1 / 49

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

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

moira
Download Presentation

Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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 IAdjuvant 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 in LN+ Letrozole for 5 years Tamoxifen for 5 years 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 DMFS) Postmenopausal adjuvant endocrine 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 IIEndocrine 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 from baseline to day 15 Percentage of patient cases attaining a natural 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 IIITreating 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.

  33. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerStudy 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.

  34. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerPatients • 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.

  35. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerEnd 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 Organizationfor Research and Treatment of Cancer quality-oflifecore questionnaire (QLQ-C30) • the breastcancer module (QLQ-BR23) N Engl J Med 2011 Dec 7.

  36. 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. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerSafety • 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.

  41. 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.

  42. N Engl J Med 2011 Dec 7.

  43. N Engl J Med 2011 Dec 7.

  44. Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast CancerOverall 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.

  45. 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.

  46. 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

More Related