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1 19CRC/ T0 T1 T2 T3 T4 M0 N0 M1 19CRC N1 N2 N3 Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Tis

2 19CRC/ Subtype of Breast Cancer by molecular marker ER+ ER- HER2+ Luminal B HER2 type HER2- Luminal A Basal like

3 19CRC/ p= (n=105) (n=185) (n=93) (Cancer 100:44-, 2004)

4 19CRC/

5 19CRC/ (n=2808) 1-3 (n=1201) 4-9 (n=504) (n=579) ( )

6 19CRC/ HER2 36 HER22

7 19CRC/ 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: Rusnak DW, et al. Mol Cancer Ther 2001;1: Survival Pathway Proliferation Pathway Biology based medicine

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

8 19CRC/ 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 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 Subtype of Breast Cancer by molecular marker ER+ ER- HR HER2 HER2+ Luminal B HER2 type HER2- Luminal A Basal like Subtype of Breast Cancer by molecular marker ER+ ER- ER HER2+ Luminal B HER2 type HER2- Luminal A Basal like

9 19CRC/ Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer ER+ ER- HER2+ trastuzumab chemo endocrine trastuzumab chemo HER2- endocrine chemo chemo Subtype of Breast Cancer by molecular marker ER+ ER- HER2+ Luminal B HER2 type HER2- Luminal A Basal like Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer ER+ ER- HER2+ trastuzumab chemo endocrine trastuzumab chemo HER2- endocrine chemo chemo

Locally-determined HER2-positive invasive breast cancer Centrally-determined HER2+; ER and PgR Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from

(For 12 weeks) Washout (6 weeks) Lapatinib (34 weeks) Lapatinib + Trastuzumab 3-weekly (For 52 weeks) Survival Pathway Proliferation Pathway Survival Pathway Proliferation

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

10 19CRC/ 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: Rusnak DW, et al. Mol Cancer Ther 2001;1: 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 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

11 19CRC/

12 19CRC/ 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:

13 19CRC/ CMF FEC docetaxel

patients) 0 49 % 89 % 1 29 % 11 % 2 22 %

14 19CRC/ 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= (Wilcoxon test) Patients and Methods Japan Breast Cancer Research Group CYP3A4H2 CYP3A4 CYP3A4 H2 H2 Grade 2(HFS)(FE)

15 19CRC/ Results H2 p0.001 TC TC Taxol weekly

Year Update of Cardiac Dysfunction on NSABP B-31:

AC->Paclitaxel with Trastuzumab in HER2 Positive,

Abstract 581,2006 Risk factors for increased risk

4% (2) Requirement for hypertension medications -

16 19CRC/ 屑 92 疼 Herceptin 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 > to 5.4% (2) Requirement for hypertension medications - 6.4% (3) Post AC LVEF values of 50-54% % (4) Age > 50 with post AC LVEF values of 50-54% %

17 19CRC/ A. Paul Lanchbury and Nassir Habboubi. Cancer Treatment Review GOT,GPT (IU/l) T.Bil (mg/dl) EC EC 4 TAM /8 12/10 1/7 2/10 2/24 3/

18 19CRC/

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untitled 19 CSPOR CRC/2009.8.8-9 2009 8 8 ( ) - CSPOR CRC SEMINAR- [email protected] http://www.oncoloplan.com - Toru Watanabe MD - 2 Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase