Neoadjuvante Therapy of Breast Cancer

Clinical Division of OncologyDepartment of Medicine I

Medical University ofVienna, Austria

Neoadjuvante Therapy Neoadjuvante Therapy of Breast Cancerof Breast Cancer



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



INCIDENCE OF CANCERINCIDENCE OF CANCER

• Colorectal cancer• Breast cancer • Lung Cancer• Prostate cancer• Cervix carcinoma

Meaning of • Prevention and• risk - behavior



Principles of treatment for Principles of treatment for malignant disease at an early malignant disease at an early

stagestage

• 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



Principles of treatment for Principles of treatment for malignant disease with distant malignant disease with distant

metastasesmetastases

• 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



Treatment modalities for Treatment modalities for malignant diseasesmalignant diseases

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



Main feedback mechanisms of cell division Main feedback mechanisms of cell division and their down-regulation in the and their down-regulation in the

development of cancer.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.



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



Characteristics of breast Characteristics of breast cancer cells cancer cells

• Growthhormone receptors HER-2/neu-Protein overexpression

• Differentiationhistopathological differentiation

• Dissemination lymph node infiltration



* NEOADJUVANT THERAPY

* ADJUVANT THERAPY

* PALLIATIV THERAPY

Medical-oncologic form of Medical-oncologic form of treatment in malign diseasestreatment in malign diseases



Medical-oncologic treatment is administered pre-surgical

NEOADJUVANT THERAPYNEOADJUVANT THERAPY



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 (!)

CONCEPT OF NEOADJUVANT CONCEPT OF NEOADJUVANT THERAPY IN BREAST CANCERTHERAPY 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?

Open question conserning the concept of Open question conserning the concept of neoadjuvant therapy in breast cancer.neoadjuvant therapy in breast cancer.



STUDY DESIGN

1.523 patients with breast cancer, who received

747 pre-surgery (neoadjuvant) chemotherapy759 post-surgery (adjuvant) chemotherapy

Chemotherapy scheme: AC

NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER:BREAST CANCER:

NSABP B-27 STUDYNSABP B-27 STUDY



TUMOR SIZE <2cm 2.1-5.0cm >5.1cm

COMPLETE REMISSION 57% 35% 17%PARTIAL REMISSION 22% 46% 58%STABLE DISEASE 15% 16% 22%PROGRESSION 5% 3% 3%

NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER:BREAST CANCER:

NSABP B-27 STUDYNSABP B-27 STUDY



TUMOR SIZE <2cm 2.1-5.0cm >5.1cm

INITIAL PRESENTATION 79% 63% 8%

AFTER CHEMOTHERAPY 81% 71% 22%

NEOADJUVANT THERAPY IN BREAST NEOADJUVANT THERAPY IN BREAST CANCER: EINFLUSS AUF CANCER: EINFLUSS AUF

BRUSTERHALTENDE CHIRURGIE.BRUSTERHALTENDE CHIRURGIE.



NEOADJUVANT ADJUVANT

DISEASE FREE 67% 67%

5-YEAR-SURVIVAL 80% 80%

NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER : SURVIVAL DATA BREAST CANCER : SURVIVAL DATA

IN THE NSABP-B27 STUDY.IN THE NSABP-B27 STUDY.



1. Neoadjuvant therapy is possible

2. Neoadjuvant therapy reduces tumour size and allows reduced surgical intervention

3. Patients have no disadvantage with a delay of surgery

NEOADJUVANT THERAPY IN NEOADJUVANT THERAPY IN BREAST CANCER : CONCLUSION BREAST CANCER : CONCLUSION

FROM THE NSABP-B27 STUDY.FROM THE NSABP-B27 STUDY.



EXTREMITY CONSERVING SURGERY IN EXTREMITY CONSERVING SURGERY IN TUMOURS OF THE BONE : 30-YEAR-TUMOURS OF THE BONE : 30-YEAR-RESULTS OF THE DEPARTMENT OF RESULTS OF THE DEPARTMENT OF

ORTHOPEDIC, UNIVERSITY HOSPITALORTHOPEDIC, 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



* 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

ADJUVANT THERAPYADJUVANT THERAPY



DECISION CRITERIA FOR ADJUVANT DECISION CRITERIA FOR ADJUVANT THERAPYTHERAPY

* Probability of relapse (= metastases) * Probability of treatment efficacy * Therapy-associated toxicity in relation to treatment result

* Only statistical consulting, not individual



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



RATIONALE OF ADJUVANT RATIONALE OF ADJUVANT THERAPYTHERAPY

* Small tumour cell clusters (<3mm) 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



ADJUVANT THERAPY IN BREAST CANCER:ADJUVANT THERAPY IN BREAST CANCER:

RISK FACTORS FOR LATER FORMATION RISK FACTORS FOR LATER FORMATION OF METASTASESOF METASTASES

* Involvement of axillar lymph nodes (none, 1-3, 4-10, >10)

* estrogen receptor status (POSITIV / NEGATIV)

* histological grading (G1-4)

* tumour size



ADJUVANT THERAPY IN BREAST ADJUVANT THERAPY IN BREAST CANCER: THERAPY OPTIONENCANCER: THERAPY OPTIONEN

* Radiation therapy

* Anti-hormone therapy

* Chemotherapy



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



* Breast cancer cells of about 50% of all patients develops and growth under the influence of estrogen.

* Tamoxifen blocks the estrogen receptor competitively.

ADJUVANT THERAPY IN BREAST ADJUVANT THERAPY IN BREAST CANCER: THERAPY OPTIONEN CANCER: THERAPY OPTIONEN

TAMOXIFENTAMOXIFEN



TAMOXIFEN AS ADJUVANT TAMOXIFEN AS ADJUVANT THERAPY IN BREAST CANCERTHERAPY IN BREAST CANCER

Patients 37.000 women from 55 worldwide, randomized studies (<1990 - 1995);

= 87% of worldwide data.

Estrogen receptor (ER)- positive18.000 patients with ER-positive tumours

12.000 patients with unknown

Median Follow-up10 Years

Statistical methodsIntention-to-treat, metaanalysis

EBCTCG, LANCET 351: 1451, 1998



REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND MORTALITY USING TAMOXIFEN IN MORTALITY USING TAMOXIFEN IN

DEPENDENCY OF TREATMENT DEPENDENCY OF TREATMENT DURATIONDURATION

Relapse Mortality 2p

1 Year 18 3 10 3 <.00001/.0006 2 Years 25 2 15 2 <.00001/.00001 5 Years 42 3 22 4 <.00001/.00001 Total 27 2 15 2 <.00001/.00001


% Reduction of



REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND

MORTALITY USING TAMOXIFEN IN MORTALITY USING TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR. DEPENDENCY OF ESTROGEN RECEPTOR.


1 Year 20 mg/day 18 4 12 5 30 - 40 mg/day 22 5 11 5 >.1/.1 5 Years 20 mg/day 45 4 21 6

30 - 40 mg/day 49 5 32 6 >.1/.1


% 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 <.00001/.00001 ER+ vs. ER- <.00001/.005


% REDUCTION OF

REDUCTION OF RELAPSE AND MORTALITY USING REDUCTION OF RELAPSE AND MORTALITY USING TAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTORTAMOXIFEN IN DEPENDENCY OF ESTROGEN RECEPTOR



SECONDARY DISEASES AFTER 5-YEARS SECONDARY DISEASES AFTER 5-YEARS OF TAMOXIFEN-TREATMENT IN OF TAMOXIFEN-TREATMENT IN

PATIENTS WITH BREAST CANCER. 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 <.00001 26 47 -21 5

GEBÄRMUTTERKREBS-INZIDENZ 43/26.9 9/23.6 <.0001 11 3 +9 2

GEBÄRMUTTERKREBS-MORTALITÄT 7/26.4 0/23.2 .02 2 0 +2 0.8




RESULTS OF BREAST CANCER RESULTS OF BREAST CANCER

PROPHYLAXIS IN WOMEN WITH GENETIC PROPHYLAXIS IN WOMEN WITH GENETIC DISPOSITION USING TAMOXIFEN.DISPOSITION USING TAMOXIFEN.

Study design

13.388 women with genetic disposition (high risk)

20 mg tamoxifen/day for 5 yearsPlacebo-controlled



DEFINITION OF INCREASED DEFINITION OF INCREASED GENETIC DISPOSITION FOR BREAST GENETIC DISPOSITION FOR BREAST

CANCER DEVELOPMENTCANCER DEVELOPMENT

1. Age > 60 Years

2. 35-59 years with an anamnesis of lobular carcinoma in situ or a 5-year-risk of >1.66% 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



RESULTS OF BREAST CANCER RESULTS OF BREAST CANCER

PROPHYLAXIS IN WOMEN WITH GENETIC PROPHYLAXIS IN WOMEN WITH GENETIC DISPOSITION USING TAMOXIFEN.DISPOSITION USING TAMOXIFEN.

Tamoxifen Placebo

invasive breast cancer 85 154non-invasive carcinomas 31 59

Bone fractures 47 71Endometrial carcinoma 33 14Thromboembolis 99 70



ADJUVANT CHEMOTHERAPY IN ADJUVANT CHEMOTHERAPY IN BREAST CANCER BREAST CANCER

Relapse -23.5 2.1% <.00001Death -15.3 2.4% <.00001

Lancet 352: 930, 1998.

Reduction of yearly risk using chemotherapy



REDUCTION OF RELAPSE AND REDUCTION OF RELAPSE AND

MORTALITY USING TAMOXIFEN AND MORTALITY USING TAMOXIFEN AND CHEMOTHERAPY IN BREAST CANCERCHEMOTHERAPY IN BREAST CANCER


5 year tamoxifen vs. 0 -46 4 -22 5

5 year tamoxifen + chemotherapy vs. chemotherapy-52 8 -47 9 >.1 />.1


% Reduction of



ADJUVANT THERAPY IN ADJUVANT THERAPY IN BREAST CANCERBREAST CANCER

CONCLUSIONCONCLUSION

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 characteristics

Improve 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



* Is administered after clinical manifestation of distant metastasis into organs and bone

* Aims: introduce a remission, increase of survival time and palliation of symptoms

PALLIATIV THERAPYPALLIATIV THERAPY



* Anti-hormone therapy

* Chemotherapy

* Antibody

* Radiation therapy

* Palliativ and supportiv therapy

PALLIATIV THERAPY PALLIATIV THERAPY MODALITIESMODALITIES



PROGNOSTIC ORIENTATED PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC TREATMENT IN METASTATIC

BREAST CANCER 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 >2 years

Anti-hormone therapy (estrogen withdrawal)



PROGNOSTIC ORIENTATED PROGNOSTIC ORIENTATED TREATMENT IN METASTATIC TREATMENT IN METASTATIC

BREAST CANCERBREAST CANCER

Poor prognosis defined by:

* hormone receptor-negativity

* formation of metastasis into organs (liver, lung).

* interval between primary diagnosis and relapse <2 years

cytostatic chemotherapy



TREATMENT OF GENERALIZED TREATMENT OF GENERALIZED BREAST CANCERBREAST CANCER

Treatment in dependency of

* Estrogen receptor status

* Her-2/neu – positively

* Criteria for prognosis



ANTI-HORMONE THERAPY OF ANTI-HORMONE THERAPY OF METASTASISED CARCINOMA METASTASISED CARCINOMA

Hormone withdrawal

* surgical

* pharmacological



ANTI-HORMONE THERAPY OF ANTI-HORMONE THERAPY OF METASTASISED CARCINOMAMETASTASISED CARCINOMA

Competitive hormone receptor blockade

* Estrogene

* Testosterone



ANTI-HORMONE THERAPY IN ANTI-HORMONE THERAPY IN METASTASISED BREAST METASTASISED BREAST

CANCERCANCER

Pre-menopausal

* Ovariectomy

* LH-RH-agonist

* Tamoxifen

Post-menopausal

* Aromataseinhibitors (letrozol, anastrozol)

* Tamoxifen



OLD AND NEW CHEMOTHERAPEUTICS:

A SELECTIONOld New

Fluorouracil CarboplatinMethotrexat Capecitabine

EpirubicinVinca Alkaloide GemcitabineCyclophosphamid IrinotecanIfosfamid Lipos.Etoposid DoxorubicinCisplatin Topotecan

Vinorelbine



POSITIVE RESULTS OF NEW POSITIVE RESULTS OF NEW CHEMOTHERAPEUTICS IN MALIGN CHEMOTHERAPEUTICS IN MALIGN

DISEASEDISEASE

Testicular carcinomaBreast cancerLung cancerColon carcinomaOvarian carcinoma

Bladder carcinomaPancreatic cancer



ADVANCES OF CHEMOTHERAPY ADVANCES OF CHEMOTHERAPY 5-year survival rate for different malignant 5-year survival rate for different malignant

diseasesdiseases1960-1993 (USA)1960-1993 (USA)

97

96

82

82

43

18

8

83

62

63

40

18

12

3

0 50 100

Thyroid

Testis

Breast

Lymphoma

Leukemia

Lung

Pancreas19601993



Influence of growth factors Influence of growth factors on tumour growthon tumour growth

Antibody inhibit growthReceptor

Growth factor

TumorprogressionNo growth



USE OF CHEMOTHERAPY PLUS A USE OF CHEMOTHERAPY PLUS A MONOCLONAL ANTIBODY AGAINST HER2 MONOCLONAL ANTIBODY AGAINST HER2 FOR METASTATIC BREAST CANCER THAT FOR METASTATIC BREAST CANCER THAT

OVEREXPRESSES HER2/NEU. *OVEREXPRESSES HER2/NEU. *

Slamon et al., N Engl J Med,Vol.344,No.11 ·March 15,2001

Progression Free Survival



Use of Chemotherapy plus a Monoclonal Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Antibody against HER2 for Metastatic

Breast Cancer that Overexpresses Breast Cancer that Overexpresses HER2/neuHER2/neu

Slamon et al., N Engl J Med,Vol.344,No.11 ·March 15,2001

Overall Survival



CHEMOTHERAPY PLUS TRASTUZUMAB CHEMOTHERAPY PLUS TRASTUZUMAB (HERCEPTIN) IN HER-2/NEU OVEREXPRESSING (HERCEPTIN) IN HER-2/NEU OVEREXPRESSING METASTATIC BREAST CANCER: RESULTS OF A METASTATIC BREAST CANCER: RESULTS OF A

RANDOMIZED PHASE-III STUDY.RANDOMIZED PHASE-III STUDY.

CHEMO+T CHEMO p

Response 50% 32% <0.001

Duration 9.1 MOS. 6.1 MOS. <0.001

1-year-death rate 22% 33% =0.008

overall survival 25.1 MOS. 20.3 MOS. =0.046

D.J. SLAMON ET AL., NEJM 344: 783, 2001



ANTIBODY THERAPY OF ANTIBODY THERAPY OF MALIGNANT DISEASESMALIGNANT DISEASES

Antibody Tumour

TRASTUZUMAB Breast cancer

(Pancreatic cancer)

(Gastric cancer)

??

RITUXIMAB Lymphoma

CETUXIMAB Head and Neck Cancer

Colon carcinoma



OPEN QUESTIONS CONCERNING OPEN QUESTIONS CONCERNING THE TREATMENT OF MALIGNANT THE TREATMENT OF MALIGNANT

DISEASESDISEASES

* 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

Documents

Neoadjuvante Therapy of Breast Cancer