1. Neoadjuvant Hormone Treatment of Breast Cancer H.S.A. Oldenburg E.J.Th. Rutgers J.M. Dixon symposium 29 juni 2005

2. Neoadjuvante Endocrine therapie Waarom geen neoadjuvante chemo? Welke endocriene therapie? Welke locoregionale behandeling? Welke patienten?

3. Neoadjuvant Endocrine vs Chemotherapy 121 Postmenopausal women ER + and/or PgR + large operable + LABC Randomised to Chemo or Hormone therapy Median age: 69y Chemo: 67y Hormones Chemo: adriamycin + paclitaxel 3 weekly x 4 n=62 Anastrozole 1mg or Exemestane 25 mg – 3 months n=59 Semiglasov et al ASCO 2004 Abstract 519

4. % Responses

5. % Adverse Events

6. % Outcomes p=0.054

7. % Outcomes p=0.054

8. In postmenopausal women with ER + cancers Neoadjuvant Hormone Therapy is as least effective as Neoadjuvant chemotherapy in Response rate Response rate Breast Conservation rate Breast Conservation rateAND Causes much less morbidity Causes much less morbidity Conclusion

9. O24 Design Double-blind, double-dummy, randomized, parallel group, multicentre (55 centres in 16 countries), phase IIb/III trial Letrozole 2.5 mg o.d. n=154 Tamoxifen 20 mg o.d. n=170 Surgery Follow-up therapy (investigator driven) 4 months Patients with 10% ER +ve Cells and needed Mx or had LABC

10. Outcomes in O24 p<0.001 35%25%34%17%45%35% % Patients responding to therapy p=0.042p=0.022 55%36% p<0.001

11. Outcomes of 83 Inoperable cases in O24 % Patients having specified treatment p = 0.011

12. Response by ER Allred category ER Score % Response rate 7.0 1.5 1.5 3.0 2.2 7.0 21.4 56.5 % in each category 0 20 40 60 80 02345678 tamoxifen letrozole

13. Randomise Anastrozole 113 Tamoxifen 108Combination 109 Pretreatment surgical assessment for Mastectomy or BCS* Surgery 3 months 330 Intent to Treat patients 292 Per Protocol patients * Breast conserving surgery Major violations/ deviations 34 (10%) IMmediate - Preoperative Arimidex, Tamoxifen, or Combined with Tamoxifen

14. Outcomes in IMPACT Overall Population (330 Intent to Treat) % Patients responding to therapy NS NSp=0.03 37 36 3924 20 2846 22 28

15. Improvement rate (%) A v T: OR 2.94 (1.11, 7.81) p=0.03 * A v T: OR 2.94 (1.11, 7.81) p=0.03 * C v T: OR 1.24 (0.44, 3.53) p=0.68 26% 22% 46% 0 10 20 30 40 50 ATC 21/46 8/36 11/42 *some pts still opted for mastectomy Conversion to Breast Conserving Surgery (%)

16. Neoadjuvant Exemestane vs Tamoxifen n=36n=37 p>0.05p<0.05 Semiglasov et al : 73 pts San Antonio Abstract 111; 2003

17. Neoadjuvant Therapy in Postmenopausal ER + Breast Cancer Letrozole superior to Tamoxifen Anastrozole possibly superior to Tamoxifen Exemestane superior to Tamoxifen (small trial) Most impressive data with letrozole

18. Response to Extended Neoadjuvant Letrozole % CR 3 months 9.5 6 months 28.6 1 year 36.4 Data from Edinburgh SABCC 2004

19. Response to Neoadjuvant Chemotherapy Path CR

20. Response to Neoadjuvant Chemotherapy Path CR 40-50%10-20% 12-20% 20%

21. Response to Neoadjuvant Hormone Therapy Path CR 70-80% 10-20% 2-5% Hardly Ever

22. Group Downstaged to lumpectomy Lumpectomy proposed initially No%IBTRNo%IBTR All Patients69154357 Age<49421721412 >5027112212 NSABP 18: Local Recurrence Rates 9 year local recurrence rates

23. Local Recurrence Free Survival Months XRT No XRT p<0.0001 Local Recurrence - BCS after Neoadjuvant Endocrine Therapy 27.8% 2.8%

24. Conclusions Neoadjuvant aromatase inhibitors in Postmenopausal large operable or LABC Response rates up to 80% in selected patients Reduces need for mastectomy in over 50% As effective as neoadjuvant chemotherapy Under utilised in many centres

25. Surgery following endocrine therapy relevant factors; patient preference tumor criteria, pre- and post-endocrine therapy: size multifocality nodal status tumor response Breast-conserving surgery or mastectomy ?

26. Surgery following endocrine therapy Assessment of tumor response Clinical assessment is not reliable Imaging is needed

27. Local control after downstaging and BCT: current opinion Increased breast relapse rates do not impact survival Good assessment with all imaging modalities Apply standard rules in BCT: WLE and free margins Standard radiotherapy

28. Surgery following endocrine therapy In the clinic For the surgeon: See the patient before endocrine therapy Refer patient to radiation oncologist before endocrine therapy Monitor patient during endocrine therapy Assess type of surgery with help of all imaging Decide together with patient type of surgery: none, BCT, mastectomy, axillary clearance SN procedure pre or post endocrine therapy?

29. Surgery following chemotherapy In the clinic Patient preferences breast-conserving surgery or not Tumor criteria size, multifocality, stage, localization, nodal status Quality assurance assessment of tumor response localization of residual tumor achieving radical margins This requires excellent collaboration between: surgeon, medical oncologist, radiotherapist, pathologist, and radiologist (breast clinic)

30. Surgery following endocrine therapy Which patients Older then 55/65 years, and T2N1 T3, T4 TXN2 Multifocal