1. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer N Engl J Med 2011 Dec 7. Presenstor : CR 周益聖 Instructor : VS 趙大中 財團法人台灣癌症臨床研究發展基金會

2. Outline Adjuvant endocrine therapy in postmenopausal ER+ women Endocrine resistance after Adjuvant endocrine therapy Treating Endocrine resistance

3. Part I Adjuvant endocrine therapy in postmenopausal ER+ women

4. Tamoxifen & Recurrence Lancet 365, 1687–1717 (2005). 41% reductions of risks of recurrence

5. Lancet 365, 1687–1717 (2005). Tamoxifen & Recurrence

6. Tamoxifen & Mortality Lancet 365, 1687–1717 (2005). 34% reductions of risks of mortality

7. Tamoxifen & Mortality Lancet 365, 1687–1717 (2005).

8. Aromatase inhibitor (AI) Non-steroidal – block the peripheral conversion of androgens to estrogens by inhibiting the heme porphyrin portion of aromatase – Letrozole (Femara®) & Anastrozle (Arimidex®) Steroidal – binding irreversibly to the androgen binding site – Exemestane (Aromasin®)

9. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)

10. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) 勝 (DFS) Lancet 359, 2131–2139 (2002)

11. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) MA.17 Tamoxifen for 5 years Letrozole for 5 years Placebo for 5 years N. Engl. J. Med. 349, 1793–1802 (2003) 勝 (DFS,OS in LN+

12. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) 勝 (DFS and OS) Lancet 365, 1687–1717 (2005) 勝 (DFS and DMFS) J. Clin. Oncol. 23, 5138–5147 (2005)

13. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) Lancet 366, 455–462 (2005) 勝 (EFS)

14. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) 勝 DFS and TTDR N. Engl. J. Med. 353, 2747–2757 (2005) J. Clin. Oncol. 25, 486–492 (2007) N. Engl. J. Med. 361, 766–776 (2009) 25.8 months

15. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011) N. Engl. J. Med. 353, 2747–2757 (2005) J. Clin. Oncol. 25, 486–492 (2007) N. Engl. J. Med. 361, 766–776 (2009) 71 months 勝 OS trend

16. Part II Endocrine resistance after adjuvant endocrine therapy

17. Loss of ER 1.Clonal selection 2.Transcription suppression of ER gene by promotor methylation Clin Cancer Res; 16(7); 1979–87.

18. EGFR/HER2 overexpression MAPK ↑ Clin Cancer Res; 16(7); 1979–87.

20. Nat Rev Cancer 2004 May;4(5):335-48

21. Clin Cancer Res 2005;11(14) July 15, 2005 S6K1 ↓ P-S6 ↓ RAD001 4E-BP1 ↑ eIF-4E ↑ eIF-4G ↓

22. Clin Cancer Res 2005;11(14) July 15, 2005

23. J Clin Oncol 2009;27:2630-7

25. Significance threshold, one sided P ≦ 0.10 PCR 2 (1.4%) vs 1 (0.8%)

26. J Clin Oncol 2009;27:2630-7

28. Reduction in percentage positive Ki67 from baseline to day 15 Percentage of patient cases attaining a natural logarithm of percentage positive Ki67 of less than 1 at day 15

29. J Clin Oncol 2009;27:2630-7

30. Part III Treating endocrine resistance

31. Fulvestrant vs. Exemestane post non- steroidal AI J Clin Oncol 2008;26:1664-70. 3.7 months Duration 9.3 months 3.7 months Duration 8.3 months P=0.6531

32. Everolimus + tamoxifen vs. tamoxifen Randomized phase 2 study 111 postmenopausal women ER-positive advanced breast cancer previously treated with an aromatase inhibitor PFS – 8.6 months vs. 4.5 months, P = 0.002 OS – median not reached vs. 24.4 months, P = 0.01 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8–12, 2010.

34. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer Study design International Double-blind randomized (2:1) Phase 3 study oral everolimus (10 mg qd) or matching placebo in conjunction with exemestane (25 mg qd) N Engl J Med 2011 Dec 7.

35. postmenopausal women ER-positive nonamplified HER2 refractory to previous letrozole or anastrozole – recurrence during or within 12 months after the end of adjuvant treatment – progression during or within 1 month after the end of treatment for advanced disease Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer Patients N Engl J Med 2011 Dec 7.

36. Primary: PFS Secondary – overall survival – overall response rate – clinical benefit rate – time to deterioration of ECOG performance status – safety – Quality of life the European Organization for Research and Treatment of Cancer quality-of life core questionnaire (QLQ-C30) the breast cancer module (QLQ-BR23) Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer End point N Engl J Med 2011 Dec 7.

41. Serious adverse events – combination-therapy vs. exemestane-alone – 23% (11% ) vs. 12% (1% ) discontinue everolimus – adverse events 19% vs. 4% – withdrawal of consent 5% vs. 2% discontinue exemestane – adverse events 7% vs. 3% – withdrawal of consent 7% vs. 2% Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer Safety N Engl J Med 2011 Dec 7.

42. 6.9 vs. 2.8 ms HR : 0.43 95% CI : 0.35-0.54 P<0.001 10.6 vs. 4.1 ms HR : 0.36 95% CI : 0.27-0.47 P<0.001 N Engl J Med 2011 Dec 7.

47. immature at the time of the interim analysis – combination-therapy vs. exemestane-alone – 10.7% vs. 13% Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer Overall survival N Engl J Med 2011 Dec 7.

48. Discussion Adverse events of everolimus – stomatitis, fatigue, asthenia, diarrhea, cough, pyrexia, and hyperglycemia Higher percentage of patients discontinued everolimus because of a lack of tolerability N Engl J Med 2011 Dec 7.

49. Summary Addition of everolimus to endocrine therapy results in an improved clinical outcome Benefit should be weighed against the side effects observed with everolimus Potential of everolimus to benefit patient survival is not yet known