Endocrine resistance in breast cancer

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Endocrine resistance in breast cancer

  1. 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. 2. Outline• Adjuvant endocrine therapy in postmenopausal ER+ women• Endocrine resistance after Adjuvant endocrine therapy• Treating Endocrine resistance
  3. 3. Part IAdjuvant endocrine therapy inpostmenopausal ER+ women
  4. 4. Tamoxifen & Recurrence 41% reductions of risks of recurrenceLancet 365, 1687–1717 (2005).
  5. 5. Tamoxifen & Recurrence Lancet 365, 1687–1717 (2005).
  6. 6. Tamoxifen & Mortality 34% reductions of risks of mortalityLancet 365, 1687–1717 (2005).
  7. 7. Tamoxifen & Mortality Lancet 365, 1687–1717 (2005).
  8. 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. 9. Postmenopausal adjuvant endocrine therapy Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
  10. 10. Postmenopausal adjuvant endocrine therapy 勝 (DFS) Lancet 359, 2131–2139 (2002) Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
  11. 11. Postmenopausal adjuvant endocrine therapy 勝 (DFS,OS Letrozole for 5 years Tamoxifen for 5 years in LN+ MA.17MA.17 Placebo for 5 years N. Engl. J. Med. 349, 1793–1802 (2003) Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
  12. 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. 13. Postmenopausal adjuvant endocrine therapy 勝(EFS) Lancet 366, 455–462 (2005) Expert Rev. Anticancer Ther. 11(2), 277–286 (2011)
  14. 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. 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. 16. Part IIEndocrine resistance after adjuvant endocrine therapy
  17. 17. 1.Clonal selection 2.Transcription suppression of ER gene by promotor methylationLoss of ER Clin Cancer Res; 16(7); 1979–87.
  18. 18. EGFR/HER2 overexpression MAPK ↑ Clin Cancer Res; 16(7); 1979–87.
  19. 19. Clin Cancer Res; 16(7); 1979–87.
  20. 20. Nat Rev Cancer 2004 May;4(5):335-48
  21. 21. RAD001S6K1 ↓P-S6 ↓eIF-4E ↑eIF-4G ↓4E-BP1 ↑ Clin Cancer Res 2005;11(14) July 15, 2005
  22. 22. Clin Cancer Res 2005;11(14) July 15, 2005
  23. 23. J Clin Oncol 2009;27:2630-7
  24. 24. J Clin Oncol 2009;27:2630-7
  25. 25. PCR 2 (1.4%) vs 1 (0.8%)Significance threshold, one sided P ≦ 0.10 J Clin Oncol 2009;27:2630-7
  26. 26. J Clin Oncol 2009;27:2630-7
  27. 27. J Clin Oncol 2009;27:2630-7
  28. 28. Reduction in percentage positive Ki67 Percentage of patient cases attaining a naturalfrom baseline to day 15 logarithm of percentage positive Ki67 of less than 1 at day 15 J Clin Oncol 2009;27:2630-7
  29. 29. J Clin Oncol 2009;27:2630-7
  30. 30. Part IIITreating endocrine resistance
  31. 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. 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. 33. 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.
  34. 34. 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.
  35. 35. 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.
  36. 36. N Engl J Med 2011 Dec 7.
  37. 37. N Engl J Med 2011 Dec 7.
  38. 38. N Engl J Med 2011 Dec 7.
  39. 39. N Engl J Med 2011 Dec 7.
  40. 40. 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.
  41. 41. 6.9 vs. 2.8 msHR : 0.4395% CI : 0.35-0.54P<0.00110.6 vs. 4.1 msHR : 0.3695% CI : 0.27-0.47P<0.001 N Engl J Med 2011 Dec 7.
  42. 42. N Engl J Med 2011 Dec 7.
  43. 43. N Engl J Med 2011 Dec 7.
  44. 44. 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.
  45. 45. 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.
  46. 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

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