1. Breast Cancer Systemic Adjuvant Treatment 長庚紀念醫院 血液腫瘤科 張獻崑 醫師

2. Early Disease Advanced Disease Adjuvant therapy ≒ 30% ≒ 50% 70% Stage 4 Incurable ！ More aggressive medical treatment !!! Endocrine therapy and/or Chemotherapy ± Biologic therapies Stage 1 Stage 2 Stage 3 Node negative Node positive

3. BREAST CANCER Determinants of Recurrence Tumor size Lymph node involvement Histological differentiation Tumor estrogen- and progesterone-receptor status Lymphatic/blood vessel invasion Specific factors: — Ploidy or DNA index — Proliferation factors (s-phase fraction, Ki-67) — Oncogene amplification/expression (HER-2/neu)

4. 2007/11  Left breast cancer s/p left partial mastectomy and dissection of axillary lymphatics  Stage IIA (T1cN1M0), Grade III invasive ductal carcinoma ER (3+), PR (3+) and Her-2 (1+) Age:36 y/o, Premenopausal 2007/12 Plan of Adjuvant therapies  Chemotherapy :  Radiotherapy :  Endocrine therapy : Patient’s Breast Cancer History

5. Breast Cancer Adjuvant Treatment --- About Chemotherapy

6. Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( I ) TABLE 1. Adjuvant drug therapy: percentage reduction in the annual odds of either recurrence or death Patient Therapy Reduction in Annual Reduction in Annual Age (y) Odds of Recurrence (%) Odds of Death (%) < 40 C/T vs. none 37 + 7 27 + 8 40-49 C/T vs. none 35 + 5 27 + 5 50-59 C/T vs. none 22 + 4 14 + 4 60-69 C/T vs. none 18 + 4 8 + 4 C/T: polychemotherapy Polychemotherapy reduce 20% annual odds of contra-lateral breast cancer Adapted from EBCTCG Lancet 1998;352:930-42

7. Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( III ) -- Anthracycline-containing v.s CMF TABLE 2. Adjuvant drug therapy: Anthracycline-containing regimens versus CMF Adjuvant Therapy Proportion Absolute Reduction Reduction (%) (%) Recurrence A-containing vs. CMF 12 + 4 3.2 +1. 5 Death A-containing vs. CMF 11 + 5 2.7 + 1.4 *A-containing: Anthracycline-containing regimens *Adapted from EBCTCG Lancet 1998;352:930-42

8. Evolution of Chemotherapy in Node-Positive Disease CMF Milan AC B-15 FEC50 ICCG = = CEF MA.5 FAC GEICAM TAC BCIRG 001 TC US9735 AC-P C9344 B-28 AC-T E1199 AC-Pw E1199 AC2w-P2w C9741 FEC100 FASG05 FEC-Pw G9906 FEC-T PACS01

9. Polychemotherapy for Early Breast Cancer : an overview of the randomized trials ( II ) -- Node Positive and Node Negative

10. Breast Cancer Adjuvant Treatment --- About Hormone Therapy

11. Estradiol Coactivator AF1 ER E E E + AF1 + AF2 ACTIVE Receptor dimerization Nuclear localization of fully active ER to ERE Coactivator ERE RNA POLII FULLY ACTIVATED TRANSCRIPTION (tumor cell division) AF1 and AF2 recruit coactivators E AF2 AF1 E Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28. Mode of Action of Estradiol (Full Agonist)

12. Mechanisms of Action of Hormonal Therapies Block estrogen action –Tamoxifen Block estrogen synthesis –Ovarian ablation (premenopausal) –Inhibition of aromatase (postmenopausal)

13. Tamoxifen Coactivator AF1 ER + ERE RNA POLII PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumor cell division) T T T T T AF1 Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28. Mode of Action of Tamoxifen

14. Tamoxifen Response in MBC 雌激素接受體 療效 病人數 ERPR 有效數 / 全部人數 ++71%188/263 +-32% 61/189 -+53% 8/15 -- 9% 16/171 From Clark GM, McGuire WL:Breast Cancer Res Treat 3:157-163,1983.

15. Tamoxifen for Early Breast Cancer: an overview of the randomized trials TABLE 5. Duration of Tamoxifenn Adjuvant Therapy on Percentage Reduction in the Annual Odds of Either Recurrence or Death Reduction in Annual Reduction in Annual Group Odds of Recurrence (%) Odds of Death (%) Tamoxifen 1 y < 50 2 + 7 -2 + 8 50-59 28 + 6 21 + 6 All 20 + 3 11 + 3 Tamoxifen 2 y < 50 14 + 5 10 + 6 50-59 32 + 4 19 + 5 All 29 + 3 17 + 3 Tamoxifen 5 y < 50 45 + 8 32 + 10 50-59 37 + 6 11 + 8 All 47 + 3 26 + 4 Adapted from EBCTCG Lancet 1998;351:1451-67

16. Tamoxifen for Early Breast Cancer: an overview of the randomized trials (Node positive and Node negative)

17. Ovarian Ablation in Early Breast Cancer: an overview of the randomized trials ( I ) TABLE 6. Meta-analysis of the Effect of Ovarian Ablation Reduction in Reduction Annual Odds Annual Odds Group of Recurrence (%) of Death (%) Ovarian ablation vs. no adju- 25 + 7 24 + 7 vant therapy (age < 50) Ovarian ablation + chemo- 10 + 9 8 + 10 therapy vs chemotherapy Adapted from EBCTCG Lancet 1996;348:1189-96

18. Ovarian Ablation in Early Breast Cancer: an overview of the randomized trials ( II ) -- Node Positive and Node Negative

19. Multiple steps involving P-450 enzymes and production of steroid intermediates Selective Versus Nonselective Aromatase Inhibition Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American Medicine. Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved. Cholesterol Cortisol AndrostenedioneAldosterone Testosterone EstroneEstradiol Selective Inhibitors Nonselective Inhibitors Aromatase Aromatase

20. *Surgery + radiotherapy + chemotherapy (Patients may start trial therapy while still receiving radiotherapy)      + Postmenopausal women with invasive breast cancer Completion of primary therapy* Randomization 1:1:1 for 5 years Anastrozole 1mg od + Tamoxifen placebo Anastrozole placebo + Tamoxifen 20mg od Anastrozole 1mg od + Tamoxifen 20mg od  Regular follow-up monitoring adverse events  Trial endpoints ATAC Trial Design

21. Table of First Events in ITT Population First event317379383 Locoregional678381 Distant156181202 Contralateral (invasive) 93023 Contralateral (DCIS)535 Death — breast cancer212 Death — other reason788170 Tamoxifen (n=3116) Anastrozole (n=3125) Combination (n=3125)

22. Curves truncated at 42 months HR95.2% CIp-value AN vs TAM0.780.65–0.930.0054 Comb vs TAM1.020.87–1.210.7786 Time to event (months) Proportion event free (%) Anastrozole Tamoxifen Combination 0 80 85 90 95 100 06121824303642 Kaplan–Meier Curves of Disease-free Survival in Receptor-positive Population *

23. AI Tamoxifen 2-3 years’ prior tamoxifen Initial adjuvant trial Switching trial Extended adjuvant trial Tamoxifen AI Tamoxifen AI Initial and sequencing trial TamoxifenAI 0 5 Time (years) AI Randomisation Placebo 5 years’ prior tamoxifen Randomisation Trial Design: types of adjuvant trial TamoxifenAI AI, aromatase inhibitor

25. 2007/11 Age:36 y/o, Premenopausal  Left breast cancer s/p left partial mastectomy and dissection of axillary lymphatics  Grade III invasive ductal carcinoma, stage IIA (T1cN1M0), ER (3+), PR (3+) and Her-2 (1+) 2007/12~2010/07 Adjuvant therapies  Chemotherapy : Epirubicin, 5-FU, and cyclophosphamide (FE90C) x 4 cycles  Taxotere+CDDP x 4 cycles  Radiotherapy (2008/6~2008/7)  Tamoxifen (20mg/day) since 2008/6/3  2010/8/6  Arimidex (1mg/day) since 2010/8/31  2011/3 Patient’s Breast Cancer History

26. Side Effect of Tamoxifen Hot flashes Thrombo-embolic disease Endometrial Malignancy — Endometrial cancer — Uterine sarcoma

27. Tamoxifen Related Endometrial Malignancy Endometrial Cancer -- P-1 study: Tamoxifen chemo-preventive trial in high risk papulation -- P-1 study: Tamoxifen chemo-preventive trial in high risk papulation Tam. Gr.:53 cases ; Placebo: 17 cases Risk Ratio: 3.28 Presentation: Vaginal bleeding 67 cases: FIGO stage I Exclusively age > 50 y/o Tam. Gr.:53 cases ; Placebo: 17 cases Risk Ratio: 3.28 Presentation: Vaginal bleeding 67 cases: FIGO stage I Exclusively age > 50 y/o -- NSABP B-14: Tamoxifen adjuvant trial in N(-) HR(+) BC -- NSABP B-14: Tamoxifen adjuvant trial in N(-) HR(+) BC Annual hazard rate of endometrial cancer Tam. Gr.:1.6/1000 ; Placebo: 0.2/1000 Relative Risk : 7.5 (population-based rate from SEER: relative risk: 2.2) Cumulative hazard rate (5yr): 6.3/1000 21/24 cases: FIGO stage I Annual hazard rate of endometrial cancer Tam. Gr.:1.6/1000 ; Placebo: 0.2/1000 Relative Risk : 7.5 (population-based rate from SEER: relative risk: 2.2) Cumulative hazard rate (5yr): 6.3/1000 21/24 cases: FIGO stage I

28. Tamoxifen Related Endometrial Malignancy Uterine sarcoma --- SEER database Uterine sarcoma --- SEER database 39,541 BC pts (Dx 1980~2000) treated with Tamoxifen v.s. 39,541 BC pts (Dx 1980~2000) treated with Tamoxifen v.s. General Population : General Population : Uterine corpus cancer relative risk [O/E] ratio: 2.17 Uterine corpus cancer relative risk [O/E] ratio: 2.17 Malignant Mixed Mullerian Tumors: O/E ratio= 4.62 Malignant Mixed Mullerian Tumors: O/E ratio= 4.62 Endometrial adenocarcinoma : O/E ratio= 2.07 Endometrial adenocarcinoma : O/E ratio= 2.07

29. Recommendations for Monitoring Women on Tamoxifen (ACOG) Premenopausal without known increased risk of uterine cancer: no additional monitoring beyond routine gynecologic care no additional monitoring beyond routine gynecologic care Postmenopausal : annual gynecologic examination annual gynecologic examination Monitoring for symptoms of endometrial hyperplasia or cancer Investigate any abnormal vaginal symptoms Limit tamoxifen use to 5-years duration Atypical endometrial hyperplasia: reassess tamoxifen use and appropriate gynecologic management reassess tamoxifen use and appropriate gynecologic management Hysterectomy in women with atypical endometrial hyperplasia whom tamoxifen therapy must be continued

30. Thank you for your attention