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					     Antitumor Effects of
Bisphosphonates and Potential
Prevention of Bone Metastases
           Luis Costa, MD, PhD
           Professor of Medicine
            University of Lisbon
        Director, Oncology Division
         Hospital de Santa Maria
             Lisbon, Portugal
 BPs Decrease the Viability of Breast Cancer Cells
 and Interact Synergistically With Cytostatic Drugs
                    Cell viability 1                                                 Apoptotic cells 2
                    (% control)                                                       (% control)
                                                                    800
100                                     Clodronate
                                                                                   Control
                                                                                   Zoledronic acid
                           Pamidronate                                             Paclitaxel
                                                                                   Zol + paclitaxel
                                                                    400
50
      Zoledronic
            acid


  0                                                                    0
      1        10       100       1000                                            Ctl         Zol    Pac     Zol
                                                                                             10 µM   2 nM   + Pac
       Bisphosphonate concentration (µM)


1. Senaratne et al. Br J Cancer. 2000;82:1459; 2. Jagdev et al. Br J Cancer. 2001;84:1126.
                                                                                                                    2
 In vitro Antitumor Activity of the
 Nitrogen Bisphosphonates
  Inhibition of cancer cell adhesion to extracellular matrix proteins1,2
  Inhibition of cancer cell proliferation and induction of apoptosis3
  Inhibition of cancer cell migration and invasion4
  Inhibition of angiogenesis5,6




1. Pluijm et al. J Clin Invest. 1996;98:698; 2. Boissier et al. Cancer Res. 1997;57:3890; 3. Shipman et al. Br J Haematol.
1997;98:665; 4. Boissier et al. Cancer Res. 2000;60:2949; 5. Fournier et al. Cancer Res. 2002;62:261; 6. Wood et al.
J Pharmacol Exp Ther. 2002;302:1055.
                                                                                                                             3
 Molecular Mechanisms of Action of
 Nitrogen-Containing Bisphosphonates
                         HMG-CoA
                                                                      NBPs inhibits FPP
                                                                      synthase, thus blocking
                        Mevalonate                                    the prenylation of small
                                                                      signaling proteins
              Geranylpyrophosphate + IPP                              required for cell function
                                                                      and survival
                            X        FPP
                                   synthase


              Farnesyl diphosphate (FPP)                           Ras     S


                                    GGPP
                                   synthase

         Geranylgeranyl diphosphate (GGPP)                         Rho      S
Kavanagh et al. PNAS, 2006; Rondeau et al. Chem Med Chem. 2006; Kavanagh et al. JBC. 2006.
                                                                                                   4
Zoledronic Acid Inhibits Invasion of MDA-MB-231
Human Breast Cancer Cells Through Matrigel
In Vitro
                              100                                                 Cell invasion (%)
                                                                            100                             Control
% Cell invasion (% control)




                              80
                                                               *P<0.05                                      ZOL alone
                                                               †P<0.01       80
                                                                                                            ZOL + MVA
                              60                           *                                                ZOL + GGOH
                                                                †            60              †
                                                                                        †

                              40                                      †      40

                              20
                                                                             20

                               0
                                                                              0
                                        0     0.01 0.1     1    10   100
                                            ZOL concentration, µM                      Rho Western blot
                                                                                                            ZOL (1 µM)
                                                                                   Control   ZOL (1 µM)
                                                                                                             + GGOH
Rho                                 S
                                                                           Rho

                                                                                  Mem Cyto       Mem Cyto   Mem Cyto
Denoyelle et al. Br J Cancer. 2003;88:1631.                                                                            5
          Sequential Treatment of Human Cancer Cells
          With Doxorubicin and Zoledronic Acid Enhances
          Apoptosis
                50 nM Dox 24h, wash, 25 µM Zol 1h,                      50 nM Dox 24h, wash, 1 µM Zol 1h,
                wash, 48h fresh medium alone                            wash, 48h fresh medium alone

                15         MCF-7 breast                    20     PC-3 prostate        *     10     3T3 fibroblast

                                                *
Apoptosis (%)




                10

                                                           10                                 5

                 5




                 0                                         0                                 0    Ctl   Dox   Zol   Dox
                     Ctl     Dox   Zol   Dox   Dox   Zol          Ctl     Dox   Zol   Dox
                                          +    then then                              then                          then
                                         Zol    Zol Dox                                Zol                           Zol
                                                                * P = 0.004
       Neville-Webbe et al. Int J Cancer. 2005;113:364.                                                               6
 Zoledronic Acid Inhibits the Progression of
 Breast Cancer Osteolytic Lesions in Animals
             D0                                     D18              D30
                                                               ZOL




                                                                           Zoledronic acid

                                                     Vehicle




                                                                           Zoledronic acid

                                                     Vehicle
Peyruchaud et al. J Bone Miner Res. 2001;16:2027.
                                                                                             7
 Zoledronic Acid Reduces Bone, Liver and
 Lung Metastases in the Murine 4T1/luc
 Orthotopic Breast Cancer Model
   Bone mets.              Lung metastases                Lung metastases                    Liver mets.
  (mm2 histo.)                                        (% area histo.) (% luc)                  (% luc)
                        Control
0.6                                                 15                            150    150
                              *                *

0.4                                                 10                            100    100
                         *
                        Zol
                                                                             *
                                                               *
0.2                                                   5                           50         50
                *             *                *
                                                                                                      *
  0                                                   0                           0           0
         C      Z                                         C    Z      C      Z                    C    Z
                                        Zoledronic acid, 250 µg/kg,
                Control                                                   * P<0.05, n = 10
                                        1x every 4 days, day 7-22

Hiraga et al. Clin Cancer Res. 2004;10:4559.
                                                                                                           8
Zoledronic Acid Preclinical Studies:
Conclusions and Ongoing Research
 Zoledronic acid exhibits anti-tumor properties in preclinical
  models, not only in bone but also in soft tissue
 Anti-tumor efficacy is dependent on dosing regimen and can
  be enhanced by prior chemotherapy
 Ongoing investigations
 Synergy with cytostatic drugs, optimize dosing regimen for
  anti-tumor activity in vivo
 Anti-angiogenic mechanism in soft tissue tumors
 Immuno-modulatory and anti-tumor effects in vivo
 Synergy with radiotherapy/radiosensitization
                                                                  9
    Looking to the Future:
Prevention of Bone Metastases




                                10
 Steps Involved in Tumor Cell
 Metastasis From Primary Site to Bone
    Primary malignant neoplasm         New vessel formation         Invasion          Embolism




                                                                                     Multi-cell aggregates
                                                                                     (lymphocytes, platelets)

                                                                                      Arrest in distant
  Bone metastases                                                                     capillary bed in bone


                                                          Extravasation        Adherence

                  Tumor-cell         Response to
                 proliferation     microenvironment




                                                                                     Endothelial
                                                                                     cell


Mundy GR, et al. Nature Reviews Cancer. 2002;2:584-593.
                                                                                                                11
Who Is at Risk for Bone
     Metastasis?




                          12
 Prediction of Bone Metastases in
 Breast Cancer
   Clinico-pathologic criteria1
   ER+ status1
   Bone sialoprotein expression (BSP+)2
   Genetic profiling3
         – 69 genes differentially expressed between patients with
           or without bone metastases
         – 31-gene classifier was developed as potential predictive
           tool


1. Coleman RE, et al. Br J Cancer. 1987;55:61-66; 2. Bellahcene A, et al. Int J Cancer. 1996;69:350-353;
3. Smid M, et al. J Clin Oncol. 2006;24:2261-2267.
                                                                                                           13
Clinical Evidence for Bone Metastases
     Prevention in Breast Cancer
        Adjuvant Clodronate Trials and
         Pilot Zoledronic Acid Trials




                                         14
 Adjuvant Clodronate Trials in Breast
 Cancer: Conflicting Results
  Encouraging results in two 2-year trials
   (N = 1,371)1-3
       – Delay in bone metastases
       – Increased DFS in 1 trial
       – Increased OS in both trials

  No treatment effect in a third trial (N = 299)4
       – No significant skeletal effect
       – No effect on DFS or OS




DFS = Disease-free survival; OS = Overall survival.
1. Diel et al. N Engl J Med. 1998;339:357; 2. Diel et al. Proc Am Soc Clin Oncol. 2000;19:82a. Abstract 314; 3. Powles et al.
Breast Cancer Res. 2006;8:R13; 4. Saarto et al. Acta Oncol. 2004;43:650.
                                                                                                                                15
 Zoledronic Acid Significantly Prolonged Bone
 Metastasis-Free Survival in Patients With
 Solid Tumors*
                              Bone metastasis-free interval (18-month analysis)
                              1.2

                                                    Zoledronic acid (4 mg/month, IV)
      Cumulative percentage




                              1.0
                                                           YES
                                                           NO
                              0.8
                                                                                        Median        Patients, n

                              0.6                          Zoledronic acid             12 months          20

                                                           Standard treatment          6 months           20
                              0.4                          Log-rank P<0.0005
                                                                                       * Tumor Type        n

                              0.2                                                      BREAST             16
                                                                                       LUNG                9
                                                                                       CERVICAL            3
                               0                                                       PROSTATE            5
                                                                                       COLORECTAL          2
                                    0   10     20     30         40     50             MELANOMA 2
                                             Time, months                              BLADDER             2
                                                                                       RENAL               1

Adapted from Mystakidou et al. Med Oncol. 2005;22:195.
                                                                                                                16
 Zoledronic Acid Eliminated Residual Isolated
 Breast Cancer Cells in the Bone Marrow
  STUDY 11
  31 patients received ZOL q 4 weeks for 6 months
       – 4 (13%) had persisting tumor cells

  Compared with 141 patients who did not receive ZOL
       – 38 (27%) patients had persisting tumor cells

  STUDY 22
  45 patients received zoledronic acid q 4 weeks for 2 years2
       – At 1 year, in 32 evaluable patients, mean OTC had decreased from
         25.4 to 8 OTC/mL (P=0.02)


OTC = occult tumor cell.
1. Rack et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 511;
2. Lin et al. Breast Cancer Res Treat. 2007;106:S40. Abstract 510.
                                                                            17
  Z- FAST: Zometa-Femara Adjuvant
  Synergy Trials
   Key end points
         – BMD; bone markers; fractures; and time to recurrence/relapse




                 2,193 patients                                               Letrozole +
                 BC stage I - IIIa                                  zoledronic acid 4 mg q 6 months
               • Postmenopausal or
                 amenorrheic due to                   R        Letrozole                    Delayed zoledronic acid
                 cancer treatment                                                           If 1 of the following occurs:
               • ER+ and/or PR+                                                             • BMD T score < –2 SD
               • T-score ≥ –2 SD                                                            • Clinical fracture
                                                                                            • Asymptomatic fracture at 36 mo

                                                                            Treatment duration 5 years

BMD = Bone mineral density; BC = Breast cancer; ER = Estrogen receptor; PR = Progesterone receptor; SD = Standard deviation;
CT = Chemotherapy.                                                                                                             18
                                                        Z-FAST: Upfront Zoledronic Acid
                                                        (4 mg q 6 months) - Disease Recurrence
AIBL Clarification mtg-may23-backups.finalV1.ppt S81




                                                                                                            Patients, n (%)

                                                                   Month                 Upfront group                       Delayed group           P value
                                                                     121                        1 (0.3)                            6 (2.0)   Δ 1.7   0.056

                                                                     242                        7 (2.3)                           12 (4.0)   Δ 1.7    0.21

                                                                     363                        9 (3.0)                           14 (5.3)   Δ 2.3    0.24




                                                       1. Brufsky et al. J Clin Oncol. 2007;25:829.
                                                       2. Brufsky et al. Breast Cancer Res Treat. 2006;100(suppl 1):S233. Abstract 5060.
                                                       3. Brufsky et al. Breast Cancer Res Treat. 2007;106(suppl 1):S8. Abstract 27.
                                                                                                                                                               19
Ongoing Bone Metastasis
  Prevention Studies




                          20
 Breast Cancer: ABCSG-12
Key End points:
Primary: Disease-free survival (DFS) at 5 y (TAM vs ANA, ZOL vs no-ZOL)
Secondary: Relapse-free survival (RFS) at 5y, OS at 3y (TAM vs ANA, ZOL vs no-ZOL)

                                         *All 4 arms treated with Goserelin
                   1,800 patients
                                                                              Long term
                   BC stage II/III            Tamoxifen 20 mg/day             monitorin
            Stratification:                                                       g
                                             Anastrozole 1 mg/day
            •BC Stage I/II
            •ER+ and/or PR+              R   TAM + ZOL 4 mg q 6 mo
                                                                              5 years for
                                                                              recurrence
            •Completely resected tumor                                            and
            •Premenopausal                   ANA + ZOL 4 mg q 6 mo              survival
            •< 10 axillary lymph nodes                                         (DFS, OS)
            affected

                                                 Treatment 3y



TAM = tamoxifen, ANA = anastrozole.                                                         21
 AZURE: Does Adjuvant Zoledronic Acid
 RedUce REcurrence in Breast Cancer?
Primary end point: Disease free survival
Secondary endpoints: Bone metastases free survival, SREs, overall survival, adverse
events, predictive biomarkers
First interim analysis expected 2008

                3,360 patients
                BC stage II/III                          Standard Therapy
            Stratification:                                                          Follow-up
                                                                                      without
            • N+/N-                                      Standard Therapy           treatment:
            • T Stage                         R                                     5 years for
            • ER Status
                                                       Zoledronic acid 4 mg         recurrence
                                                         6 doses (q 3-4 wk)             and
            • Chemotherapy type
                                                        8 doses (q 3 months)          survival
            • Pre-/ Postmenopausal
                                                        5 doses (q 6 months)
            • Statins
                                                       Treatment duration 5 years
SREs = Skeletal-related events; BC = Breast cancer; ER = Estrogen receptor.
PI: Rob Coleman
Accrual completed February 2006
                                                                                                  22
 NSABP-B-34/CTSU: Phase III Study of
 Adjuvant Clodronate in Breast Cancer
Primary end point: Disease-free survival
Secondary end points: Incidence of metastases, overall survival, SREs,adverse events
and prognostic serum markers




                                                              Clodronate
               3,400 patients
            Breast cancer stage                               1,600 mg qd
                                                  R
                   I/II/III
          • Receiving adjuvant CT                                Placebo

                                                         Treatment duration 3 years



SREs = Skeletal-related events; CT = Standard therapy.
Accrual completed 2005
Results expected 2009
                                                                                       23
 S0307/Intergroup/NSABP: Phase III Study of
 Adjuvant Bisphosphonates in Breast Cancer
Primary end point: Disease Free Survival
Secondary end points: overall survival, distribution of sites of first recurrence, adverse
events, and predictors of bone metastases




             4500 patients                         IV zoledronic acid 4 mg q month × 6,
        Breast cancer stage I - III                          then q 3 months              Follow
            • Nonmetastatic disease                                                        -up:
            • Receiving adjuvant CT
                                             R           Oral clodronate 1,600 mg/day        3
                                                                                          years
                                                         Oral ibandronate 50 mg/day


                                                        Treatment duration 3 years


DFS = Disease-free survival; CT = Standard therapy; IV = Intravenous.
Current accrual 900+.
                                                                                                   24
 SUCCESS
 Simultaneous Study of Gemcitabine-Docetaxel Combination
 Adjuvant Treatment, as well as Extended Bisphosphonate and
 Surveillance-Trial
Primary end point: Disease-free survival
Secondary end points: Overall survival, distant disease-free survival, QOL, SREs, safety,
and predictive and prognostic value of minimal residual disease surveillance




           3,754 patients
           Breast cancer                      3 cycles FEC;                    Zoledronic acid 4 mg
                                              3 cycles DOC                    Year 1-2; every 3 months
       • pT1-4, pM0 and                                                       Year 3-5; every 6 months
       • pN1-3 or high-risk pN0/NX    R                               R
         (pT ≥ 2, grade 3
         histopath., ≤ 35 years, or          3 cycles FEC;                   Zoledronic acid
                                                                              4 mg every 3
         ER–)                             3 cycles DOC + Gem                     months

                                          Sequential chemotherapy             2 years vs 5 years
                                                                           Tamoxifen       Anastrozole


QOL = Quality of life; SREs = Skeletal-related events; ER = Estrogen receptor; Accrual completed
FEC = 5-Fluorouracil, Epirubicin, Cyclophosphamide; DOC = Docetaxel; Gem = Gemcitabine.
                                                                                                         25
Breast Cancer Bone Metastasis
Prevention Studies: Conclusions
 Clodronate (adjuvant) and zoledronic acid delayed bone
  metastases in clinical studies
 Z-FAST: non-significant decrease in recurrences at 36
  months
 Several large trials are currently evaluating adjuvant
  bisphosphonates for prevention of recurrences




                                                           26

				
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