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®)
11. Postmenopausal adjuvant endocrine
therapy
勝
( DF S , OS Letrozole for 5 years
in L N+
MA.17 Tamoxifen for 5 years
MA.17 Placebo for 5 years
N. Engl. J. Med. 349, 1793–1802 (2003)
Expert Rev. Anticancer Ther. 11(2), 277–286
12. 勝
Postmenopausal adjuvant endocrine
( DF S
a nd D MF S )
therapy
勝 ( DF S
a nd O S )
Lancet 365, 1687–1717 (2005)
J. Clin. Oncol. 23, 5138–5147 (2005) Expert Rev. Anticancer Ther. 11(2), 277–286
14. Postmenopausal adjuvant endocrine
therapy勝
D F S a nd
TTD R
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
15. Postmenopausal adjuvant endocrine
therapy
勝
O S tre nd
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
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
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.
33.
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.
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.
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,
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
DFS was not significantly better than with letrozole monotherapy (tamoxifen followed by letrozole: HR: 1.05; 99% CI: 0.84–1.32; letrozole followed by tamoxifen: HR: 0.96; 99% CI: 0.76–1.21), providing support for the use of an AI upfront N. Engl. J. Med. 361, 766–776 (2009 The updated analysis of monotherapy showed that there was a nonsignificant difference in overall survival between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (hazard ratio for letrozole, 0.87; 95% CI, 0.75 to 1.02; P=0.08).
