Neoadjuvante Therapy of Breast Cancer

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Neoadjuvante Therapy of Breast Cancer
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• Cancer statistics
• Genesis of cancer
• Cancer in detail
• Treatment of cancer
• Prevention
• Follow-up
• NEWS
• Research

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INCIDENCE OF CANCER

• Colorectal cancer
• Breast cancer
• Lung Cancer
• Prostate cancer
• Cervix carcinoma
• Meaning of
• Prevention and
• risk - behavior

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Principles of treatment for malignant disease at
an early stage

• most possible radical removal of tumour with
  maximal protection of healthy structures and
  precise indication.
• preventing the growth of possible metastasis
  depending on the availability of effective
  treatment and tumour characteristics

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Principles of treatment for malignant disease
with distant metastases

• Maintain organ function
• Quality of life
• Prolongation of life with consideration of QoL
  and tolerance of treatment
• Psychological support, if wished for
• Adequate pain management

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Treatment modalities for malignant diseases

• Surgery
• Radiation therapy
• Chemotherapy
• Anti-hormone therapy
• Antibodies
• Disturbance of the capillary supply
• Gene manipulation

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Main feedback mechanisms of cell division and
their down-regulation in the development of
cancer.
1. Independence of cell replication from
exogeneous growth factors. 2. Insensitivity to
growth factors inhibition signaling 3.
Resistance to induction of apoptosis 4.
Unlimited span of life5. Neoangiogenesis 6.
Cellular mobility and cell growth in foreign
tissue
Hanahan Weinberg, Cell 100 57, 2000.
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Cancer treatment in breast cancer as an example

• Treatment dependent from
• Tumour characteristics
• time of treatment
• desired short- and middle term results
• At a cleat long-term goal of a disease free
  survival

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Characteristics of breast cancer cells

• Growth
• hormone receptors
• HER-2/neu-Protein overexpression
• Differentiation
• histopathological differentiation
• Dissemination
• lymph node infiltration

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Medical-oncologic form of treatment in malign
diseases
NEOADJUVANT THERAPY
ADJUVANT THERAPY
PALLIATIV THERAPY
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NEOADJUVANT THERAPY
Medical-oncologic treatment is administered
pre-surgical
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CONCEPT OF NEOADJUVANT THERAPY IN BREAST CANCER
Administration of substances that known to
inhibit cell division (chemotherapy, anti-hormone
therapy) pre-operatively with the goal to
decrease tumour size and thereby decrease the
extension of surgical intervention. Response to
neoadjuvant therapy is a parameter for tumour
cells and their treatment sensitivity (!)
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Open question conserning the concept of
neoadjuvant therapy in breast cancer.
1. ZEITVERSÄUMNIS by surgery-delay ( potential
danger for the patient?) 2.Quality of treatment
result in comparison to post-surgery (adjuvant)
therapy 3. Advantages?
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NEOADJUVANT THERAPY IN BREAST CANCERNSABP B-27
STUDY
STUDY DESIGN1.523 patients with breast cancer,
who received747 pre-surgery (neoadjuvant)
chemotherapy759 post-surgery (adjuvant)
chemotherapyChemotherapy scheme AC
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NEOADJUVANT THERAPY IN BREAST CANCERNSABP B-27
STUDY
TUMOR SIZE lt2cm 2.1-5.0cm
gt5.1cmCOMPLETE REMISSION 57 35
17PARTIAL REMISSION
22 46
58STABLE DISEASE
15 16
22PROGRESSION
5 3
3
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NEOADJUVANT THERAPY IN BREAST CANCER EINFLUSS
AUF BRUSTERHALTENDE CHIRURGIE.
TUMOR SIZE lt2cm 2.1-5.0cm
gt5.1cmINITIAL PRESENTATION 79
63 8AFTER CHEMOTHERAPY
81 71
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NEOADJUVANT THERAPY IN BREAST CANCER SURVIVAL
DATA IN THE NSABP-B27 STUDY.
NEOADJUVANT
ADJUVANTDISEASE FREE
67 675-YEAR-SURVIVAL
80 80
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NEOADJUVANT THERAPY IN BREAST CANCER CONCLUSION
FROM THE NSABP-B27 STUDY.
1. Neoadjuvant therapy is possible2.
Neoadjuvant therapy reduces tumour size and
allows reduced surgical intervention 3.
Patients have no disadvantage with a delay of
surgery
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EXTREMITY CONSERVING SURGERY IN TUMOURS OF THE
BONE 30-YEAR-RESULTS OF THE DEPARTMENT OF
ORTHOPEDIC, UNIVERSITY HOSPITAL
Period 1 Period 2 Period
3 (1965-1974) (1975-1984)
(1985-1994) Died 116 (71.6) 104 (53.3) 152
(37.3) Alive 46 (28.4) 91 (46.7) 256
(62.7) 3-year-survival 76 (46.9) 120
(61.5) 295 (72.3)
R. Kotz et al., 2000
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ADJUVANT THERAPY
Is administered after surgery in patients who
have no clinical manifestation of
distant-metastases, however the probability of
disease relapse. Goal prolongation of
disease-free interval and survival time
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DECISION CRITERIA FOR ADJUVANT THERAPY
Probability of relapse ( metastases)
Probability of treatment
efficacy
Therapy-associated toxicity in relation to
treatment result Only statistical
consulting, not individual
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ADJUVANT THERAPY PROGNOSTIC DISEASE VARIABLES
Affected local lymph nodes Tumour size
Radical surgery concerning the removal of tumour
cells Tumour characteristics that can be
influenced biologically and therapeutically
Biologic characteristics of the tumours that
make a relapse probable
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RATIONALE OF ADJUVANT THERAPY
Small tumour cell clusters (lt3mm) are not
visible even with the best radiological methods.
Their presence can only be assumed using the
known risk factors. Disseminated tumour
cells awaken from their dormant state,
growth and form undetectable metastases.
small tumour cell cluster are treatable more
effectively than large, radiological detectable
metastases
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ADJUVANT THERAPY IN BREAST CANCERRISK FACTORS
FOR LATER FORMATION OF METASTASES
Involvement of axillar lymph nodes (none,
1-3, 4-10, gt10) estrogen receptor status
(POSITIV / NEGATIV) histological grading
(G1-4) tumour size
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ADJUVANT THERAPY IN BREAST CANCER THERAPY
OPTIONEN
Radiation therapy Anti-hormone therapy
Chemotherapy
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FUNCTION OF ESTROGEN RECEPTOR

1. Localisation within the tumour cell 2.
Interaction with estrogen causes activation of
cell growth 3. Blockade inhibits growth of
malignant cells
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ADJUVANT THERAPY IN BREAST CANCER THERAPY
OPTIONEN TAMOXIFEN
Breast cancer cells of about 50 of all
patients develops and growth under the influence
of estrogen. Tamoxifen blocks the estrogen
receptor competitively.
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TAMOXIFEN AS ADJUVANT THERAPY IN BREAST CANCER
Patients 37.000 women from 55 worldwide,
randomized studies (lt1990 - 1995) 87 of
worldwide data. Estrogen receptor (ER)-
positive18.000 patients with ER-positive tumours
12.000 patients with unknown Median
Follow-up10 YearsStatistical
methodsIntention-to-treat, metaanalysis
EBCTCG, LANCET 351 1451, 1998
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REDUCTION OF RELAPSE AND MORTALITY USING
TAMOXIFEN IN DEPENDENCY OF TREATMENT DURATION
Reduction of
Relapse Mortality 2p 1 Year 18 ? 3 10 ? 3
lt.00001/.0006 2 Years
25 ? 2 15 ? 2 lt.00001/.00001
5 Years 42 ? 3 22 ? 4
lt.00001/.00001
Total 27 ? 2 15 ? 2 lt.00001/.00001
EBCTCG, LANCET 351 1451, 1998
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REDUCTION OF RELAPSE AND MORTALITY USING
TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR.
REDUCTION OF
Relapse Mortality 2p 1 Year 20 mg/day 18 ?
4 12 ? 5 30 - 40 mg/day 22
? 5 11 ? 5 gt.1/.1 5
Years 20 mg/day 45 ? 4 21 ? 6
30 - 40 mg/day 49 ? 5 32 ? 6
gt.1/.1
EBCTCG, LANCET 351 1451, 1998
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REDUCTION OF RELAPSE AND MORTALITY USING
TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR
REDUCTION OF
Relapse Mortality 2p
ER low 6 ? 11 3 ? 11 ER unknown
37 ? 8 21 ? 9 ER
positive 50 ? 4 28 ? 5
Subtotal 43 ? 3 23 ? 4
lt.00001/.00001 ER vs.
ER- lt.00001/.005
EBCTCG, LANCET 351 1451, 1998
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SECONDARY DISEASES AFTER 5-YEARS OF
TAMOXIFEN-TREATMENT IN PATIENTS WITH BREAST
CANCER.
EVENTS/1000 YEAR 10-YEAR-RISK/1000
TAM. KONTR. 2p TAM. KONTR.
DIFFERENZ KONTRALATERALE MAMMACARCINOM-INZIDENZ
93/23.6 159/21.0 lt.00001 26 47
-21 ? 5GEBÄRMUTTERKREBS-INZIDENZ
43/26.9 9/23.6 lt.0001 11 3 9 ? 2
GEBÄRMUTTERKREBS-MORTAL
ITÄT 7/26.4 0/23.2
.02 2 0 2 ? 0.8
EBCTCG, LANCET 351 1451, 1998
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RESULTS OF BREAST CANCER PROPHYLAXIS IN WOMEN
WITH GENETIC DISPOSITION USING TAMOXIFEN.
Study design 13.388 women with genetic
disposition (high risk) 20 mg tamoxifen/day for
5 years Placebo-controlled
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DEFINITION OF INCREASED GENETIC DISPOSITION FOR
BREAST CANCER DEVELOPMENT

• Age gt 60 Years
• 2. 35-59 years with an anamnesis of lobular
  carcinoma in situ or a 5-year-risk of gt1.66
  including
• one first degree relatives or
• two aunts with breast cancer with breast
  cancer
• preceding breast biopsy to verify radiological
  suspect areas
• pathologic diagnose of a atypical hyperplasia

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RESULTS OF BREAST CANCER PROPHYLAXIS IN WOMEN
WITH GENETIC DISPOSITION USING TAMOXIFEN.
Tamoxifen Placebo inva
sive breast cancer 85
154 non-invasive carcinomas 31
59 Bone fractures
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71 Endometrial carcinoma 33
14 Thromboembolis
99 70
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ADJUVANT CHEMOTHERAPY IN BREAST CANCER
Reduction of yearly risk using chemotherapy
Relapse -23.5 ? 2.1 lt.00001Death -15.3 ?
2.4 lt.00001
Lancet 352 930, 1998.
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REDUCTION OF RELAPSE AND MORTALITY USING
TAMOXIFEN AND CHEMOTHERAPY IN BREAST CANCER
Reduction of
Relapse Mortality 2p 5 year tamoxifen vs.
0 -46 ? 4 -22 ? 5 5
year tamoxifen chemotherapy vs.
chemotherapy -52 ? 8 -47 ? 9 gt.1 /gt.1
EBCTCG, LANCET 351 1451, 1998
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ADJUVANT THERAPY IN BREAST CANCERCONCLUSION
Adjuvant therapy with tamoxifen and/or
chemotherapy leads to a significant reduction of
incidence of metastases and mortality. Choice
of treatment modality depends on tumour
characteristicsImprove of criteria's for
selection is necessary to identify patients with
a principally good prognosis. Patients with
breast cancer and their existing data
patientinnen mit mammacarcinom sollte auf grund
vorliegender daten adjuvante therapie empfohlen
werden
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PALLIATIV THERAPY
Is administered after clinical manifestation
of distant metastasis into organs and bone
Aims introduce a remission, increase of
survival time and palliation of symptoms
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PALLIATIV THERAPY MODALITIES
Anti-hormone therapy Chemotherapy
Antibody Radiation therapy Palliativ and
supportiv therapy
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PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC
BREAST CANCER
Good prognosis defined by       
Hormone-receptor positively formation of
metastasis into skin, bone, lymph node,
connective tissue         Interval between
primary diagnosis and relapse gt2 years  ?  
Anti-hormone therapy (estrogen withdrawal)
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PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC
BREAST CANCER
Poor prognosis defined by        hormone
receptor-negativity         formation of
metastasis into organs (liver, lung).       
interval between primary diagnosis and relapse lt2
years  ?    cytostatic chemotherapy
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TREATMENT OF GENERALIZED BREAST CANCER
Treatment in dependency of         Estrogen
receptor status        Her-2/neu positively
        Criteria for prognosis
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ANTI-HORMONE THERAPY OF METASTASISED CARCINOMA
Hormone withdrawal surgical
pharmacological
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ANTI-HORMONE THERAPY OF METASTASISED CARCINOMA
Competitive hormone receptor blockade
Estrogene Testosterone
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ANTI-HORMONE THERAPY IN METASTASISED BREAST CANCER
Pre-menopausal Ovariectomy
LH-RH-agonist TamoxifenPost-menopausal
Aromataseinhibitors (letrozol, anastrozol)
Tamoxifen
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OLD AND NEW CHEMOTHERAPEUTICSA SELECTION
Old New Fluorouracil Carboplatin Methotrex
at Capecitabine Epirubicin Vinca
Alkaloide Gemcitabine Cyclophosphamid Irinotec
an Ifosfamid Lipos. Etoposid
Doxorubicin Cisplatin Topotecan Vinorelb
ine
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POSITIVE RESULTS OF NEW CHEMOTHERAPEUTICS IN
MALIGN DISEASE
Testicular carcinoma Breast cancer Lung
cancer Colon carcinoma Ovarian carcinoma Bladder
carcinoma Pancreatic cancer
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ADVANCES OF CHEMOTHERAPY 5-year survival rate
for different malignant diseases 1960-1993 (USA)
1960 1993
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Influence of growth factors on tumour growth
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USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY
AGAINST HER2 FOR METASTATIC BREAST CANCER THAT
OVEREXPRESSES HER2/NEU.
Progression Free Survival
Slamon et al., N Engl J Med,Vol.344,No.11 March
15,2001
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Use of Chemotherapy plus a Monoclonal Antibody
against HER2 for Metastatic Breast Cancer that
Overexpresses HER2/neu
Overall Survival
Slamon et al., N Engl J Med,Vol.344,No.11 March
15,2001
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CHEMOTHERAPY PLUS TRASTUZUMAB (HERCEPTIN) IN
HER-2/NEU OVEREXPRESSING METASTATIC BREAST
CANCER RESULTS OF A RANDOMIZED PHASE-III STUDY.
CHEMOT CHEMO p
Response 50 32 lt0.001Duration 9
.1 MOS. 6.1 MOS. lt0.001
1-year-death rate 22 33
0.008overall survival 25.1 MOS. 20.3
MOS. 0.046
D.J. SLAMON ET AL., NEJM 344 783, 2001
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ANTIBODY THERAPY OF MALIGNANT DISEASES
Antibody TumourTRASTUZUMAB Breast
cancer (Pancreatic cancer) (Gastric
cancer) ??RITUXIMAB LymphomaCETUXIMAB Head
and Neck Cancer Colon carcinoma
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OPEN QUESTIONS CONCERNING THE TREATMENT OF
MALIGNANT DISEASES
Role of chemoprevention
Surgical modalities Improve of treatment
modalities - new chemotherapeutics
- optimizing endocrine therapy -
new drug combination Factors to predict
biology of disease and response to treatment
Biological treatment modalities
(antibodies, cytokines, inhibition of
neo-angiogenesis) Gene
therapy