1. St. Gallen 2007 Consensusmeeting P. Berteloot

2. First select the target : better choice of adjuvant treatments for breast cancer patients St Gallen 2005 1 Target = endocrine sensivity 1 Target = endocrine sensivity (low – intermediate -high) 2 defining the riskgroups 2 defining the riskgroups (low – intermediate- high)

3. Break-throughs since 2005 Herceptin! Herceptin! Confirmation A.I. Confirmation A.I. Lower threshold for Taxanes Lower threshold for Taxanes

4. Present Problems Past trials : large but not selective Past trials : large but not selective General conclusions General conclusions Possibly not suitable for all subgroups Possibly not suitable for all subgroups Not pre-planned subgroup analysis are statistically not reliable Not pre-planned subgroup analysis are statistically not reliable

5. Need for Inclusion criteria for future trials should be selective for important targets Inclusion criteria for future trials should be selective for important targets Individualised therapy should be based on reliable and selective tumor information Individualised therapy should be based on reliable and selective tumor information Pitfalls of diagnostic procedures Pitfalls of diagnostic procedures DCIS ~ micro-invasion DCIS ~ micro-invasion Passive transportation of malignant cells -> axilla Passive transportation of malignant cells -> axilla Error rate in HR assessement Error rate in HR assessement Depending on different kits Depending on different kits Fixation Fixation Eroor rate in HER 2 status Eroor rate in HER 2 status Viale G.

6. Importance of local control by surgery and Radiotherapy Improved local control at 5 years of follow-up Proportional survival benefit at 15 years of follow- up Ratio 4:1

7. Important highlights of St Gallen 2007 MRI staging in breastcancer MRI staging in breastcancer Ipsilateral : 15-20 % Ipsilateral : 15-20 % Contralateral : 3-5 % Contralateral : 3-5 % Independent of : Independent of : Age Age Pathology Pathology Mammographic density Mammographic density C. Kuhl NEJM

8. Breast surgery in advanced breast cancer Regained importance due to : Regained importance due to : Better and longer control of distant disease Better and longer control of distant disease Ability of detecting small metastatic foci Ability of detecting small metastatic foci Large retrospective reviews of patients treated by surgical resection of the primary tumor to clear borders have demonstrated longer survival

9. Predictive factors for chemosensitivity TOPO II  TOPO II  Sensitivity for anthracyclines Sensitivity for anthracyclines Gene level ~ protein level Gene level ~ protein level if proliferation index ( KI67) is elevated Taxanes Taxanes Tau-protein Tau-protein HER 2 pos ? HER 2 pos ? P-53 mutations P-53 mutations

10. Predictive factors for chemosensitivity Alkylantia AlkylantiaPlatinum ER positive ER positive < 35 years < 35 years HER 2 signaling HER 2 signaling worse prognosis DNA Damaging Agents in BRCA1 patients

11. Association HER 2 – ER-pos Chances of finding HER 2 positivity associated with ER-positivity is higher in young than in older women Chances of finding HER 2 positivity associated with ER-positivity is higher in young than in older women

12. Herceptin Update Hera-trial Update Hera-trial 2 years of follow-up 2 years of follow-up 1 year of Herceptin 1 year of Herceptin DFS : 6,3 % DFS : 6,3 % OS : 2,7 % OS : 2,7 % Compairable gain for all subgroups Compairable gain for all subgroups 2 important questions 2 important questions Sequencing ? Sequencing ? Duration of therapy ? Duration of therapy ? absolute gain

13. Consensus issues concerning Herceptin Chemo in Her 2 positive patients Chemo in Her 2 positive patients Dependent on receptor status: 60 % yes Dependent on receptor status: 60 % yes Anthracyclines to all: 73 % yes Anthracyclines to all: 73 % yes Taxanes to all: 43 % yes Taxanes to all: 43 % yes 6 to 8 cycles: 63 % yes 6 to 8 cycles: 63 % yes

14. Chemotherapy schedules in HER 2 + CAF ~ CEF: 62 % yes CAF ~ CEF: 62 % yes AC-T: 32 % yes AC-T: 32 % yes FEC: 32 % yes FEC: 32 % yes TAC: 30 % yes TAC: 30 % yes FEC-TAX: 32 % yes FEC-TAX: 32 % yes TAX + carbo: 51 % yes TAX + carbo: 51 % yes The opinions are very devided

15. Sequencing Herceptin-Chemotherapy Sequential : 38 % Sequential : 38 % Concommittant: 40 % Concommittant: 40 % No preference: 22 % No preference: 22 %

16. Duration of Herceptin administration Shorter in elderly: 51 % yes Shorter in elderly: 51 % yes Shorter for node neg: 38 % yes Shorter for node neg: 38 % yes Is duration riskdependent: 40 % yes Is duration riskdependent: 40 % yes Importance of early onset: 60 % yes Importance of early onset: 60 % yes 12 months: 91 % yes 12 months: 91 % yes 9 weeks + Docetaxel: 14 % yes 9 weeks + Docetaxel: 14 % yes 2 years: ? 2 years: ?

17. Herceptin indications IHC +++: 92 % IHC +++: 92 % FISH requested: 15 % yes FISH requested: 15 % yes T<1 cm T<1 cm Node neg: 56 % yes Node neg: 56 % yes Receptor neg Receptor neg Tx node neg: 58 % yes Tx node neg: 58 % yes Receptor pos  independent of node and receptorstatus

18. Safety of Herceptin Avoid low LVEF (  50-55): 74 % yes Avoid low LVEF (  50-55): 74 % yes > 70 years: 30 % yes > 70 years: 30 % yes Preventive use of ace inhibitors: 7 % yes Preventive use of ace inhibitors: 7 % yes

19. Hormonal therapy Postmenopausal consensus topics Tam alone Tam alone Node neg: 50 % Node neg: 50 % Node pos: / Node pos: / High ER-PR: 54 % High ER-PR: 54 % HER 2 neg: 52 % HER 2 neg: 52 %

20. Hormonal therapy Postmenopausal consensus topics AI upfront AI upfront In all patients: 19 % yes In all patients: 19 % yes High risk: 65 % yes High risk: 65 % yes HER 2 pos: 66 % yes HER 2 pos: 66 % yes HER 2 neg: 33 % yes HER 2 neg: 33 % yes

21. Hormonal therapy Postmenopausal consensus topics If started with TAM If started with TAMSwitch all: 50 % yes After 2 to 3 years: 89 % yes After 5 years: 60 % yes Only for TAM-intolerance: 65 % yes

22. Preference 1. AI upfront: 31 % 2. TAM  AI: 63 % 3. TAM x 5  : 5,7 %

23. After 5 years of TAM  AI All: 84 % yes All: 84 % yes Node pos: 92 % yes Node pos: 92 % yes HER 2 neg: 40 % yes HER 2 neg: 40 % yes HER 2 pos: 74 % yes HER 2 pos: 74 % yes

24. Total duration of hormonal therapy 5 years: 58 % 5 years: 58 % 5 to 10 years: 75 % 5 to 10 years: 75 % > 10 years : ? > 10 years : ? Life-time for high-risk patients:37 % Life-time for high-risk patients:37 %

25. Evaluation ovarian function at the start of AI By onset: 55 % yes By onset: 55 % yes After 6 to 12 weeks: 48 % yes After 6 to 12 weeks: 48 % yes

26. Supportive care + AI Ca + Vit D: 61 % yes Ca + Vit D: 61 % yes Bifosfanates for all: 3 % Bifosfanates for all: 3 % Fysical exercise: 100 % Fysical exercise: 100 % BMC: 88 % BMC: 88 %

27. Pre-menopausal : consensus topics TAM alone is an option: 92 % yes TAM alone is an option: 92 % yes OFS + TAM is an option: 83 % yes OFS + TAM is an option: 83 % yes OFS alone OFS alone For everyone: 7 % yes For everyone: 7 % yes For low risk: 32 % yes For low risk: 32 % yes

28. Modality of ovarian suppression LHRH analogue: 100 % LHRH analogue: 100 % Surgery: 76 % Surgery: 76 % Radiotherapy: 19 % Radiotherapy: 19 % Depending on age and: 75 % histological subtype Depending on age and: 75 % histological subtype

29. Duration of ovarian suppression 2 years for all: 29 % 2 years for all: 29 % 2 years node negative : 43 % 2 years node negative : 43 % node positive node positive 5 years node positive : 66 % 5 years node positive : 66 % HER 2 positive HER 2 positive 5 years for all: 25 % 5 years for all: 25 % Individualisation: 79 % Individualisation: 79 %

30. Chemo + OFS Concurrently: 30 % Concurrently: 30 % Sequentially: 82 % Sequentially: 82 % Concurrently to preserve : 65 % fertility Concurrently to preserve : 65 % fertility

31. OFS + AI All: 6 % All: 6 % Contra-indication for Tam: 68 % Contra-indication for Tam: 68 % Trials: 54 % Trials: 54 %

32. AI : timing attempt to conclusions Upfront : patients with high risk for early relapse Upfront : patients with high risk for early relapse High tumorload :  T2 ;  N2 High tumorload :  T2 ;  N2 Biological agressiveness Biological agressiveness gr III gr III HER 2 pos HER 2 pos vascular invasion vascular invasion Negative hormone receptor status Negative hormone receptor status Mauriac, Ann Oncol

33. AI : timing Switch after 2-3 years : intermediate risk Switch after 2-3 years : intermediate risk Adjuvant hormonal therapy ≥ 5 years Adjuvant hormonal therapy ≥ 5 years Relapse curve receptor positive patients Relapse curve receptor positive patients Increased benefit ~ duration extended adjuvant therapy Increased benefit ~ duration extended adjuvant therapy

34. Saphner et al. J Clin Oncol. 1996;14:2738. 0 0.1 0.2 0.3 0123456789101112 Recurrence hazard rate Years ER– (n=1305) ER+ (n=2257) Long-Term Risk of Breast Cancer Recurrence Remains High in ER+ Patients

35. Annual Risk of Recurrence by Nodal Status The risk of late recurrence remains substantial even in patients with node-negative tumors The risk of late recurrence remains substantial even in patients with node-negative tumors Recurrence hazard rate 0 0.1 0.2 0.3 N0 N1-3 N4+ 0123456789101112 Saphner et al. J Clin Oncol. 1996;14:2738. Years

36. Benefit of TAM +/- OS No clear evidence found ! No clear evidence found ! N. Davidson No large prospective randomised trials available No large prospective randomised trials available Actual SOFT trial and TEXT trial Actual SOFT trial and TEXT trial Meta-analysis by Jack Cuzick Meta-analysis by Jack Cuzick Limited benefit likely Limited benefit likely Age dependent ? Age dependent ?

37. Chemotherapy Hormone sensitivity Hormone sensitivity indicate indicate : the additional gain of chemotherapy eg postmenopausal patients : hormone receptor positive 3 % and hormone receptor negative 8% Preference of schedule No consensus at all Tendency to be more aggressive in HR neg en HER 2 pos patients HER 2 Status HER 2 Status

38. Incorporation of taxanes Only trials in node pos patients3 – 7 % gain Only trials in node pos patients3 – 7 % gain Level 1 evidence ? Level 1 evidence ? Only PACS 01 has an optimal control arm Only PACS 01 has an optimal control arm PACS 01: imbalance of ER status and unexplained age difference PACS 01: imbalance of ER status and unexplained age difference Dependent on: Dependent on: Hormone receptor status Hormone receptor status HER 2 positivity ? HER 2 positivity ?

39. Conclusion St. Gallen 2007 No consensus yet No consensus yet We don’t expect large changes in our home strategy We don’t expect large changes in our home strategy

40. Guidelines: UZ leuven Adjuvant therapy?