-related events
Dose ZOL needed
4 mg IV q6mo
4 mg IV up 8x/yr
4 mg IV q3–4wk
And hereby the final situation of using zoledronic acid in patients with breast cancer, and as we can see it is clearly indicated in patients with metastatic disease and heavy tumor burden aiming at stopping the cycle of bone destruction where it will be administered at a dose of 4 mg every 3-4 weeks with careful eye upon renal functions as well as jaw status. Adjuvant therapy is clearly indicated as 4 mg every 6 months for 2 years in early cases with low tumor burden as indicated by ABCSG 12 trial while a higher administration schedule in patients with stage II-III is now explored in AZURE trial and both are aimining at prevention of metastases as well as improvement in Disease and relapse free survival.
1. Gnant M, et al. Presented at ASCO, May 30-Jun 3, Abstract LBA4. 4. Rosen LS, et al. Cancer J. 2001;7(5):
2. Brufsky A, et al. Oncologist. 2008;13(5): Kohno N, et al. J Clin Oncol. 2005;23(15):
3. Coleman R, et al. Eur J Cancer Suppl. 2007;5(4). Abstract 0-48.

42. Keep in Mind:
Immediate use of zoledronic acid (4 mg IV q6mo) prevents bone loss in women with early stage BC receiving adjuvant letrozole
Disease free survival was significantly improved with the use of zoledronic acid upfront
The safety results were as expected and consistent with the known safety profiles of the drug.
The growing body of evidence of zoledronic acid anti-tumor effect.
At the end of the day

43. Thank You