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

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

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

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

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

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

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

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

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

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

16. Part II
Endocrine resistance after adjuvant
endocrine therapy

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

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

19. Clin Cancer Res; 16(7); 1979–87.

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

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

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

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

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

25. PCR
2 (1.4%) vs 1 (0.8%)
Significance threshold, one sided P ≦ 0.10
J Clin Oncol 2009;27:2630-7

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

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

28. Reduction in percentage positive Ki67 Percentage of patient cases attaining a natural
from baseline to day 15 logarithm of percentage positive Ki67
of less than 1 at day 15
J Clin Oncol 2009;27:2630-7

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

30. Part III
Treating endocrine resistance

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

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. Everolimus in Postmenopausal
Hormone-Receptor–Positive Advanced Breast Cancer
Patients
• 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
N Engl J Med 2011 Dec 7.

36. Everolimus in Postmenopausal
Hormone-Receptor–Positive Advanced Breast Cancer
End point
• 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)
N Engl J Med 2011 Dec 7.

37. N Engl J Med 2011 Dec 7.

38. N Engl J Med 2011 Dec 7.

39. N Engl J Med 2011 Dec 7.

40. N Engl J Med 2011 Dec 7.

41. Everolimus in Postmenopausal
Hormone-Receptor–Positive Advanced Breast Cancer
Safety
• 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%
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.

43. N Engl J Med 2011 Dec 7.

44. N Engl J Med 2011 Dec 7.

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

48. Discussion
• Adverse events of everolimus
– stomatitis, fatigue, asthenia, diarrhea, cough, pyre
xia, 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