Breast cancer treatment: The future is bright

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Breast cancer treatment The future is bright
Professor Brian Leyland-Jones McGill University,
Canada
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Breast cancer the facts

• More than a million cases of breast cancer are
  diagnosed each year
• Second leading cause of cancer deaths in women
• Causes of breast cancer
• Exact causes not known
• Risk factors include
• Family history of breast cancer
• Early puberty
• Late childbearing
• Obesity
• Lifestyle factors e.g. smoking
• Age (over 60 years)

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Turnaround decline in mortality rates
35
30
25
20
Mortality rate
15
UK
Netherlands
10
Sweden
Italy
5
France
0
1951
1954
1957
1960
1963
1966
1969
1972
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
Year
Veronesi et al 2005
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Improvements in breast cancer survival
Relative survival ()
90
80
Ten year survival
70
60
Twenty year survival
50
40
1991-1993
1996-1998
2001-2003
Calendar period
Source Cancer Research UK / Office for National
Statistics, October 2005
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This is tremendous news for breast cancer
patients who have been recently diagnosed. This
is the first time we have been able to predict
such a huge improvement in long-term survival
figures. Dr Richard Sullivan Director of
clinical programmes Cancer Research UK

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Treatment modalities
Surgery - Lumpectomy - Mastectomy-
Sentinel lymph-node biopsy
Hormonal therapy- Traditional- Improved
Radiotherapy - Traditional -
Intraoperative
Breast Cancer Treatments
Antibody therapy
Management of complications from disease
treatment
Chemotherapy- Traditional- Improved
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Improved chemotherapy e.g. Xeloda (capecitabine)
A smart tumor-activated tablet, targeting the
tumor
Intestine
Liver
Tumour
Xeloda swallowed by patient
Enzyme action on Xeloda
Special Enzyme
Cancer killing 5-FU
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Xeloda extends womens survival
1.0 0.8 0.6 0.4 0.2 0.0
Xeloda Taxotere Taxotere
Estimated probability
11.5
14.5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
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Can the benefits of Xeloda Taxotere be seen
earlier?
S URGERY
RANDO MIS ATION
Taxotere alone
Chemotherapy (AC)
Chemotherapy (AC)
Xeloda plus Taxotere
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Fighting complications from breast cancer and
its treatment
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Bone metastases key facts

• In breast cancer approximately 65 - 75 of
  patients develop bone metastases.
• 3 out of 4 patients with metastatic bone disease
  suffer from bone pain.
• Bone pain is one of the most difficult kinds of
  pain to treat.
• Most common sites are spine, pelvis, femur,
  humerus and ribs.

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BondronatPain reduction from day 3 on
8 7 6 5 4 3 2 1 0
80 70 60 50 40 30 20 10 0
Patient functioning
VAS pain score
Karnofsky Index
Bone pain
0 14 28 42 56 70 84 98 112 126 140
Time (days)
Day 3plt0.001
Heidenreich A, et al. Eur J Cancer 20031(Suppl.
5)S270
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Anaemia is under-recognised and under-treated
Proportion of patients and oncologists reporting
that fatigue and/or pain affects the patients
daily life
Patients
Fatigue
Oncologists
Pain
Both
0
10
20
30
40
50
60
70
Respondents ()
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Management patterns of anaemia in Europe
Transfusion14.9
Iron alone6.5
No treatment 61.1
Epoetin 17.4
ECAS data With or without ironWith or without
iron or transfusions
Ludwig et al. Eur J Cancer 2004402293306
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Anaemia can be conquered

• NeoRecormon (epoetin beta) rapidly and
  effectively corrects anaemia, which leads to
  significant improvements in patients quality of
  life

1.5
NeoRecormon
Control
1.0
Mean change in quality of life
0.5
0.0
0.5
Weeks 34
Weeks 68
Week 12
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Fighting complicationsfrom cancer treatments

• Nausea and Neutropenia
• Nausea and vomiting (emesis) affect about 70 of
  patients
• Can combat this with anti-emetic drugs e.g.
  Kytril (granisetron)

• Neutropenia (reduced white blood cell count
  which may increase risk of infection) is a common
  chemotherapy induced effect
• Medication e.g. Neupogen (filgrastim) means
  treatment can proceed as scheduled and the risk
  of potentially life-threatening infections is
  reduced

Picture
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Hormonal therapy
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Hormonal therapy

• Tamoxifen
• Most commonly prescribed hormonal therapy for
  breast cancer, used for the last 30 years
• Blocks oestrogen receptors which stimulate cancer
  cell growth
• Aromatase inhibitors
• Lowers amount of oestrogen produced by the body
  therefore less available for cancer cell growth

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Hormonal therapy

• Post-Menopausal
• Three aromatase inhibitors have shown promising
  results in post-menopausal women
• Arimidex (anastrozole)
• Femara (letrozole)
• Aromasin (exemestane)
• Pre-Menopausal
• In pre-menopausal women, Gonadotrophin-releasing
  Hormone (GnRH) analogues

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Anastrozole more effective than tamoxifen (ATAC
Trial)
50
40
Number of cases where cancer spread to other
breast
30
20
10
0
tamoxifen
anastrozole
ATAC trialists group 2002
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Each breast cancer has unique features
Luminal B
Normal
HER-2
Basal-like
Luminal A
Sorlie T et al, PNAS 2001
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Breast cancer events in ER/PgR subgroup (n5704)
Proportion of patients
- Anastrozole - Tamoxifen - Combination
Time to event (months)
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Breast cancer events in ER/PgR- subgroup
Proportion of patients
- Anastrozole - Tamoxifen - Combination
Time to event (months)
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Bead array platform
DASL ASSAY

• Millions of fibers per bead (1 unique address)
• 50,000 beads per array
• 1534 different addresses
• 3 unique addresses per gene
• Therefore, 500 genes per array panel at
  30-fold redundancy

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What is targeted therapy?
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Herceptin (trastuzumab)

• Innovative biological treatment for HER2-positive
  disease, a distinct form of breast cancer
• Up to 30 of breast cancers are HER2-positive
• Accurate HER2 testing at diagnosis is essential
• Blocks activity of HER2, which is involved in
  cell growth control
• Targets cancerous cells, without harming healthy
  cells
• Only treatment approved specifically for
  HER2-positive disease

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How Herceptin works
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Herceptin plus docetaxel
1.0
Probabilityofsurvival
0.9
Herceptin docetaxel
Docetaxel
0.8
0.7
0.6
0.5
0.4
0.3
37
0.2
0.1
0.0
22.7
31.2
0
5
10
15
20
25
30
35
40
45
50
Time (months)
8.5 months
Extra et al. ASCO 2005 abs 555
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Herceptin in early breast cancer

• Herceptins efficacy and safety profile has been
  established in one of the largest clinical trial
  programs ever in early breast cancer (gt13,000
  patients)
• Regardless of therapy regimen, patient
  characteristics and tumour profile, Herceptin
• Halves the risk of the tumour coming back
• Is the best chance for a cure of HER2-positive
  disease
• No new or unexpected Herceptin-associated side
  effects have been reported

Piccart et al 2005 Romond et al 2005
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HERA (HERceptin Adjuvant) trial Herceptin
reduces the risk of recurrence
Piccart et al 2005
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Time to first distant recurrence
100
AC?TH
90
90
90
AC?T
AC-gtT
80
81

74
70
N Events
60
AC?TH 1672 96 AC?T 1679 194
HR0.47, 2P8x10-10
50
0
1
2
3
4
5
B31/N9831
Years from randomization
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US studies combined analysisHerceptin reduces
the risk of death
Romond et al 2005
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Tumors need blood supply to grow
Tumorgrowth
Premalignant stage
Malignant tumor
Vascular Endothelial Growth Factor (VEGF)
creates new blood vessels
Adapted from Poon RT, et al. J Clin Oncol
200119120725
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Bevacizumab (Avastin)- first effective anti-VEGF
targeted agent

• Bevacizumab (Avastin) - a major breakthrough in
  cancer treatment
• Monoclonal antibody
• Mode of action that differs fundamentally from
  chemotherapy
• Novel target anti-VEGF/angiogenesis
• First agent to specifically target VEGF and show
  improved survival

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Phase III trial of Avastin in first-line
Metastatic Breast Cancer (mBC) (E2100)
Paclitaxel
Progression
Previously untreated MBC (n685)
Paclitaxel Avastin 10mg/kg every2 weeks
Progression

• Endpoints include time to progression of disease,
  overall response rate and survival

Miller KD. Clin Breast Cancer 200334212
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E2100 MBC progression-free survival
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Paclitaxel Avastin 10.97 months Paclitaxel
6.11 months
Progression-free survival proportion
HR0.49 plt0.001
6.11
10.97
0
10
20
30
Months
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New cancer treatments present a complex picture
IGF-1R inhibitors
HER2-R inhibitors
EGFR inhibitors
MUC-1 Directed antibodies
Metastases Inhibitors
Src inhibitor
mTOR inhibitors
Anti- Angiogenesis
HIF inhibitor
Farnesyl Transferase Inhibitors
MEK inhibitors
Cell Cycle inhibitors
Raf inhibitor
Aurora Kinase inhibitor
HSP90 inhibitors
Pro-apoptotic drugs
Proteasome inhibitor
Mdm2 inhibitor
Kinesins
Tubulin- interacting agents
HDAC Inhibitors
Death Receptors
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Cancer is a multistep processCures need to
attack many features of tumors
Creating own instructions to grow
Endless potential to replicate
Adapted from Hanahan and Weinberg, Cell 2000
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The future of breast cancer treatmentcombined
targetedtherapy
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Exploiting multiple pathwaysin human cancers
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Phase I/II trial of trastuzumab bevacizumab in
relapsed/MBC
Phase I
COHORT 1 (N3) Trastuzumab qw bevacizumab 3
mg/kg day 7 then q2w
HER2 (FISH)N9
COHORT 2 (N3) Trastuzumab qw bevacizumab 5
mg/kg day 7 then q2w
COHORT 3 (N3) Trastuzumab qw bevacizumab 10
mg/kg day 7 then q2w

• Investigator-initiated, investigator held IND
• First report of 2 humanized MAbs in human
  subjects
• Primary endpoints
• PK no evidence for a PK interaction between
  these humanized MAbs
• Safety generally well tolerated, one pt with
  ?LVEF

Pegram et al. Breast Cancer Res Treat.
200488(suppl 1)S124. Abstract 3039.
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Phase I trastuzumab bevacizumab clinical
efficacy 2CR, 3PR, 2SD (gt6months)
Day 0
9 months
Post-treatment
Pre-treatment
Pegram, et al., SABCS (2004) 3039
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Future treatment of breast cancer
Molecular targets

Multiple targeted therapies
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Questions and discussion
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Coffee break

• Until 1100 am

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