Christian Jackisch Head of the Department of Gynaecology at Klinikum Offenbach Senior Lecturer at Philipps University of Marburg, Germany Chairman of the

Christian JackischHead of the Department of Gynaecology at Klinikum Offenbach

Senior Lecturer at Philipps University of Marburg, Germany

Chairman of the Breast Centre at Klinikum Offenbach

Past deputy director of the Department of Gynaecology at the University Hospital in Marburg

Long-standing member of national and international steering committees for breast and ovarian cancer trials

Member of the German Task Force developing national guidelines for the diagnosis and treatment of breast cancer

Published more than 100 papers and book chapters on obstetrics and gynaecology

Klinikum Offenbach

Philipps University of Marburg

A decade of success: trastuzumab in HER2-positive metastatic breast

cancer

Christian JackischKlinikum Offenbach

Germany

Presentation objectives

Discuss the central role of trastuzumab in the treatment of HER2-positive MBC, in the context of other available treatment options

– review the evidence base to support currently available trastuzumab-based regimens

Consider the potential benefits to our patients of the introduction of new trastuzumab-based regimens

– evaluate the latest evidence for selected novel therapeutic approaches

Introduce pertuzumab as the first in a new class ofanti-HER2 therapy

HER2 = human epidermal growth factor receptor 2 MBC = metastatic breast cancer

HER2-positive disease

HER2 amplification leads to HER2 overexpression

Normal HER2 expressionHER2 overexpression leads totumour proliferation

HER2 expression in breast cancer

Binding of trastuzumab to HER2

1Lewis GD, et al. Cancer Immunol Immunother 1993;37:255–63

HER2 protein levels on the surface of HER2-positive tumour cells are several orders of magnitude greater than on adjacent normal breast epithelium1

HER2 is a transmembrane protein and part of the HER family of growth factor receptors

Gene or DNA amplification and protein overexpression are indicators of HER2 status

Role of HER2 in breast cancer

20–30% of patients with breast cancer haveHER2-positive disease1,2

HER2-positive status is associated with poor prognosis, including reduced relapse-free and overall survival (OS)3,4

– suggests key role for HER2 in pathogenesis

HER2 status is also an important predictor of response to chemotherapy and hormonal therapy5,6

1Owens MA, et al. Clin Breast Cancer 2004;5:63–9; 2Ross JS, et al. Mol Cell Proteomics 2004;3:379–98; 3Hynes NE, Stern DF. Biochim Biophys Acta 1994;1198:165–84

4Menard S, et al. Oncology 2001;61(Suppl. 2):67–72; 5Lohrisch C, et al. Clin Breast Cancer 2001;2:129–35; 6Piccart M, et al. Oncol 2001; 61(Suppl. 2)73–82

Trastuzumab: anti-HER2 epitope monoclonal antibody

Recombinant humanised monoclonal antibody directed against the extracellular domain of HER2

Extracellular domain(632 amino acids)Ligand-binding site

Intracellular domain(580 amino acids)Tyrosine kinase activity

Transmembrane domain(22 amino acids)

Cytoplasm

Plasmamembrane

Trastuzumab: four mechanisms of action

Prevention of p95HER2 formation

Inhibition of cell proliferation

Activation of ADCC

Inhibition of angiogenesis

ADCC = antibody-dependent cellular cytotoxicity

Patient tumoursample

Accurate HER2 testing is vital for appropriate patient selection

+–

FISH/CISH IHC

2+ 3+1+0

+

FISH/CISH

+–

Trastuzumab therapy

Trastuzumab therapy

Trastuzumab therapy

Bilous M, et al. Mod Pathol 2003;16:173–82

IHC = immunohistochemistry FISH = fluorescence in-situ hybridisationCISH = chromogenic in-situ hybridisation

A decade of success: tailored treatment for HER2-positive MBC

Hormonal therapy ± trastuzumab

Trastuzumab + other CT

Trastuzumab +taxanes

ER-positive; low risk

Trastuzumab monotherapy

Prior taxanesNo prior taxanes

HER2-positive MBC

ER-negativeER-positive; high risk

ER = oestrogen receptor; CT = chemotherapy

ER-negativeER-positive; high risk

Data from monotherapy trials show that trastuzumab is active in HER2-positive MBC

114 first-line patients randomised to trastuzumab at standard or high dose (8mg/kg followed by 4mg/kg weekly)

Clinical benefit rate (CR + PR + SD >6m) = 48%; IHC2-positive RR=0

Vogel CL, et al. J Clin Oncol 2002;20:719–26

RR = response rateCI = confidence interval; CR = complete response; PR = partial response SD = stable disease;

Patients RR (%) (95% CI)

All 26 (18–34)

IHC3-positive 35 (24–44)

IHC2-positive 0 (0–15)

FISH-positive 34 (26–56)

Trastuzumab plus taxanes

Trastuzumab plus taxanes: well-established survival benefit of first-line therapy

T = trastuzumab; P = paclitaxelD = docetaxel; ORR = overall response rate; TTP = time to progression

*53 patients (57%) crossed over to receive trastuzumab after discontinuation of docetaxel;OS in this group was 30.3 months, vs 16.6 months in patients who did not cross over

Baselga J. Oncology 2001;61(Suppl. 2):14–21 Herceptin® EU Summary of product characteristics

Marty M, et al. J Clin Oncol 2005;23:4265–74 Smith IE. Anticancer Drugs 2001;12(Suppl. 4):S3–10

H0648g(HER2 IHC3-positive)

M77001(HER2 FISH-/IHC3-positive)

OutcomeT + P(n=68)

P(n=77) p value

T + D(n=92)

D(n=94) p value

ORR (%) 49.0 17.0 Not reported 61.0 34.0 0.0002

TTP (months) 7.1 3.0 <0.05 11.7 6.1 0.0001

OS (months) 25.0 18.0 Not reported 31.2 22.7* 0.0325

Trastuzumab plus docetaxel: long-term survival

Long-term survival (years)

Marty M, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S102 (Abstract 2067)

Pat

ien

ts (

n)

Trastuzumab + docetaxel

Docetaxel

>3 >4 >4.5

79% of the patients in the docetaxel-alone arm who survived ≥3 years had crossed over to receive trastuzumab

50

40

30

20

10

0

Evidence suggests trastuzumab should be used upfront

Marty M, et al. J Clin Oncol 2005;23:4265–74

Months

Est

imat

ed p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Trastuzumab + docetaxel (n=92)

Docetaxel alone/cross over (n=53)

Docetaxel alone (n=41)

16.6 30.3 31.2

Trastuzumab plus taxanes

Dramatic improvements in survival demonstrated with trastuzumab in the first-line setting– similar magnitudes of improvement have been reported only

rarely (in any therapeutic area)– trastuzumab is the only HER2-targeted therapy shown to

improve survival in MBC patients with HER2-positive tumours– benefits of trastuzumab were apparent regardless of age,

ER/PR status, or tumour burden– cross-over patients in M77001 did benefit from later

trastuzumab, but survival times were shorter than withfirst-line use

Evidence indicates trastuzumab should be initiated as soon as possible

PR = progesterone receptor

Case study

13.10.00

Invasive ductal breast cancer confirmed by high speed biopsy

HER2-neu overexpression (IHC3-positive), ER-positive, PR-negative

Locally-advanced breast cancer (LABC)and MBC: what are your options?

13.10.00

14.12.00

Paclitaxel weekly: 80mg/m² q7d x 8 + trastuzumab: 4/2mg/kg q7d x 8

q7d = every 7 days

LABC and MBC: what are your options?

LABC and MBC: what are your options?Still alive and doing fine

100.000

10.000

1000

100

10

0

02.10.00

30.10.00

27.11.00

25.12.00

22.01.01

19.02.01

19.03.01

16.04.01

14.05.01

11.06.01

09.07.01 20032002

Year 1 Year 2Year 3

Year 4

2004 2005 2006

Year 5Year 6

q3w = every 3 weeks; p.o. = by mouth; CEA = carcinoembryonic antigen; CA = cancer antigen; TCT = computed tomography of the thorax; ACT = computed tomography of the abdomen

Trastuzumab q3wTamoxifen

Bisphosphonate (p.o.)

CA 125

CA 15-3

CEA

Bone scan

TCT

ACT

Radiation

Trastuzumab

Paclitaxel

Are other trastuzumab-based treatment options needed for HER2-positive MBC?

Unmet clinical need, i.e.– patient has received prior taxanes– patient is not responding to taxanes

Other trastuzumab-based options include– non-taxane chemotherapy– triplet combinations– endocrine therapy

Potential for new treatment options based on trastuzumab

1. Trastuzumab plus non-taxane combinations

30 25 2525 25

1Jahanzeb M, et al. Oncologist 2002;7:410–17; 2Burstein HJ, et al. J Clin Oncol 2003;21:2889–95 3Bernado G, et al. J Clin Oncol 2004;22(Suppl. 23):59s (Abstract 731)

4Chan A, et al. Br J Cancer 2006;95:788–93; 5Bayo J, et al. J Clin Oncol 2004;22(Suppl. 23):67s (Abstract 763) 6Glogowska I, et al. J Clin Oncol 2004;22(Suppl. 23):235s (Abstract 3165)

7De Wit M, et al. J Clin Oncol 2004;22(Suppl. 23):84s (Abstract 831)8Burstein HJ, et al. J Clin Oncol 2001;19:2722–30; 9Papaldo P, et al. Ann Oncol 2006;17:630–6

30 25 25 35

Weekly vinorelbine schedule (mg/m2)

OR

R (

%)

First-line1–4

Trastuzumab plus vinorelbine:phase II trials

100

80

60

40

20

0

Second-line7–9First-/second-line5,6

Trastuzumab plus gemcitabine in MBC

Phase II study O’Shaughnessy et al. Christodoulou et al.

Patients (n) 64 28

Gemcitabineregimen

1,200mg/m2 days 1, 8 q3w

1,000mg/m2 days 1, 8, 15 q4w

Anthracycline-/taxane-pretreated (%) 95 100

ORR (%) 38 36

CR (%) 0 4

PR (%) 38 32

Median TTP (months) 5.8 7.8

Median OS (months) 14.7 18.7

O’Shaughnessy JA, et al. Clin Breast Cancer 2004;5:142–7Christodoulou C, et al. Proc Am Soc Clin Oncol

2003;22:42 (Abstract 166)q4w = every 4 weeks

Trastuzumab plus anthracycline: clinical trials in MBC

Untch M, et al. Eur J Cancer 2004;40:988–97Baselga J, et al. Eur J Cancer 2004;2:132 (Abstract 262)

Theodoulou M, et al. Proc Am Soc Clin Oncol 2002;21:55a (Abstract 216)

AuthorRegimen

(+ trastuzumab) nORR (%)

CHF (%)

Untch et al. 2004 EC (60/600mg/m2)EC (90/600mg/m2)

2625

6264

08

Baselga et al. 2004 Liposomal doxarubicin (50mg/m2 q3w) P (80mg/m2 qw)

24 91 0

Theodoulou et al. 2002 Liposomal doxarubicin(60mg/m2 q3w)

37 58 3

EC = epirubicin/cyclophosphamideCHF = congestiveheart failure

Trastuzumab plus non-taxane combinations

Promising phase II data for trastuzumab plus vinorelbine in HER2-positive MBC; high activity, favourable safety and tolerability– RR 6080% in first line; activity comparable to weekly taxane– active and well tolerated when used beyond disease

progression

Trastuzumab plus gemcitabine has shown activity in several phase II trials

High RR shown with trastuzumab plus anthracycline

Further clinical trials will better define the role for non-taxane combinations


2. Trastuzumab-based triplet regimens

Trastuzumab-based triplet regimens

Combining more than two agents has the potential to further improve ORR and increase survival

Several trastuzumab combinations of interest – trastuzumab/docetaxel/capecitabine (CHAT study)– trastuzumab/paclitaxel/carboplatin– trastuzumab/docetaxel/epirubicin– trastuzumab/paclitaxel/gemcitabine

Phase II study of trastuzumab plus docetaxel ± capecitabine in first-line MBC (CHAT)

Trastuzumab 8mg/kg loading dose,then 6mg/kg

+ docetaxel 75mg/m2, q3w+ capecitabine 950mg/m2 b.i.d.,

days 1–14 (n=112)

Death or disease

progression

*Three patients did not receive treatmentb.i.d. = twice daily

Trastuzumab 8mg/kg loading dose,then 6mg/kg

+ docetaxel 100mg/m2, q3w(n=110)

Wardley A, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S101 (Abstract 2063)

HER2-positive LABC and

MBC patients(n=225*)

CHAT: TTP significantly increased with the triplet than the doublet

Est

imat

ed p

rob

abili

ty

13.6 18.6

Events HR 95% CI p value

TDC 70TD 82

HR = hazard ratioC = capecitabine


1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Months

0.704 0.51–0.971 0.029

CHAT: longer median PFS with the triplet than the doublet

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

rob

abili

ty

0 5 10 15 20 25 30 35 40 45 50

Months

12.8 17.9

PFS = progression-free survival

Events HR 95% CI p value

TDC 75TD 85

0.725 0.529–0.99 0.0402


Manageable safety profile

Patients with grade 3/4treatment-related AEs (%)

Adverse event (AE)TDC

(n=112)TD

(n=110)

Alopecia 6 8

Diarrhoea 11 4

Nausea 1 0

Hand-foot syndrome 17 1

Vomiting 4 0

Asthenia 4 3

Fatigue 1 2

Mucosal inflammation 1 2

Peripheral oedema 1 4

Myalgia 0 1


CHAT: summary

Effective first-line strategy for HER2-positive MBC

TDC significantly prolonged both TTP (0.029) and PFS (0.0402) by approximately 5 months compared with TD

High tumour RRs and good tolerability

The potential of these agents as sequential therapy was not addressed in this trial


Paclitaxel plus trastuzumab plus carboplatin

1Perez E, et al. Breast Cancer Res Treat 2003;82(Suppl. 1) (Abstract 216)2Robert N, et al. J Clin Oncol 2006;24:2786–92

3Slamon DJ, et al. N Engl J Med 2001;344:783–92*HER2 IHC3+

RR1

RR2

RR3

Paclitaxel

17 41

Paclitaxel +trastuzumab

57* 36*

Paclitaxel + trastuzumab+ carboplatin

Weekly paclitaxel+ trastuzumab+ carboplatin

7165

(%)


3. Trastuzumab plus endocrine therapy

Trastuzumab plus hormonal therapy: rationale

Up to 50% of HER2-positive breast cancers are also ER-positive

Evidence of crosstalk between HER2 and ERsignalling pathways

Simultaneous targeting of both pathways may improve outcomes over monotherapy

Not all patients require chemotherapy (i.e. ER-positive patients at low risk)

Ellis M. Oncologist 2004;9(Suppl. 3):20–26Piccart-Gebhart MJ, et al. N Engl J Med 2005;353:1659–72

Crosstalk between signal transduction and endocrine pathways

Adapted from Johnston S.Clin Cancer Res 2005;11:889s–99s

SOSRAS

RAF

Basaltranscription

machineryp160

ERE ER target gene transcription

ER CBPPP P P

ER

Pp90RSK

AktP

MAPK P

Cellsurvival

Cytoplasm

Nucleus

ER

PI3-KP

P

PPP

P

Cellgrowth

MEKP

Plasmamembrane

Anastrozole

EGFR/HER2IGFR

Growth factorOestrogen Trastuzumab

EGFR = epidermal growth factor receptorERE = oestrogen response elementIGFR = insulin-like growth factor receptor

Phase III study of first-line trastuzumabplus anastrozole in MBC (TAnDEM)

Anastrozole 1mg/day p.o.*(n=104)

Anastrozole 1mg/day p.o. + trastuzumab 4mg/kg i.v. loading

dose then 2mg/kg weekly (n=103)

Disease progression

*Trastuzumab offered to patientswho progressed on anastrozole alone

Postmenopausal women with HER2-

positive (IHC3-positive and/or FISH-

positive) and ER- and/or PR-positive

MBC(n=207)

Mackey JR, et al. Breast Cancer ResTreat 2006;100(Suppl. 1):S5–6 (Abstract 3)

Doubled PFS in HER2-positive MBC: TAnDEM trial

An = anastrozole

103 48 31 17 14 13 11 9 4 1 1 0 0An + T104 36 22 9 5 4 2 1 0 0 0 0 0An only

Pro

bab

ility

95% CI

3.7–7.02.0–4.6

p value

0.0016

Median PFS(months)

4.82.4

Events

8799

Months

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50 55 60

No. at risk

HR

0.63

Mackey JR, et al. Breast Cancer Res Treat2006;100(Suppl. 1):S5–6 (Abstract 3)

An + TAn only

TAnDEM: summary

Addition of trastuzumab to anastrozole significantly extended PFS in women with HER2-positive, hormone receptor-positive MBC

>15% of patients receiving anastrozole plus trastuzumab experienced 2 years PFS– could allow delay in use of chemotherapy

Addition of trastuzumab improved median OS– although increase was non-significant (p=0.325)

AEs were as expected and manageable

Mackey JR, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S5–6 (Abstract 3)

Trastuzumab therapy in multiple lines

No resistance to trastuzumab

Issue of anti-HER2 therapy resistance remains unproven– is this true resistance?

Various options can be considered– continue with trastuzumab, but change

chemotherapy i.e. TBP– use of other HER2 agent, i.e. lapatinib plus

capecitabine after progression on trastuzumab therapy for MBC (EGF100151 study)

– retreatment with trastuzumab after second-/third-line therapy

Geyer CE, et al. J Clin Oncol2007;25(Suppl. 18):40s (Abstract 1035)TBP = treatment beyond progression

Patients still benefit from trastuzumab after progression in the metastatic setting Treatment in multiple lines

No. of patients

ORR for second trastuzumab-based regimen (%)

Fountzilas et al. 2003 80 24 Gelmon et al. 2004 65 32 Tripathy et al. 2004 93 11 Garcìa-Sáenz et al. 2005 31 26 Stemmler et al. 2005 23 39 Bartsch et al. 2006 54 26 Montemurro et al. 2006 40 18 Morabito et al. 2006 7 29 Orlando et al. 2006 11 18 Tokajuk et al. 2006 27 50 Bachelot et al. 2007 17 29 Baselga et al. 2007 33 18 Metro et al. 2007 37 29 Antoine et al. 2007 107 NR Von Minckwitz et al. 2007 78 49 NR = not reported

GBG-26: trastuzumab beyond progression study

Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w

Capecitabine 1,250mg/m² b.i.d. days 1–14 q3w +

trastuzumab continuation 6mg/kg q3w

Randomisationn=78 each arm

CapecitabineCapecitabine

+ trastuzumab HR

ORR (%) 24.6 48.9

Median PFS (months)

5.653 events

8.5 48 events

0.71

Median OS (months)

19.931 events

20.3 26 events

0.79

Von Minckwitz G, et al. Breast Cancer Res Treat 2007;106(Suppl. 1):S185 (Abstract 4056)

Patients who progressed or died during 2-year follow-up

(n=185*)

Hermine cohort study

Trastuzumab continued after

disease progression(n=107)

Trastuzumab stopped at disease

progression(n=70)

Trastuzumab as first-line therapy(n=221)

Trastuzumab as second-line therapy(n=138)

Patients who progressed or died during 2-year follow-up

(n=121†)

*Data unavailable for eight patients†Data unavailable for four patients

Patients with HER2-positive MBC(n=623)

Antoine EC, et al. Eur J Cancer 2007;5 (Suppl. 4):213 (Abstract 2099)

Trastuzumab continued after

disease progression(n=87)

Trastuzumab stopped at disease

progression(n=30)

HERMINE study: longer OS for patientsreceiving trastuzumab as first-line therapy

0 5 10 15 20 25 30 35 40

1.0

0.8

0.6

0.4

0.2

0

Months

Pro

bab

ility

T continued after disease progressionT stopped at disease progression

16.8

Median OS from date of progression: 4.6 vs 21.3 months

Antoine EC, et al. Eur J Cancer 2007;5(Suppl. 4):213 (Abstract 2099)

Median follow-up: 24.1 months

<0.0001NR 16.8

30.4–NR 12.5–19.4

Median OS (months) p value95% CI

HERMINE study: cardiac safety in patients receiving trastuzumab as first-line therapy

LVEF = left ventricular ejection fraction


Patients, n (%)

Trastuzumab stopped at PD (n=70)

Trastuzumab continued after PD (n=107)

LVEF assessed during study 57 (81) 97 (91)

LVEF worst value

Absolute decrease 15%

Value of <40%

Value of <50%

5 (21.7)

3 (7.3)

10 (24.4)

9 (20.5)

2 (2.6)

10 (12.7)

Congestive heart failure 1 (1.4) 1 (0.9)

HERMINE study: longer OS for patientsreceiving trastuzumab as second-line therapy

Median OS from date of progression: 11.0 vs 15.3 months


T continued after disease progressionT stopped at disease progression

27.115.6

22.7–32.96.0–NR

Median OS (months) p value95% CI

0 5 10 15 20 25 30 35 40

1.0

0.8

0.6

0.4

0.2

0

Months

Pro

bab

ility

15.6

Median follow-up: 23.1 months

0.08

27.1

Importance of side effects in the treatment of breast cancer

Patients with breast cancer can expect to receive multiple lines of therapy during the course of their disease

Safety is important for all women with breast cancer, but for women receiving multiple lines of treatment, safety is of particular importance

First diagnosis Surgery

Neoadjuvant Adjuvant

MBC

First line Second line

Trastuzumab: safety and tolerability

Trastuzumab is generally well tolerated and not associated with the typical side effects of chemotherapy

The most relevant AEs associated with trastuzumab are

– serious infusion-related reactions (0.3%)

– congestive heart failure (2% in MBC trials)1

Patients at risk can be identified prior to therapy and the majority of events are manageable

Cardiac safety and clinical symptoms should be continuously monitored (i.e. every 3 months) during trastuzumab therapy

1Ewer MS, O’Shaughnessy JA. Clin Breast Cancer 2007;7:600–7

Pertuzumab: a new class ofanti-HER2 therapy

Pertuzumab

Monoclonal antibody against HER2

Binds different HER2 epitope to trastuzumab1

– prevents receptor dimerisation1

– inhibits HER2-mediated signalling1

First in a new class of HER2-targeted therapies

Complementary mechanism of action to trastuzumab suggested by preclinical evidence2,3

1Agus DB, et al. J Clin Oncol 2005;23:2534–432Friess T, et al. Ann Oncol 2006;17(Suppl. 9):ix58

3Arpino G, et al. J Natl Cancer Inst 2007;99:694–705

The study is being monitored by an IDSMBNo safety objections raised, study continuing to stage II

– only two patients had a falling LVEF (≤50% and ≥10%)

n=58 fully evaluable patients ORR = 18.2% Clinical benefit rate = 39.4% Updated efficacy data will be reported in 2008

Phase II trial: pertuzumab plus trastuzumab in MBC progressing during treatment with

trastuzumab

Stop trial

Stage II (n=66)Stage I (n=24)Trastuzumab +pertuzumab*

NO

YES

*Trastuzumab: 4mg/kg loading dose 2mg/kg qw or8mg/kg loading dose 6mg/kg q3w;Pertuzumab: 840mg loading dose 420mg q3wIDSMB = International Data Safety Monitoring Board

Baselga J, et al. J Clin Oncol2007;25(Suppl. 18S):33s (Abstract 1004)

2 PR or 1 PR + 12 SDor 13 SD

Safety evaluationfor IDSMB

Phase III trastuzumab plus pertuzumabtrial in first-line MBC

Endpoints PFS OS Quality of life

Placebo + trastuzumab + docetaxel

Pertuzumab + trastuzumab + docetaxel

A

B

400 patients

400 patients

Tumour assessments Survival follow-upR

A decade of success: the first agent to improve survival in HER2-positive MBC

Introduction of first-line trastuzumab has shown OS can be significantly improved in HER2-positive MBC

Trastuzumab is effective and well tolerated

– adding little to the toxicity of systemic chemotherapy regimens and without impacting quality of life

– limited long-lasting/acute side effects

Trastuzumab should be used as soon as HER2-positive status is identified for best results

Several trastuzumab-based regimens are now available, providing clinicians with treatment options in different lines of therapy and for a broad range of patients

Documents

Christian Jackisch Head of the Department of Gynaecology at Klinikum Offenbach Senior Lecturer at Philipps University of Marburg, Germany Chairman of the