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'Arimidex' _anastrozole_ The Ideal Profile for an Aromatase Inhibitor

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'Arimidex' _anastrozole_ The Ideal Profile for an Aromatase Inhibitor Powered By Docstoc
					           Ongoing
  Clinical Research & Trials
Multidisciplinary Breast Centre


            P. Neven
  GYN ONCOL & MBC, UZ-KULeuven


                            May 2007
              Ten most frequently occuring tumours in Flanders, 2000 - 2001




Source: Vlaams Kankerregistratienetwerk, VLK
    Age-specific incidence of breast cancer in
                      women,
              Flanders, 1997-2001




Source: Vlaams Kankerregistratienetwerk, VLK
                                               SABCS 2006 2003: A decrease in breast cancer incidence
May be the incidence will come down?
    I. Ongoing
   Clinical Trials

   II. Ongoing
MBC Research Projects

                        May 2007
            I. Clinical Trials

        Prevention, Adjuvant, Metastatic

       Completed, Recruiting, Future Trials
Endocrine Therapy, Chemotherapy, Targeted Therapy


                                         May 2007
              Recently Closed
               Clinical Trials
Adjuvant:        BIG-1-98, TEAM, (E-)ZOFAST
                 TACT, FEC-TXT (dd), Caelyx-Endoxan
                 HERA, AC-AT,

Metastatic:      Lapatinib trials, Tam + Iressa,
                 EFECT, Lapatinib + Zarnestra, …

Radiotherapy:    MSP-trial

                                             May 2007
           Recruiting Clinical Trials
     Prevention:    IBIS-2 DCIS/High Risk

     Neo- Adjuvant: Taxotere-Xeloda-Herceptin

     Adjuvant:      SOFT, TEXT, TAGAS,
                    Pregnancy (pharmacokinetics & outcome)

     Metastatic:    MoAb IGF-1R, FINDER-2,
                    Vinflunin, Oral Navelbine,
                    Xeloda +/- Sutent, BIBW, HKI
May 2007            Eye trial   (Maxidex vs Lacrystat Taxotere related dacrocystostenosis)
        Future Clinical Trials
Neo- Adjuvant: Neo-Allto
              Neoadjuvant Paclitaxel + Herceptin +/- Pertuzumab


Adjuvant:     Fertility trial, SOLE, ALTTO
              MINDACT,
              CASA

Metastatic:   Lapatanib +/- Pazopanib



                                                     May 2007
Recruiting Clinical Trials

    IBIS-2   DCIS (tamoxifen standard)
             High Risk (placebo standard)
                            Aromatase Inhibitors
 Why IBIS-II?
 Prevention                  versus Tamoxifen
                 Incidence of Contralateral Breast Cancers
Number of
  cases

                ATAC                IES              MA17                 BIG 1-98
50
40
30                 48

20
        21                                26                    26                    28
10                                                                         16
                               12                    14
 0
            A       T           E          T          L          T         L           T
      (n=3125)   (n=3116)    (n=2352)   (n=2372)   (n=2582)   (n=2575)   (n=4003)   (n=4007)
                              Ongoing
                           Clinical Trials
                       Breast Cancer Prevention
                        Postmenopausal Women

             IBIS-2: 20 countries recruiting
Prevention: Placebo vs Anastrozole 36/1516
ER+ DCIS: Tamoxifen vs Anastrozole 63/1014
Lateage 1st pregnancy, parity, age menopause, breast density, familial history, LCIS, ADH
Subprotocol: Bone, Lipid, Cognitive function

                                                                               May 2007
                       IBIS-2
                 Recruiting Centres
   St.Luc Brussel
   St.Pierre Brussel
   VUB Brussel
   Virga Jesse Hasselt               If you have small cell LCIS,
   St.Elisabeth Namen                NSABP-P1 included 850 such patients
   St.Augustinus Wilrijk             7-years of follow-up
   Erasmus Brussel                   Tamoxifen versus Placebo
   Bordet Brussel                    Events13 (Tam) vs 38 (Placebo)
   Heilig Hart Leuven                If placebo: incidence of event is 1-2%
   OLVrouwZH Aalst
   ZOL Genk
   Clinique St.Pierre Ottignies
   CHR Citadelle Luik
   Brugmann Brussel
   Centre Hospitalier de l’Ardenne
 Recruiting Clinical Trials

        FINDER-II

2nd line Metastatic Endocrine
          First Line: TTP Benefit of Fulvestrant over Tamoifen
                        in ER+ & PgR+ Patients*

    Proportion 1.0                        Median TTP:       Fulvestrant: 11.4 months
    not                                                     Tamoxifen: 8.5 months
    progressed                            Hazard ratio = 0.85 CI (0.63–1.15); p=0.31
               0.8

                                                                                    Fulvestrant
                   0.6
                                                                                    Tamoxifen

                   0.4


                   0.2


                   0.0
                         0    100   200      300      400       500      600        700        800
ORR
F 44.3% vs T 29.8%; p=0.02                         TTP (days)

    *Retrospective analysis                                             Howell et al. JCO 2004; 22: 1605-13
   Fulvestrant 250 mg/month Provides
 Long-term Downregulation of ER Levels
                                           p=0.001
Mean    30               p=0.01
ER       0
H-      25
score    0
        20
         0
        15
         0
        10
         0
        50

        0
                Pre-                4-6                6              PD
             treatment            weeks              months          (n=8)
               (n=29)             (n=26)             (n=20)

                                    Time on treatment
                                                          Gutteridge et al. SABCS 2004
   Fulvestrant induces dose-related ER downregulation
                     (PgR and Ki67)*
Change           0
from
baseline    -10
(%)                   –13%
            -20

            -30

            -40
                                  –39%
            -50
                                                       –50%
            -60
                                                                          –59%
                     Placebo    Fulvestrant         Fulvestrant        Fulvestrant
                      (n=29)   50 mg (n=31)        125 mg (n=32)      250 mg (n=32)
 Pre-treatment
 mean H-score         125          136                  124                 113


*Data not shown                               Robertson et al. Cancer Res 2001; 61: 6739–6746
                                 Finder-II
                                                                                Endpoints
     135 postmenopausal women with HR+ ABC
                                                                                 TTP (primary)
     after failure on one prior endocrine therapy
                                                                                 ORR
                           Randomisation 1:1
                                                                                 CB
                                                                                 Safety

Fulvestrant AD                                       Fulvestrant HD
                         Fulvestrant LD
                                                                3-monthly
                                                                follow-up
                             Progression

HD, high-dose (500 mg IM on Day 0, 500 mg on Days 14 and 28 and 500 mg every 28 3 days thereafter)
LD, high-dose (500 mg IM on Day 0, 250 mg on Days 14 and 28 and every 28 3 days thereafter)
AD, approved dose (250 mg IM every 28 3 days)
                    Finder II Overview of Eligibility
                   (2nd line Breast Cancer Treatment)
Patients who previously received adjuvant treatment
  EBC                                  ABC                 Eligible?
                                12 Month                               KEY
                 R                 gap
                                                            Yes
                                                                       Adjuvant Treatment
                                   R
                                                            Yes
                                                                       Eligible (randomised into
                                                                       study)
                                           R
                                                            No
                                                                       Not Eligible
                                           R          P
                                                            Yes
                                                                       First Line Treatment

 Patients who were diagnosed with Advanced Breast Cancer
                                                                       R = Recurrence
                                                                       P = Progression
                                                      P      Yes

 Regulatory Definition of 2nd line Breast Cancer
Current & Future Clinical Trials
    Targeted Therapies
           ALTTO

           Adjuvant
                      Two Targets, One Drug
                        Lapatinib Profile

Lapatinib is a novel oral dual-tyrosine                                                  Cl
kinase inhibitor with specificity for                                                            O
the ErbB-1 and
ErbB-2 receptors                                                                HN
                                                N            O                       N                  F
  Belongs to the 4-                            H
                                                                                                 O
    anilinoquinazoline class of               S O                                N               S OH
                                             O CH
    tyrosine kinase inhibitors                    3
                                                                            2
                                                                                                 O
                                                                                H3C
  Binds reversibly to the
    cytoplasmic ATP-binding site of                                 GW572016
                                                                    Lapatinib
    the kinase, thereby preventing
    receptor phosphorylation and          N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-
                                          [5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-
    activation                            4-quinazolinamine
                    ALTTO STUDY DESIGN

   Four-arm, randomised, open-label and multicentre study in women
    with primary breast cancer that over expresses or amplifies HER2.
   Sample Size 8000 patients
   Primary Endpoint: DFS
   Secondary Endpoints
      OS

      TTR (time to recurrence)

      TTDR (Time to distant recurrence)

      Safety and tolerability

   Proposed start 2Q07
   Study duration: 5 years (4 years for enrolment and 1 year as follow-
    up)
      2 Interim analyses (at 600 and 1000 DFS events, approximately)
                   ALTTO STUDY DESIGN

   4 Arms:
       Trastuzumab for 52 wks
       Lapatinib for 52 wks
       Trastuzumab + Lapatinib for 52 wks
       Trastuzumab for 12 wks, 6 wk washout, Lapatinib for
        34 wks

   Treatment Schema 1 - all (neo-)adjuvant chemotherapy completed
    prior to administering targeted therapy

   Treatment Schema 2 - targeted therapy is initiated after
    (neo)adjuvant anthracycline-based chemotherapy and given
    concurrently with weekly paclitaxel
                                                                                     52 Weeks

         Local            R                                                 Trastuzumab 3- weekly
      Determined
        HER 2             A                                                   8mg/kg then 6mg/kg
                                                                          (+ radiotherapy when indicated)
       positive
                          N
B                         D
                                                                             Lapatinib 1500 mg/day
A      Central            O                                               (+ radiotherapy when indicated)
      Determined
S       HER 2             M
E      positive           IS
LI                         A                      Trastuzumab 4mg/kg
                                                                                     6 weeks
                                                                                                       Lapatinib 1500
                                                 then 2mg/kg weekly for                               mg/day for 34 wks
N      Surgery,           TI                             12 wks
                                                                                     Washout
       complete                                   (+ radiotherapy when indicated)
E    Neo-adjuvant         O
     Chemotherapy         N
                                                                               Lapatinib 1000
                                                                            mg/day + Trastuzumab
                                                                                 3- weekly
      LVEF  50%                                                             8mg/kg then 6mg/kg
                                                                         (+ radiotherapy when indicated)


       Patients with ER or PgR-positive tumours receive endocrine therapy selected according to menopausal status:
     endocrine therapy will be started after the end of the chemotherapy, will be administered concurrently with targeted
                                       therapies and will be planned for at least 5 years
                             NEO - ALTTO STUDY DESIGN
                                 (T>2 cm, Nx, M0, FISH +, IHC 3+)
Lapatinib (L)         L 1500 mg/day
1500 mg/day                   +
                paclitaxel 80 mg/m2 weekly                                             L 1500 mg/day




                                                              FEC x 3 courses
Trastuzumab
     (T)               T 2 mg/kg weekly
4 mg/kg, then                   +                                               T 6 mg/kg at 3 week intervals




                                                  Surgery
   2 mg/kg        paclitaxel 80 mg/m2 weekly
   weekly




L 1000 mg/day           L 1000 mg/day
      +                         +
  T 4 mg/kg,           T 2 mg/kg weekly
                                                                                       L 1000 mg/day
  then 2 mg/                    +                                                             +
  kg weekly       paclitaxel 80 mg/m2 weekly                                    T 6 mg/kg at 3 week intervals




 6 weeks              12 weeks                    9 weeks                          34 weeks

                                               Tumor biopsy
Tumor biopsy
PET
        New drugs for targetting HER-1 / HER-2 / …
         Dual-Target HER-1 Drugs in the Pipeline

   Lapatinib    HER-1, HER-2          GSK          Phase III breast
   HKI-272      HER-1, HER-2          Wyeth        Phase II breast
   BIBW-2992    HER-1, HER-2          Boehringer   Phase II breast
   AEE788       HER-1, HER-2, VEGF    Novartis     Solid tumours
   BMS-599626   HER-1, HER-2          BMS          Solid Tumours
   CI-1033      HER-1, HER-2, HER-4   Pfizer       Phase II breast
   …

                  Metastatic
       Recruiting Clinical Trials
Targetted Therapies

      Exemestane +/-IGF-1R

      1st Line Metastatic Endocrine
       IGF and its receptor
Important mediators of cell growth
     Combining Endocrine and Biological Agents in M+ Breast Cancer

   Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer

                                               IGF
                                 IGF regulates the malignant phenotype
                                 IGF is a strong breast cancer mitogen
                                 There is cross talk between ER and IGF signalling
                                            Non-genomic or genomic ER
                                 IGF is a regulator of estrogen-mediated growth
                                 IGF induces proliferation of ER+ breast cancer cells
                                 Upregulation in tamoxifen-resistant breast cancer cells
   Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer


                           IGF-1R
                       IGFR is Tyrosine Kinase type 1 receptor
                       Small molecules and MoAb
                       Monoclonal AB
   Oestrogen Receptor- Mediated
Signalling Pathways in Breast Cancer
 Exemestane + MoAb/IGF-1R vs Exemestane
                                                              Pfizer
    ER+ FirstLine Measurable Metastatic
    Randomized (1:1) and Open Label
    150 patients
                   CP 751,871 // 20mg/kg // q3w
    PFS            Arm A Exemestane 2.5mg + CP     Fulvestrant + CP q4w
                   Arm B Exemestane 2.5mg          CP
    CB,
    Safety,
    PK parameters,
    CTC markers for expression of IGF-1R,
    HRQoL
II. Own Clin. And Basic Research
Recently Published …(leaving out clin. trials)
 Prophylactic mastectomy and subclinical breast pathologies
 HER-2 expression by body weight
 Arthralgia and AIs
 The prognostic value of PR in breast cancer
 LHRH-agonists to protect ovarian function in ER-pos BrCa
 The continuous importance of tamoxifen as an adjuvant therapy
 Endometrial thickness on AI-switch
 MMP in breast cancer
 Associations between ER/ PR/ HER2 expression in operable BrCa

                                                         May 2007
                   Ongoing         May 2007

          Clinical & Basic Research
 Early relapse by ER/ PR/ HER2 expression: “Improving NPI”
 HER-1 / uPAR in triple negative and other breast cancers
 PET-CT in staging large and locally advanced breast cancer
 Correlations LN-status - ER/PR/HER-2, LN-status - age
 Correlations Age - ER/PR/HER-2 expression
 Retrospective and prospective registration study: Breast cancers & Mirena
 Postmenopausal breast cancer characteristics by use of HRT
 Paloprai, ER-PR+ breast cancers, Fulvestrant and uterine volume
Molecular genetic analysis as an addition to the morphologic classification of breast cancers
The clinical relevance of protease in breast cancer: matrix metalloproteinasen and cathepsines
Menopausal symptoms of breast cancer therapies
Proteonomics in breast cancer
Genetics in breast and ovarian cancer
                                                        PhD topics
                         Breast Cancer Prognosis

                         Global molecular genetic approach
                  ER -                             ER +




                         ?
basal-like   HER-2 +                  luminal type (subtype A, B/C)
DFS in 1962 operable breast cancers
Subgroup Analysis by ER/PR/HER-2


                                                    subgroup



                       Mean NNN           NNP       PNN      PNP       PPN      PPP        All
   Numbers
                                    173       91       191       31     1361       115     1962
   Age at diagnosis
                                  55,65    56,37     60,53    58,68     57,72    51,70    57,41
   NPI
                                   4,95      5,04     4,33     4,61      4,11     4,98     4,30
   DFS at 3.5 yrs of FU (%)
                                  84.40    75.81     89,49    80,42     93,76    81,47    90,16



                        Thesis Lic Biomed. Sc. (S. Pintens) and Project Co-Assist. (O. Brouckaert)
                         Early breast cancer relapse
                          by ER/PR/HER-2 – n=1962
O Brouckaert & S Pintens DFS by ER/PR/HER-2




                                                 UZ Leuven 2000 - 2005
Annual incidence of relapse
   NNN Early relapse
Can we improve NPI?
            Subgroup                DFS (%)
            NPI <3,4                 96,18
            NPI 3,4-5,4              91,81
            NPI > 5,4                80,69
            NPI <3.4       HER-2-    96,45
            NPI <3,4       HER-2+    90,62
            NPI 3,4- 5,4   HER-2-    93,24
            NPI 3.4- 5,4   HER-2+    82,84
            NPI > 5,4      HER-2-    83,37
            NPI > 5,4      HER-2+    68,08
The futureCyclin E as a prognostic factor

       Stage I-II breast cancer: Total cyclin E predicts Survival
                             Interaction ER-status and age by HER-2 status
ER/PR and HER-2


                  1.0                                                                          1.0

                  0.9                                                                          0.9
                                                                                                                                  HER-2 negative
                  0.8                                                                          0.8

                  0.7                                                                          0.7




                                                                             ER+ Probability
ER+ Probability




                  0.6                                                                          0.6

                  0.5                                                                          0.5
                                                                                                                                      HER-2 positive
                  0.4                                                                          0.4

                  0.3                                                                          0.3

                  0.2                                                                          0.2

                  0.1                                                                          0.1
                                                                                                          HER-2 status        Negative (N = 1971)
                                             N = 2227                                                                           Positive (N = 256)
                  0.0                                                                          0.0
                        20    30   40   50   60     70   80   90   100                               20   30   40   50   60      70      80    90    100

                                        Age (years)                                                                 Age (years)


                                                  The interaction between ER and age is HER-2 dependent
                                                  The negative association between ER and HER-2 is age dependent
                          Interaction PR-status and age by HER-2 status
ER/PR and HER-2




                                                                                                  1.0
                   1.0
                                                                                                  0.9
                   0.9

                                                                                                  0.8
                   0.8

                                                                                                  0.7
                   0.7




                                                                                PR+ Probability
                                                                                                                                    HER-2 negative
 PR+ Probability




                   0.6                                                                            0.6


                   0.5                                                                            0.5


                   0.4                                                                            0.4

                   0.3                                                                            0.3
                                                                                                                                    HER-2 positive
                   0.2                                                                            0.2

                                                                                                  0.1
                   0.1                                                                                       HER-2 status        Negative (N = 1971)
                                             N = 2227                                                                              Positive (N = 256)
                   0.0                                                                            0.0
                         20   30   40   50   60     70   80   90   100                                  20   30   40   50   60      70     80     90    100

                                        Age (years)                                                                    Age (years)


                                              The interaction between PR and age is HER-2 dependent
                                              The negative association between PR and HER-2 is age dependent
                                  Interaction HER-status and age by ER/PR
ER/PR and HER-2


                       1.0
                                                    N = 2227                                             1.0
                                                                                                                    ER/PR status        ER-/PR- (N = 281)
                       0.9                                                                               0.9                            ER+/PR- (N = 230)
                                                                                                                                        ER+/PR+ (N = 1716)
                       0.8                                                                               0.8
  HER-2+ Probability




                                                                                    HER-2+ Probability
                       0.7                                                                               0.7

                       0.6                                                                               0.6

                       0.5                                                                               0.5

                       0.4                                                                               0.4

                       0.3                                                                               0.3

                       0.2                                                                               0.2


                       0.1                                                                               0.1


                       0.0                                                                               0.0
                                                                                                               20   30   40   50   60      70    80     90   100
                             20   30      40   50    60    70   80   90   100

                                                Age (years)                                                                   Age (years)




                                       The interaction between HER-2 and age is ER/PR dependent
                                       The older one is the less likely HER-2 positive is only if the tumour is ER-positive
Adjuvant Therapy


            Breast Cancer: Adjuvant Therapy
                Treatment Side Effects
    Lani Morales

                   Quality of Life
        PROGRESS IN BREAST CANCER ADJUVANT THERAPY
Average treatment                                                      Financial
                                 d)  20.000 $
     effect                      c) 13.800 $                           toxicity
                                 b)  7.400 $        + Herceptin: 40.000 euro
                                 a)  800 $                 TAC x 6
 +++                                                    FEC  docetaxel        +++
                                                    AC  paclitaxel dose-dense
 ++                               FAC  FEC x 6                                    ++
                                    A(E)  CMF
  +                  CMF x 6   AC x 4  Paclitaxel x 4                              +
                     AC x 4
  ±      L-PAM, MF                                                                  ±

       1970’s        1980’s        1990’s            2000’s

                Successive generations of adjuvant CT regimens
                               ++ ADJUVANT AIs ++
                                                                  Adapted from G. Hortobagyi
            Multidisciplinary Breast Centre- UZLeuven
                             May 2007
                                                           Centrum Vergadering
                                                           Medical Director
   Coordinator: MR Christiaens                            Head of departments
                                                                      Pathology
   Radiology: A Van Steen, C Van Ongeval                             Radiology
   Pathology: M Drijkoningen                                         Surgery
                                                                      Med Oncol
   Surgery: MR Christiaens, A Smeets                                 Radiotherapy
                                                                      Obstet & Gyn
   Gynaecology: P Neven, K Leunen, F Amant, P Berteloot
   Plastic Surgery: M Vandevoort, G Fabre
   Med Oncology: R Paridaens, H Wildiers
   Radiotherapy: W Van den Bogaert, E Van Limbergen, C Weltens
   Human Genetics: E Legius
   KanActief: L Serrien
   Data Manager: W Hendrickx
   Breast “nurses”, Physiotherapists, Trial “nurses”
   PhD: I Van den Bempt, A Smeets, J De Cock
   Assistents
 I hope I gave you a touch of our
             ongoing
Clinical Research & Trial Activities


 Multidisciplinary Breast Centre

				
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