Endocrine resistance in breast cancer

955 views
791 views

Published on

Published in: Health & Medicine, Business
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
955
On SlideShare
0
From Embeds
0
Number of Embeds
263
Actions
Shares
0
Downloads
20
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • 在停經後荷爾蒙受體陽性開刀後使用抗荷爾蒙療法
  • Tamoxifen 可以降低乳癌復發的風險
  • Tamoxifen 可以降低因乳癌造成的死亡
  • AI 的種類
  • 美國各乳癌治療指引的建議
  • 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). 
  • 對抗荷爾蒙治療產生抗藥性的機制
  • 都跟 mTOR 有很大的關係
  • 基本實驗證實與 mTOR 相關
  • 第二期臨床試驗在開刀前使用 everolimus 和 letrozole 治療動情激素受體陽性的乳癌
  • 在病理標本達到完全反應的比例有統計學上顯著的意義
  • 也可以顯著下降 Ki67
  • 並下降下游的產物
  • Mutations in the catalytic domain of PI3K have been identified in 20% to 25% of breast cancers, especially in ER+ disease
  • 副作用主要是口角炎和血小板低下
  • 在 AI 無效之後其他藥物治療的效果並不好
  • 使用 mTOR 抑制劑
  • 第三期臨床試驗使用 everolimus 加上 exemestane
  • 用在停經後婦女,之前使用抗荷爾藥物失敗
  • 病人特徵
  • dysgeusia 味覺異常,其他的副作用主要是口角炎,咳嗽
  • 高血糖和肺炎
  • 在無疾病存活率有統計學上的意義
  • 穩定疾病率高達 7 成
  • 所有次組群都有幫助
  • 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
    10. 10. Postmenopausal adjuvant endocrine therapy 勝 ( DF S ) Lancet 359, 2131–2139 (2002) Expert Rev. Anticancer Ther. 11(2), 277–286
    11. 11. Postmenopausal adjuvant endocrine therapy 勝 ( DF S , OS Letrozole for 5 years in L N+ MA.17 Tamoxifen for 5 yearsMA.17 Placebo for 5 years N. Engl. J. Med. 349, 1793–1802 (2003) Expert Rev. Anticancer Ther. 11(2), 277–286
    12. 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
    13. 13. Postmenopausal adjuvant endocrine therapy 勝 ( EFS) Lancet 366, 455–462 (2005) Expert Rev. Anticancer Ther. 11(2), 277–286
    14. 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. 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
    16. 16. Part IIEndocrine resistance after adjuvant endocrine therapy
    17. 17. 1.Clonal selection 2.Transcription suppression of ER gen 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, pyrexia, 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
    47. 47. • Thanks for your attention!

    ×