endocrine resistance in breast cancer
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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
Outline
• Adjuvant endocrine therapy in postmenopausal ER+ women
• Endocrine resistance after Adjuvant endocrine therapy
• Treating Endocrine resistance
Part IAdjuvant endocrine therapy in postmenopausal ER+ women
Tamoxifen &
Recurrence
Lancet 365, 1687–1717 (2005).
41% reductions of risks of recurrence
Lancet 365, 1687–1717 (2005).
Tamoxifen &
Recurrence
Tamoxifen & Mortality
Lancet 365, 1687–1717 (2005).
34% reductions of risks of mortality
Tamoxifen & Mortality
Lancet 365, 1687–1717 (2005).
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®)
Postmenopausal adjuvant endocrine therapy
Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
Postmenopausal adjuvant endocrine therapy
Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
勝 (DFS)
Lancet 359, 2131–2139 (2002)
Postmenopausal adjuvant endocrine therapy
Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
MA.17MA.17 Tamoxifen for 5 yearsLetrozole for 5 years
Placebo for 5 years
N. Engl. J. Med. 349, 1793–1802 (2003)
勝(DFS,OS in LN+
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)
Postmenopausal adjuvant endocrine therapy
Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
Lancet 366, 455–462 (2005)
勝(EFS)
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
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
Part IIEndocrine resistance after adjuvant
endocrine therapy
Loss of ER
1.Clonal selection2.Transcription suppression of ER geneby promotor methylation
Clin Cancer Res; 16(7); 1979–87.
EGFR/HER2 overexpression
MAPK ↑
Clin Cancer Res; 16(7); 1979–87.
Clin Cancer Res; 16(7); 1979–87.
Nat Rev Cancer 2004 May;4(5):335-48
Clin Cancer Res 2005;11(14) July 15, 2005
S6K1 ↓P-S6 ↓
RAD001
4E-BP1 ↑
eIF-4E ↑
eIF-4G ↓
Clin Cancer Res 2005;11(14) July 15, 2005
J Clin Oncol 2009;27:2630-7
J Clin Oncol 2009;27:2630-7
J Clin Oncol 2009;27:2630-7
Significance threshold, one sided P 0.10≦
PCR2 (1.4%) vs 1 (0.8%)
J Clin Oncol 2009;27:2630-7
J Clin Oncol 2009;27:2630-7
J Clin Oncol 2009;27:2630-7
Reduction in percentage positive Ki67 from baseline to day 15
Percentage of patient cases attaining a natural logarithm of percentage positive Ki67of less than 1 at day 15
J Clin Oncol 2009;27:2630-7
Part IIITreating endocrine resistance
Fulvestrant vs. Exemestane post non-steroidal AI
J Clin Oncol 2008;26:1664-70.
3.7 monthsDuration 9.3 months
3.7 monthsDuration 8.3 months
P=0.6531
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 CancerSymposium, San Antonio, TX, December 8–12, 2010.
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.
• 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.
• 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
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• 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.
6.9 vs. 2.8 msHR : 0.4395% CI : 0.35-0.54P<0.001
10.6 vs. 4.1 msHR : 0.3695% CI : 0.27-0.47P<0.001
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• 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.
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.
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
• Thanks for your attention!