Systemische therapie: zijn alle doelen nu bereikt

2. Systemische therapie:zijn alle doelen nu bereikt? Dr. Yvonne Kamm internist-oncoloog UMC St Radboud Nijmegen

3. Onderwerpen Hormonale therapie: Hoe lang? Tamoxifen of AI? - HST - CYP2D6 en Tamoxifen Targeted therapie: Trastuzumab Lapatinib Pertuzumab

4. ATLAS-trial Adjuvant Tamoxifen, Longer Against Shorther Internationale gerandomiseerde trial 10 vs 5 jaar tamoxifen 11.500 vrouwen – voorlopige resultaten

5. ER-status en compliance ER+ 59% ER niet getest 41% ? gedeelte ER+ ~ 90%, niet 100% Hormonale behandeling 2 jaar na randomisatie 83% v 4% ? verschil ~ 80%, niet 100%

6. Mogelijke verdere effecten 10 v 5 jaar tamoxifen in ER+

7. ATAC-trial‘Arimidex’, Tamoxifen, Alone or in Combination Analyse effectiviteit en veiligheid 100-maanden mediane follow-up Anastrozole v Tamoxifen

8. ATAC trial design The ATAC trial was designed to compare anastrozole (1 mg/day) with tamoxifen (20 mg/day), alone or in combination. At a planned interim analysis (median follow-up of 33 months), no additional benefits could be found in the combination arm over the monotherapy arms and so the combination arm was closed.The ATAC trial was designed to compare anastrozole (1 mg/day) with tamoxifen (20 mg/day), alone or in combination. At a planned interim analysis (median follow-up of 33 months), no additional benefits could be found in the combination arm over the monotherapy arms and so the combination arm was closed.

9. Efficacy endpoints for all patients and HR+ patients The ATAC trial demonstrated that anastrozole was consistently superior to tamoxifen for all efficacy endpoints except overall survival, death after recurrence and death without recurrence where no significant change was observed. Anastrozole has proven superiority over tamoxifen, in terms of significant reduction in all forms of recurrence, ensuring that women can live cancer-free for longer. Overall survival, after a median follow-up of 100 months, is similar for both anastrozole and tamoxifen. Anastrozole reduces the risk of death following recurrence by 10% Although currently not statistically significant (p=0.2), there is a 90% chance that time to death following recurrence is longer with anastrozole. Deaths without recurrence were slightly but not significantly higher in the anastrozole group but no specific cause of death was elevated; most likely this is due to play of chance. There was no evidence of increased cardiovascular mortality or morbidity. This makes it difficult to show a benefit when patients are dying from other causes by virtue of their old age (mean age 72 years) The ATAC trial demonstrated that anastrozole was consistently superior to tamoxifen for all efficacy endpoints except overall survival, death after recurrence and death without recurrence where no significant change was observed. Anastrozole has proven superiority over tamoxifen, in terms of significant reduction in all forms of recurrence, ensuring that women can live cancer-free for longer. Overall survival, after a median follow-up of 100 months, is similar for both anastrozole and tamoxifen. Anastrozole reduces the risk of death following recurrence by 10% Although currently not statistically significant (p=0.2), there is a 90% chance that time to death following recurrence is longer with anastrozole. Deaths without recurrence were slightly but not significantly higher in the anastrozole group but no specific cause of death was elevated; most likely this is due to play of chance. There was no evidence of increased cardiovascular mortality or morbidity. This makes it difficult to show a benefit when patients are dying from other causes by virtue of their old age (mean age 72 years)

10. Time to recurrence HR+ patients Recurrence rates continued to be lower with anastrozole after treatment completion In the HR+ subgroup, the absolute difference in recurrence increased from 2.8% at 5 years to 4.8% at 9 years in favour of anastrozole. Tamoxifen has a known carryover effect in years 5-9, of about two-thirds the size of that during active treatment. There is a statistically significant larger carryover effect for anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01). Recurrence rates continued to be lower with anastrozole after treatment completion In the HR+ subgroup, the absolute difference in recurrence increased from 2.8% at 5 years to 4.8% at 9 years in favour of anastrozole. Tamoxifen has a known carryover effect in years 5-9, of about two-thirds the size of that during active treatment. There is a statistically significant larger carryover effect for anastrozole (HR=0.75, 95% CI 0.61-0.94, p=0.01).

11. Aantal recidieven blijft lager na stop behandeling met anastrozol Tamoxifen heeft bekend carry-over effect in jaar 5-9 van ~ 2/3 de grootte tijdens actieve behandeling Statistisch significant groter carry-over effect voor anastrozol (HR=0.75, 95% CI 0.61-0.94, p=0.01) Ernstige bijwerkingen tijdens en na behandeling Anastrozol v tamoxifen: Fractuur episoden (%) - Tijdens 2.93 v 1.90* - Na 1.56 v 1.51 TTR: Carry-over effect in periode na behandeling Absolute difference in recurrence in the HR+ population in ATAC at 9 years is 4.8% in favour of anastrozole The larger carryover effect seen with anastrozole compared with tamoxifen means that starting with anastrozole has a highly significant impact in the long term References Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717. Absolute difference in recurrence in the HR+ population in ATAC at 9 years is 4.8% in favour of anastrozole The larger carryover effect seen with anastrozole compared with tamoxifen means that starting with anastrozole has a highly significant impact in the long term References Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687-717.

12. Conclusie effectiviteit 100 maanden mediane follow-up: Anastrozole v tamoxifen ? recidief: Locoregionaal Contralateraal Op afstand ? verschil TTR na behandeling: HR+ : 2.8% na 5 jaar ? 4.8% na 9 jaar HR ANA v TAM (5-9 j) = 0.75 (p=0.01) Anastrozole is the only aromatase inhibitor that significantly reduces all forms of breast cancer recurrence: distant, locoregional, contralateral.Anastrozole is the only aromatase inhibitor that significantly reduces all forms of breast cancer recurrence: distant, locoregional, contralateral.

13. Conclusie veiligheid Tijdens behandeling: Risico op fractuur Na 5 jaar behandeling met Anastrozol: Geen overmaat fractuurrisico Geen nieuwe morbiditeit of mortaliteit

14. HST: oestrogeen + progesteron Kruisende lijnen: ? BC-risico Cheblowsky

15. HST: oestrogenen ? BC-risico (of =)

16. HST-gebruik ?? in midden 2002 Ravdin

17. HST-gebruik ? in midden 2002

18. BC-incidentie ? in US = in NL

21. COBRA Tamoxifen Trial  297 BC-patiënten Genotype bepaald CYP2D6 score bepaald o.b.v. allelactiviteit (0 - 2) Vraagstelling Hebben vrouwen die ‘poor metabolizers’ (PMs) van CYP2D6 zijn minder voordeel van tamoxifen t.g.v. lage endoxifenspiegels? En minder bijwerkingen? Stoppen daardoor minder vaak met tamoxifen?

22. Conclusies CYP2D6-score 0 (PMs): geen uitvallers CYP2D6-activiteit: ? kans op uitvallers t.g.v. bijw. CYP2D6-score ?: ? aantal uitvallers Implicaties Meeste kans op voordeel TAM = Meeste kans op vroegtijdig stoppen Vroege interventies om bijw. ?

23. HER-paden Yarden Geïntegreerde netwerken: weerstaan enkelvoudige verstoringen

24. HER receptoren Osborn

25. Trastuzumab Blokkeert 2-2

27.   Prim. eindpunt Sec. eindpunt PFS OS 5.6 v 8.5 mnd 19.9 v 20.3 mnd HR = 0.71 HR = 0.79med. FU 11.8 mnd (planned 18 mnd) RR 24.6 v 48.9%

28. Lapatinib Blokkeert 1-1, 1-2, 1-3, 2-3

30. Pertuzumab ? HER2 homo- en heterodimerisatie, ? HER signalering, blokkeert 1-2, 2-3

31. Pertuzumab plus trastuzumab (Cardiale) veiligheid na progressie op trastuzumab

32. Veiligheid n = 61 Graad 3 toxiciteit: diarree (1x) LVEF: gem. verandering 1.1% Effectiviteit n = 33 Overall response rate = 18,2 % Clinical benefit rate = 39,4 %

33. Conclusies targeted therapie Signalerend HER-pad is een complex, robuust en zich aanpassend netwerk Remming van dit netwerk is zeer effectief bij HER2+ De novo en verworven resistentie vindt plaats via vele mechanismen M.n. incomplete blokkade van de receptorlaag Gecombineerde receptor inhibitoren verdienen klinische evaluatie Voorspelling van resistentiemechanisme van prim. tumor is van wezenlijk belang

34. Discussie ATLAS Groter carry-over effect 10 v 5 jaar TAM > 5 jaar adjuvante hormonale therapie: impact op uitkomsten voor minstens 14 jaar Moet verlengde adjuvante hormonale therapie als standaard behandeling overwogen worden bij HR+ vroege borstkanker? Voorlopige resultaten

35. Discussie ATAC Groter carry-over effect ANA v TAM Begin behandeling met anastrozol: impact op uitkomsten voor minstens 9 jaar Moet anastrozol als initiële adjuvante therapie als standaard behandeling overwogen worden bij postmenopausale vrouwen met HR+ vroege borstkanker? Publication: The Lancet Oncology, Jan 08

36. Discussie Cytochroom P450 2D6 activiteit CYP2D6-activiteit ~: 8% Poor Metabolizers ? CYP2D6-activiteit: ? kans op bijw. ? kans op stop tamoxifen v ? kans op voordeel tamoxifen Rekening houden met CYP2D6-activiteit bij tamoxifen? Bijwerkingen? 2D6 inhibitie door fluoxetine, paroxetine Dosering?

37. Discussie targeted therapie Trastuzumab: - Adjuvante strategie: 1 jaar - Palliatieve strategie: treatment beyond progression? Bevacizumab Lapatinib: - Palliatieve strategie: na trastuzumab? bij hersenmeta’s? Pertuzumab: - Nog geen indicatie