19CRC/2009.8.8-9 T0 T1 T2 T3 T4 M0 N0 M1 19CRC 2009.8.8 1 2 N1 N2 N3 Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Tis 3 4 5 6 1
19CRC/2009.8.8-9 7 8 Subtype of Breast Cancer by molecular marker ER+ ER- HER2+ Luminal B HER2 type HER2- Luminal A Basal like 9 10 11 12 2
19CRC/2009.8.8-9 13 14 15 16 p=0.09 1995-2000 (n=105) 1990-1994 (n=185) 1974-1979 (n=93) (Cancer 100:44-, 2004) 17 18 3
19CRC/2009.8.8-9 19 20 21 22 23 24 4
19CRC/2009.8.8-9 25 26 27 28 1 0.8 0.6 0.4 0 (n=2808) 1-3 (n=1201) 4-9 (n=504) 0.2 10 (n=579) 0 0 1 2 3 4 5 6 7 8 9 10 ( 19621990) 29 30 5
19CRC/2009.8.8-9 6 31 32 33 34 35 HER2 36 HER22
19CRC/2009.8.8-9 37 38 Lapatinib - Mechanism of Action Normal activation by ATP Activation blocked by lapatinib PI3K ATP Shc Grb2 Sos Ras Raf Lapatinib Akt MAPK P Akt MAPK Survival Pathway Proliferation Pathway Xia W, et al. Oncogene 2002;21:6255-63. Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94. Survival Pathway Proliferation Pathway 39 40 Biology based medicine 41 42 7
19CRC/2009.8.8-9 Development of Adjuvant Chemotherapy for Breast Cancer Evolution of Adjuvant Chemotherapy 1970s Initial use of anthracyclines 1 st Generation 2 nd Generation 3 rd Generation 4 th Generation 1980s 1990s 2000 2005+ Anthracyclines Taxanes Monoclonal antibody therapy HER family / VEGF / TK inhibition CMF ACx4 FEC FAC ACx4Px4 CALGB 9344 NSABP B28 FE 100 C FASG 05 ACx4Px4(q2w) CALGB 9741 FECx3Tx3 PACS 01 TAC BCIRG 001 AC P (w or q3w) vs AC T (w or q3w) ECOG 1199?? TC? USO9735 Therapy based on genomic profile and molecular biomarkers 43 44 Subtype of Breast Cancer by molecular marker ER+ ER- HR HER2 HER2+ Luminal B HER2 type HER2- Luminal A Basal like 45 46 Subtype of Breast Cancer by molecular marker ER+ ER- ER HER2+ Luminal B HER2 type HER2- Luminal A Basal like 47 48 8
19CRC/2009.8.8-9 Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer ER+ ER- HER2+ trastuzumab chemo endocrine trastuzumab chemo HER2- endocrine chemo chemo 49 50 Subtype of Breast Cancer by molecular marker ER+ ER- HER2+ Luminal B HER2 type HER2- Luminal A Basal like 51 52 Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer ER+ ER- HER2+ trastuzumab chemo endocrine trastuzumab chemo HER2- endocrine chemo chemo 53 54 9
19CRC/2009.8.8-9 Lapatinib - Mechanism of Action Normal activation by ATP Activation blocked by lapatinib DESIGN 1: Completion of ALL (neo)adjuvant chemotherapy prior to targeted therapy Locally-determined HER2-positive invasive breast cancer Centrally-determined HER2+; ER and PgR Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list) ATP Shc Grb2 Sos Ras Lapatinib LVEF 50% Max 12 w PI3K Akt Raf MAPK P Akt MAPK Trastuzumab 3-weekly (For 52 weeks) Lapatinib (For 52 weeks) Trastuzumab Weekly (For 12 weeks) Washout (6 weeks) Lapatinib (34 weeks) Lapatinib + Trastuzumab 3-weekly (For 52 weeks) Survival Pathway Proliferation Pathway Survival Pathway Proliferation Pathway Xia W, et al. Oncogene 2002;21:6255-63. 55 Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94. 56 Patients with ER or PgR-positive tumours receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years Radiotherapy if indicated Subtype of Breast Cancer by molecular marker ER+ ER- HER2+ Luminal B HER2 type HER2- Luminal A Basal like 57 58 Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, A PARP Inhibitor 59 60 10
19CRC/2009.8.8-9 61 62 63 64 65 66 11
19CRC/2009.8.8-9 67 68 69 70 71 Emetic Risk Agent High(90%) Cisplatin Moderate (30 to 90%) CPA, Doxorubicin, Epirubicin Irinotecan Low (10 to 30%) Paclitaxel, Docetaxel, Mitoxantrone Methotrexate, Gemcitabine Fluorouracil, Mitomycin Trastuzumab Minimal(10%) Vinorelbine JCO 24:2006 72 12
19CRC/2009.8.8-9 CMF 73 74 FEC100 75 76 docetaxel 77 78 13
19CRC/2009.8.8-9 Elasto-Gel (glycerin) Cold cap principle * - 20F (- 30 C) Direct contact protected Frozen 3 hours before use Hand Grade NAIL TOXICITY RESULTS Control (45 patients) Protected Hand (45 patients) 0 49 % 89 % 1 29 % 11 % 2 22 % 0 % p=0.0001 (Wilcoxon test) 79 80 81 82 Patients and Methods 2007420083 Japan Breast Cancer Research Group CYP3A4H2 CYP3A4 CYP3A4 H2 H2 Grade 2(HFS)(FE) 83 84 14
19CRC/2009.8.8-9 Results H2 p0.001 TC TC 85 86 Taxol weekly 87 88 89 90 15
19CRC/2009.8.8-9 91 屑 92 疼 Herceptin 93 94 Trastuzumab Four Year Update of Cardiac Dysfunction on NSABP B-31: A Randomized Trial of AC->Paclitaxel vs. AC->Paclitaxel with Trastuzumab in HER2 Positive, Node Positive Operable Breast Cancer : ASCO Abstract 581,2006 Risk factors for increased risk of CHF identified: (1) Age > 50-5.1 to 5.4% (2) Requirement for hypertension medications - 6.4% (3) Post AC LVEF values of 50-54% - 12.0% (4) Age > 50 with post AC LVEF values of 50-54% - 17.2% 95 96 16
19CRC/2009.8.8-9 97 A. Paul Lanchbury and Nassir Habboubi. Cancer Treatment Review 1993 19 197-228 98 GOT,GPT (IU/l) T.Bil (mg/dl) EC EC 4 TAM 15 10 5 99 10/8 12/10 1/7 2/10 2/24 3/24 100 101 102 17
19CRC/2009.8.8-9 103 18