Building Partnerships in Breast Cancer

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The latest in treatments, testing and clinical
trials
Dr Michael Untch Breast Cancer Service, Ludwig -
Maximilans - University, Munich
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Charter of Paris 2000
1 Human rights 2 Stigmacancer to be banned 3
Priorities in research 4 Quality assurance 5
Prevention
6 Early diagnosis 7 Patient is an active
partner 8 Patients life quality 9 Development
of new strategies 10 Globalisation
Klinik und Poliklinik für Frauenheilkunde und
Geburtshilfe Klinikum Großhadern
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Treatment for Early Breast Cancer
Multimodal therapy
Surgery
Radiation
Breast Cancer
Chemotherapy
Endocrine Therapy
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Genetic Risk Evaluation
5 - 10 genetic predisposition
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Sample of Individuals Counselled and Tested
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The New Era in Breast Cancer

• Within the next 10 years
• DCIS 33 of all breast cancers
• Invasive cancer max 1cm in diameter
• Therapy will be easier
• Adjuvant therapy based on factors in the
• primary tumor and Sentinel node status

Cady B, Arch Surg., 1996
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Vacuum-Aspiration-Biopsy
b

• Birad Malignity
• 3 3
• 4a 11
• 4b 45
• 5 85

Heywang- Köbrunner, 2002
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International Consensus ConferenceImage -
Detected Breast Cancer - State of the Art
Diagnosis and Treatment

• Technology innovations, particularly
  mammography, have resulted in marked improvement
  in disease free survival for the average woman
  with breast cancer... It is threatened by
  inadequate reimbursement for diagnostic
  radiology, pathology and surgery. Inadequate
  reimbursement has created an economic
  disincentive that constitutes a major barrier to
  the shift in clinical practice from open surgical
  breast biopsies to image guided biopsies

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International Consensus ConferenceImage -
Detected Breast Cancer - State of the Art
Diagnosis and Treatment

• The costs of adequate compensation for radiology
  and pathology services are minuscule compared
  with the costs of treatment, especially for
  patients with advanced breast cancer

Silverstein, et al. J Am Coll Surg, 2002
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Sentinel Node Biopsy
Peritumoral Injection of blue dye or Tc Nanocoll
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Sentinel Node Biopsy
Axillary drainage
Medial drainage
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International Consensus Conference on Sentinel
Node Biopsy

• The panel considered SLNB to be equivalent to
  axillary dissection as a staging and diagnostic
  procedure in T1 and small T2 (3cm or less) breast
  cancers with surgeons and management teams that
  have had appropriate and adequate training and
  experience

Schwartz , Giuliano , Veronesi, Cancer
942543-2551, 2002
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National Practice Patterns of Sentinel Lymph
Node Dissection for Breast Cancer
Questionnaire to 1000 ACS fellows, at
random 41 Response Rate 77 perform
SLND private practice , academic 90 blue dye
isotope 55 part of trial 60 pre-op
lymphoscintigraphy 28 remove IMN 28
DCIS 80 routine IHC 52 lt 30 cases with
ALND 28 lt 10 cases with ALND 90 lt 5 FN
acceptable 26 self taught Lucci, A et al J
Am Coll Surg 2001
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Change of Paradigms Paradigm of Fisher
Breast cancer is a systemic disease
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Treatment Decisions Consensus Conference

• Factors to be used to select adjuvant therapy?
• For which patients hormonal therapy?
• For which patients adjuvant chemotherapy?
• Agents and dose?
• For which patients postmastectomy radiation?
• Side effects and quality of life. Individual
  decision making?
• Promising new research directions for adjuvant
  chemotherapy?

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Adjuvant Therapy in Germany
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Adjuvant Breast Cancer
1975
1980
1985
1990
1995
00
Pre 1970
Future
1975 - cyclophosphamide methotrexate flourocil
(CMF)
1989 - tamoxifen
Mid 1980s - doxorubicin
2002 - anastrozole
1999 - paclitaxel
2002 - docetaxel
1999 - epirubicin
We are now able to curesix out of every ten
women with breast cancer. Even greater
improvements in the cure rates of breast cancer
will be seen in the next two years. Professor
Gordon McVie, Director General, Cancer Research UK
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Improved Chemotherapy
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CALGB 9344 Overall Survival
Median Follow-up 69 Months
1
1.0
2
3
0.8
6
AC ? T AC
0.6
Survival
0.4
p 0,01
0.2
0.0
Years
0
2
4
6
Henderson, 2002
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BCIRG 001
Median follow up 33 Months
100
92
TAC
90
87
FAC
80
Alive
70
60
50
0
6
12
18
24
30
36
42
48
Nabholtz et. al, ASCO 2002
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Survival Update XelodaInvestigator Meeting,
ASCO 2002
1.0 0.8 0.6 0.4 0.2 0.0
Log-rank plt0.01
Overall survival
11.5
14.5
0 4 8 12 16 20 24 28 32 36 40 44 48
Months
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Improved Chemotherapy

• Xeloda alone or in combination with docetaxel is
  available for the treatment of metastatic breast
  cancer in over 50 countries worldwide
• Studies are being conducted to see if advantages
  of Xeloda alone or plus docetaxel can be found at
  an earlier stage of the disease

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Fighting Complications From the Disease, From
its Treatment
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1st Generation Targeted Therapies Hormonal
Therapy
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Hormonal Therapy

• Tamoxifen
• Works by blocking oestrogen receptors which
  stimulate cancer cell growth
• First and most commonly prescribed hormone
  therapy used to treat breast cancer
• Used for the last 30 years

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1st Generation Targeted Therapies Hormonal
Therapy

• Three aromatase inhibitors which have shown
  promising results include
• Arimidex (anastrozole), Femara (letrozole),
  Aromasin
• exemestane)
• Clinical trials have shown them to be equal to or
  superior to tamoxifen for the treatment of
  metastatic breast cancer and earlier stages of
  the disease

Bonneterre, J. et al. J Clin Oncol 2000, 183748
- 3767 ATAC Group. Lancet 2002, 3592131 -
2139 Mouridsen, H. et al. J Clin Oncol 2001, 19
2596 - 2606
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Adjuvant Therapy in Germany
Decision Factors
98
LN
97
HR
93
Menopausal status
93
Grading
93
Tu size
91
Age
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HER 2
0
20
40
60
80
100
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Positive or Negative HER2 Status
Abnormal 2
Abnormal 3
Normal 0
Normal 1
Normal
Amplification
IHC Images courtesy of MJ Kornstein MD, Medical
College of Virginia
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The Importance of HER2

• Prognostic marker
• Predictor of response to therapy
• resistance to hormonal therapy
• resistance to CMF
• sensitivity to anthracyclines / taxanes
• Target for Herceptin

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Konecny G et al. Proc ASCO, 2001
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HER2 and ER
Cohort A
Cohort B
600
1600
2000
700
HER2 HR r - 0.31 p 0.009
HER2 HR r - 0.29 p 0.001
1400
500
1200
600
400
1000
1500
300
800
500
600
200
400
400
100
ER (fmol/mg)
ER (fmol/mg)
1000
200
0
300
0
2000
4000
6000
0
0
10
20
30
40
50
60
70
r - 0.13 p lt 0.001
r - 0.12 p 0.02
200
500
100
0
0
0
10
20
30
40
50
60
70
0
2000
4000
6000
8000
10000
12000
HER2 gene copies (Signals/cell)
HER2 Protein (fmol/mg)
Konecny, Untch, JNCI,2002
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Letrozol vs Tamoxifen
Clinical Response
Odds Ratio Let vs Tam
P -value
Tamoxifen
Letrozol
IHC
0.0004
28 (4.5-177)
4/19 (21)
15/17 (88)
ErbB1/2
0.078
1.7 (0.9-2.9)
42/100 (42)
55/101 (54)
ErbB1/2
Ellis et al., JCO19, 2001
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Next Generation Targeted Therapies
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Overall Survival HER2 3 PatientsPaclitaxel
Subgroup
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HER Family Multiple Opportunities for
Intervention
2C4
HERCEPTINâ
HER2
EGFR
HER2
HER2
EGFR
EGFR
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
TARCEVATM
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Angiogenesis is a Necessary Condition for
Sustained Tumour Growth
VEGF is important for angiogenesis
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Conclusion

• An evolving understanding of molecular
  pathogenesis of breast cancer, using tools of
  genomics, is likely to provide a large number of
  molecular targets for which to develop novel
  treatments
• Targeted therapies are likely to play an
  increasing role in the systemic management of
  breast cancer
• Careful evaluation of efficacy and safety of
  novel agents in appropriately designed clinical
  trials can lead to novel avenues of research to
  discover the next generation of targeted
  therapies

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Cancer Drug Development the Surge of Targeted
Drugs

• 1730 drugs in (pre)clinical development
• 124 targets ( 400 tangible molecular targets
  exist in malignancies)
• 50 launched by 2005, another 50 by 2010

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Molecular Staging - Vision 2002

• Screening-Programs
• DCIS detection
• Small invasive cancer
• Predictive Gene tests (BRCA 1 / 2)

• Lymph Node Dissection
• Less radicality
• Sentinel-Lymphnode

• Primary Tumor
• Breast conservation
• Primary Chemotherapy
• Identification of Responders

• Adjuvant Therapy
• Risk-oriented (low / high)
• Predictive planning
• Drug targeting (Herceptin)

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The HER Family of Receptors
Ligands
HER1
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HER1 Inhibition

• HER1, also known as epidermal growth factor
  receptor (EGFR), plays a crucial role in the
  growth and survival of tumour cells
• New class of EGFR inhibitors, e.g.
  Tarceva(erlontinib) act by blocking the growth
  of these cells
• Tarceva stops signals being sent to the nucleus,
  preventing tumour growth

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2C4 Summary

• 2C4 blocks the growth of a number of solid-tumour
  cell lines including
• lung, breast, prostate and colon
• It may sensitize tumour cells to chemotherapy
• Unlike Herceptin, 2C4 does not require high HER2
  expression for anti-tumour activity
• Phase I clinical trial of 2C4 is ongoing

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HER1(EGFR) Inhibition

• EGFR is associated with poor prognosis
• EGFR is present in a variety of cancers
• non-small cell lung (NSCLC)
• breast
• ovarian
• pancreatic
• head and neck
• Although NSCLC is primary focus for current phase
  III trials, use of Tarceva in other cancers,
  including breast, is being investigated

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HER2 Activation in Cancer
Ligand-independent (HER2 ve tumours)
Ligand-dependent (HER2 ve tumours)
TGFa
TGFa
P
P
HER1 (EGFR)
P
HRG
HRG
P
HER2
X
P
P
X
Eligible for Herceptin
HER3
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2C4 Disrupts Ligand-Dependent HER2 Signaling
HER2
Low- affinity receptor
High- affinity receptor
Ligand-activated hetero-oligomer
Ligand
ATP
ADP
HERX
Akita R
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Xeloda/Taxotere (XT) SignificantlyImproved
TTP and Response
1.0 0.8 0.6 0.4 0.2 0.0
XT 42 Taxotere 30
TTP
p0.0001
4.2
6.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Months
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Improved Chemotherapy

• Oral form of chemotherapy
• e.g. Xeloda (capecitabine)
• more convenient
• can lead to increased quality of life
• Used for the treatment of advanced (metastatic)
  breast cancer ( colorectal cancer)

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Improved ChemotherapyProlongs Survival

• Large clinical trial, involving over 500 patients
  with metastatic breast cancer, conducted to
  investigate use of Xeloda in combination with
  docetaxel compared to docetaxel alone
• Adding Xeloda to docetaxel resulted in
• a three month survival advantage (26?)
• superior tumour shrinkage (45?)
• prevention of tumour growth for longer (40?)

OShaughnessy J et al. J Clin Oncol 2002,
202812-23
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Fighting Complications From the Disease

• In metastatic breast cancer approximately 80
  patients develop bone metastases
• Class of drugs, bisphosphonates, can combat bone
  metastases
• Significant pain reduction and a reduction in
  skeletal related events (e.g. bone fractures)

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Fighting ComplicationsFrom the Treatment -
Anaemia

• 60 of patients experience anaemia due to cancer
  therapy
• Anaemia has significant impact on quality of
  life
• it can limit length intensity of chemotherapy
• 10 of breast cancer patients receive lt85 of
  planned chemotherapy dose
• Prevention or reversal of anaemia with treatment
  (e.g. with recombinant erythropoetins) may
  improve quality of life, and prolong it by
  allowing effective chemo- and radiotherapy

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Fighting Complications From the
Treatment - Nausea, Neutropenia

• Nausea and vomiting (emesis) are two of the most
  common side effects of chemotherapy, affecting
  about 70 of patients, and representing a major
  therapeutic challenge in cancer and
  post-operative care
• Therapy with anti-emetic drugs (e.g. 5HT
  antagonists)
• Neutropenia (reduced white blood cell count may
  increase risk of infection) is a common
  chemotherapy induced effect
• With G-CSFs treatment can proceed as scheduled
  and the risk of potentially life-threatening
  infections is reduced