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Ongoing Clinical Research & Trials Multidisciplinary Breast Centre

Ongoing Clinical Research & Trials Multidisciplinary Breast Centre. P. Neven GYN ONCOL & MBC, UZ-KULeuven. May 2007. Ten most frequently occuring tumours in Flanders, 2000 - 2001. Source: Vlaams Kankerregistratienetwerk, VLK.

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Ongoing Clinical Research & Trials Multidisciplinary Breast Centre

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  1. OngoingClinical Research & TrialsMultidisciplinary Breast Centre P. Neven GYN ONCOL & MBC, UZ-KULeuven May 2007

  2. Ten most frequently occuring tumours in Flanders, 2000 - 2001 Source: Vlaams Kankerregistratienetwerk, VLK

  3. Age-specific incidence of breast cancer in women, Flanders, 1997-2001 Source: Vlaams Kankerregistratienetwerk, VLK SABCS 2006 2003: A decrease in breast cancer incidence

  4. May be the incidence will come down?

  5. I. OngoingClinical Trials II. Ongoing MBC Research Projects May 2007

  6. I. Clinical Trials Prevention, Adjuvant, Metastatic Completed, Recruiting, Future Trials Endocrine Therapy, Chemotherapy, Targeted Therapy May 2007

  7. Recently Closed Clinical Trials Adjuvant: BIG-1-98, TEAM, (E-)ZOFAST TACT, FEC-TXT (dd), Caelyx-Endoxan HERA, AC-AT, Metastatic: Lapatinib trials, Tam + Iressa, EFECT, Lapatinib + Zarnestra, … Radiotherapy: MSP-trial May 2007

  8. Prevention: IBIS-2 DCIS/High Risk Neo- Adjuvant: Taxotere-Xeloda-Herceptin Adjuvant: SOFT, TEXT, TAGAS, Pregnancy (pharmacokinetics & outcome) Metastatic: MoAbIGF-1R, FINDER-2, Vinflunin, Oral Navelbine, Xeloda +/- Sutent, BIBW, HKI Eye trial (Maxidex vs Lacrystat Taxotere related dacrocystostenosis) Recruiting Clinical Trials May 2007

  9. Future Clinical Trials Neo- Adjuvant: Neo-Allto Neoadjuvant Paclitaxel + Herceptin +/- Pertuzumab Adjuvant: Fertility trial, SOLE, ALTTO MINDACT, CASA Metastatic: Lapatanib +/- Pazopanib May 2007

  10. Recruiting Clinical Trials IBIS-2 DCIS (tamoxifen standard) High Risk (placebo standard)

  11. Aromatase Inhibitors versus Tamoxifen Why IBIS-II? Prevention Incidence of Contralateral Breast Cancers Number ofcases ATAC IES MA17 BIG 1-98 50 40 30 48 20 28 26 26 21 10 16 14 12 0 T (n=2575) L (n=2582) E (n=2352) T (n=2372) A (n=3125) T (n=3116) L (n=4003) T (n=4007)

  12. OngoingClinical Trials Breast Cancer Prevention Postmenopausal Women IBIS-2: 20 countries recruiting Prevention: Placebo vs Anastrozole 36/1516 ER+ DCIS: Tamoxifen vs Anastrozole 63/1014 Late age 1st pregnancy, parity, age menopause, breast density, familial history, LCIS, ADH Subprotocol: Bone, Lipid, Cognitive function May 2007

  13. IBIS-2Recruiting Centres • St.Luc Brussel • St.Pierre Brussel • VUB Brussel • Virga Jesse Hasselt • St.Elisabeth Namen • St.Augustinus Wilrijk • Erasmus Brussel • Bordet Brussel • Heilig Hart Leuven • OLVrouwZH Aalst • ZOL Genk • Clinique St.Pierre Ottignies • CHR Citadelle Luik • Brugmann Brussel • Centre Hospitalier de l’Ardenne If you have small cell LCIS, NSABP-P1 included 850 such patients 7-years of follow-up Tamoxifen versus Placebo Events13 (Tam) vs 38 (Placebo) If placebo: incidence of event is 1-2%

  14. Recruiting Clinical Trials FINDER-II 2nd line Metastatic Endocrine

  15. 0.8 0.6 0.4 0.2 0.0 1.0 Fulvestrant Tamoxifen 700 500 200 400 600 300 100 800 0 First Line: TTP Benefit of Fulvestrant over Tamoifenin ER+ & PgR+ Patients* Proportionnotprogressed Median TTP: Fulvestrant: 11.4 months Tamoxifen: 8.5 months Hazard ratio = 0.85 CI (0.63–1.15); p=0.31 ORR F 44.3% vs T 29.8%; p=0.02 TTP (days) Howell et al. JCO 2004; 22: 1605-13 *Retrospective analysis

  16. Fulvestrant 250 mg/month Provides Long-term Downregulation of ER Levels p=0.001 Mean ERH-score 300 p=0.01 250 200 150 100 50 0 Pre-treatment (n=29) 4-6weeks (n=26) 6months (n=20) PD(n=8) Time on treatment Gutteridge et al. SABCS 2004

  17. Fulvestrant induces dose-related ER downregulation(PgR and Ki67)* Changefrom baseline(%) –13% –39% –50% –59% Placebo (n=29) Fulvestrant50 mg (n=31) Fulvestrant 125 mg (n=32) Fulvestrant 250 mg (n=32) Pre-treatmentmean H-score 125 136 124 113 *Data not shown Robertson et al. Cancer Res 2001; 61: 6739–6746

  18. Finder-II Endpoints • TTP (primary) • ORR • CB • Safety 135 postmenopausal women with HR+ ABC after failure on one prior endocrine therapy Randomisation 1:1 Fulvestrant AD Fulvestrant HD Fulvestrant LD 3-monthly follow-up Progression HD, high-dose (500 mg IM on Day 0, 500 mg on Days 14 and 28 and 500 mg every 28 3 days thereafter)LD, high-dose (500 mg IM on Day 0, 250 mg on Days 14 and 28 and every 28 3 days thereafter) AD, approved dose (250 mg IM every 28 3 days)

  19. Finder II Overview of Eligibility(2nd line Breast Cancer Treatment) Patients who previously received adjuvant treatment Eligible? ABC EBC 12 Month gap KEY Adjuvant Treatment Eligible (randomised into study) Not Eligible First Line Treatment R = Recurrence P = Progression R Yes R Yes R No P R Yes Patients who were diagnosed with Advanced Breast Cancer P Yes Regulatory Definition of 2nd line Breast Cancer

  20. Current & Future Clinical TrialsTargeted Therapies ALTTO Adjuvant

  21. Two Targets, One DrugLapatinib Profile Lapatinib is a novel oral dual-tyrosine kinase inhibitor with specificity for the ErbB-1 andErbB-2 receptors • Belongs to the 4-anilinoquinazoline class of tyrosine kinase inhibitors • Binds reversibly to the cytoplasmic ATP-binding site of the kinase, thereby preventing receptor phosphorylation and activation N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine Lapatinib

  22. ALTTO STUDY DESIGN • Four-arm, randomised, open-label and multicentre study in women with primary breast cancer that over expresses or amplifies HER2. • Sample Size 8000 patients • Primary Endpoint: DFS • Secondary Endpoints • OS • TTR (time to recurrence) • TTDR (Time to distant recurrence) • Safety and tolerability • Proposed start 2Q07 • Study duration: 5 years (4 years for enrolment and 1 year as follow-up) • 2 Interim analyses (at 600 and 1000 DFS events, approximately)

  23. ALTTO STUDY DESIGN • 4 Arms: • Trastuzumab for 52 wks • Lapatinib for 52 wks • Trastuzumab + Lapatinib for 52 wks • Trastuzumab for 12 wks, 6 wk washout, Lapatinib for 34 wks • Treatment Schema 1 - all (neo-)adjuvant chemotherapy completed prior to administering targeted therapy • Treatment Schema 2 - targeted therapy is initiated after (neo)adjuvant anthracycline-based chemotherapy and given concurrently with weekly paclitaxel

  24. 52 Weeks BASE LINE RANDOMISATION Trastuzumab 3- weekly 8mg/kg then 6mg/kg (+ radiotherapy when indicated) Local Determined HER 2 positive Lapatinib 1500 mg/day (+ radiotherapy when indicated) Central Determined HER 2 positive 6 weeks Washout Trastuzumab 4mg/kg then 2mg/kg weekly for 12 wks Lapatinib 1500 mg/day for 34 wks Surgery, complete Neo-adjuvant Chemotherapy (+ radiotherapy when indicated) Lapatinib 1000 mg/day + Trastuzumab 3- weekly 8mg/kg then 6mg/kg (+ radiotherapy when indicated) LVEF  50% Patients with ER or PgR-positive tumours receive endocrine therapy selected according to menopausal status: endocrine therapy will be started after the end of the chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years

  25. L 1500 mg/day + paclitaxel 80 mg/m2 weekly Surgery FEC x 3 courses Lapatinib (L) 1500 mg/day L 1500 mg/day Trastuzumab (T) 4 mg/kg, then 2 mg/kg weekly T 2 mg/kg weekly + paclitaxel 80 mg/m2 weekly T 6 mg/kg at 3 week intervals L 1000 mg/day + T 4 mg/kg, then 2 mg/ kg weekly L 1000 mg/day + T 2 mg/kg weekly + paclitaxel 80 mg/m2 weekly L 1000 mg/day + T 6 mg/kg at 3 week intervals NEO - ALTTO STUDY DESIGN (T>2 cm, Nx, M0, FISH +, IHC 3+) 6 weeks 12 weeks 9 weeks 34 weeks Tumor biopsy Tumor biopsy PET

  26. New drugs for targetting HER-1 / HER-2 / …Dual-Target HER-1 Drugs in the Pipeline • Lapatinib HER-1, HER-2 GSK Phase III breast • HKI-272 HER-1, HER-2 Wyeth Phase II breast • BIBW-2992 HER-1, HER-2 Boehringer Phase II breast • AEE788 HER-1, HER-2, VEGF Novartis Solid tumours • BMS-599626 HER-1, HER-2 BMS Solid Tumours • CI-1033 HER-1, HER-2, HER-4 Pfizer Phase II breast • … Metastatic

  27. Recruiting Clinical Trials Targetted Therapies Exemestane +/-IGF-1R 1st Line Metastatic Endocrine

  28. IGF and its receptorImportant mediators of cell growth

  29. Combining Endocrine and Biological Agents in M+ Breast Cancer Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer IGF IGF regulates the malignant phenotype IGF is a strong breast cancer mitogen There is cross talk between ER and IGF signalling Non-genomic or genomic ER IGF is a regulator of estrogen-mediated growth IGF induces proliferation of ER+ breast cancer cells Upregulation in tamoxifen-resistant breast cancer cells

  30. Oestrogen Receptor- Mediated Signalling Pathways in Breast Cancer IGF-1R IGFR is Tyrosine Kinase type 1 receptor Small molecules and MoAb Monoclonal AB

  31. Oestrogen Receptor- Mediated Signalling Pathways in Breast CancerExemestane + MoAb/IGF-1R vs Exemestane Pfizer ER+ First Line Measurable Metastatic Randomized (1:1) and Open Label 150 patients PFS CB, Safety, PK parameters, CTC markers for expression of IGF-1R, HRQoL CP 751,871 // 20mg/kg // q3w Arm A Exemestane 2.5mg + CP  Fulvestrant + CP q4w Arm B Exemestane 2.5mg  CP

  32. II. Own Clin. And Basic ResearchRecently Published …(leaving out clin. trials) Prophylactic mastectomy and subclinical breast pathologies HER-2 expression by body weight Arthralgia and AIs The prognostic value of PR in breast cancer LHRH-agonists to protect ovarian function in ER-pos BrCa The continuous importance of tamoxifen as an adjuvant therapy Endometrial thickness on AI-switch MMP in breast cancer Associations between ER/ PR/ HER2 expression in operable BrCa May 2007

  33. May 2007 OngoingClinical & Basic Research Early relapse by ER/ PR/ HER2 expression: “Improving NPI” HER-1 / uPAR in triple negative and other breast cancers PET-CT in staging large and locally advanced breast cancer Correlations LN-status - ER/PR/HER-2, LN-status - age Correlations Age - ER/PR/HER-2 expression Retrospective and prospective registration study: Breast cancers & Mirena Postmenopausal breast cancer characteristics by use of HRT Paloprai, ER-PR+ breast cancers, Fulvestrant and uterine volume Molecular genetic analysis as an addition to the morphologic classification of breast cancers The clinical relevance of protease in breast cancer: matrix metalloproteinasen and cathepsines Menopausal symptoms of breast cancer therapies Proteonomics in breast cancer Genetics in breast and ovarian cancer PhD topics

  34. Breast Cancer Prognosis Global molecular genetic approach ER - ER + basal-like HER-2 + ? luminal type (subtype A, B/C)

  35. DFS in 1962 operable breast cancersSubgroup Analysis by ER/PR/HER-2 Thesis Lic Biomed. Sc. (S. Pintens) and Project Co-Assist. (O. Brouckaert)

  36. Early breast cancer relapse by ER/PR/HER-2 – n=1962 O Brouckaert & S Pintens DFS by ER/PR/HER-2 UZ Leuven 2000 - 2005

  37. Annual incidence of relapseNNN Early relapse

  38. Can we improve NPI?

  39. The futureCyclin E as a prognostic factor Stage I-II breast cancer: Total cyclin E predicts Survival

  40. Interaction ER-status and age by HER-2 status ER/PR and HER-2 HER-2 negative HER-2 positive The interaction between ER and age is HER-2 dependent The negative association between ER and HER-2 is age dependent

  41. Interaction PR-status and age by HER-2 status ER/PR and HER-2 HER-2 negative HER-2 positive The interaction between PR and age is HER-2 dependent The negative association between PR and HER-2 is age dependent

  42. Interaction HER-status and age by ER/PR ER/PR and HER-2 The interaction between HER-2 and age is ER/PR dependent The older one is the less likely HER-2 positive is only if the tumour is ER-positive

  43. Adjuvant Therapy Breast Cancer: Adjuvant TherapyTreatment Side Effects Quality of Life Lani Morales

  44. PROGRESS IN BREAST CANCER ADJUVANT THERAPY Average treatment effect Financial toxicity d)  20.000 $ c) 13.800 $ b)  7.400 $ a)  800 $ + Herceptin: 40.000 euro TAC x 6 FEC  docetaxel AC  paclitaxel dose-dense +++ +++ FAC  FEC x 6 A(E)  CMF AC x 4  Paclitaxel x 4 ++ ++ CMF x 6 AC x 4 + + L-PAM, MF ± ± 1970’s 1980’s 2000’s 1990’s Successive generations of adjuvant CT regimens ++ ADJUVANT AIs ++ Adapted from G. Hortobagyi

  45. Multidisciplinary Breast Centre- UZLeuvenMay 2007 Centrum Vergadering Medical Director Head of departments Pathology Radiology Surgery Med Oncol Radiotherapy Obstet & Gyn • Coordinator: MR Christiaens • Radiology: A Van Steen, C Van Ongeval • Pathology: M Drijkoningen • Surgery: MR Christiaens, A Smeets • Gynaecology: P Neven, K Leunen, F Amant, P Berteloot • Plastic Surgery: M Vandevoort, G Fabre • Med Oncology: R Paridaens, H Wildiers • Radiotherapy: W Van den Bogaert, E Van Limbergen, C Weltens • Human Genetics: E Legius • KanActief: L Serrien • Data Manager: W Hendrickx • Breast “nurses”, Physiotherapists, Trial “nurses” • PhD: I Van den Bempt, A Smeets, J De Cock • Assistents

  46. I hope I gave you a touch of ourongoingClinical Research & Trial ActivitiesMultidisciplinary Breast Centre

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