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Breast cancer study group. Outline Adjuvant endocrine therapy Systemic disease Local disease Metastatic disease

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Rationale for endocrine therapy of breast cancer Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age. Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age. Daidone MG, Coradini D, Martelli G, Veneroni S. Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 2003;45:313–325

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Breast cancer study group Outline Adjuvant endocrine therapy Systemic disease Local disease Metastatic disease Rationale for endocrine therapy of breast cancer Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age. Estrogen and/or progesterone receptor expression is found in 85% of breast cancers. This proportion increases with age. Daidone MG, Coradini D, Martelli G, Veneroni S. Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 2003;45:313325 70% Adjuvant endocrine therapy Invasive cancernodal statusHER2 statusadjuvant chemotherapyHR (+)adjuvant endocrine therapy Invasive cancernodal statusHER2 statusadjuvant chemotherapyHR (+)adjuvant endocrine therapy endocrine therapy 1yr from antiestrogen therapy AI superior to Tamoxifen Post menopausal with antiestrogen nave or > 1yr from antiestrogen therapy AI superior to Tamoxifen Systemic disease Endocrine therapy: Premenopausal with previous antiestrogen therapy and within 1 year of antiestrogen exposure surgical or radiotherappeutic oophorectomy or LHRH agonist + endodrine as postmenopausal women Premenopausal with previous antiestrogen therapy and within 1 year of antiestrogen exposure surgical or radiotherappeutic oophorectomy or LHRH agonist + endodrine as postmenopausal women Premenopausal with antiestrogen nave antiestrogen LHRH agonist or ovarian ablation Premenopausal with antiestrogen nave antiestrogen LHRH agonist or ovarian ablation Systemic disease (SDPRCR) (SDPRCR) Fulvestrantpure antiestrogen, monthly IM injection, longer duration of response than anastrozole Fulvestrantpure antiestrogen, monthly IM injection, longer duration of response than anastrozole Premenopausalendocrine therapypost- menopausalLHRH agonist surgical or radio-oophorectomy Premenopausalendocrine therapypost- menopausalLHRH agonist surgical or radio-oophorectomy endocrine therapy endocrine therapy Systemic disease Cytotoxic chemotherapy WhoHR(-) not localized in bone or soft tissue, symptomatic visceral involvement, HR (+) but refractory to endocrine therapy WhoHR(-) not localized in bone or soft tissue, symptomatic visceral involvement, HR (+) but refractory to endocrine therapy Combined regimenresponse ratetime to progressionsingle agentside effect OScombined regimen Combined regimenresponse ratetime to progressionsingle agentside effect OScombined regimen progression progressionPFS QoL progression progressionPFS QoL Systemic disease Single agentdoxorubicinlipodox epirubicintaxoldocetaxol capacitabinevinorelbinegemcitabine Single agentdoxorubicinlipodox epirubicintaxoldocetaxol capacitabinevinorelbinegemcitabine Combined regimenFAC/CAFFEC ACECATCMF Combined regimenFAC/CAFFEC ACECATCMF Optional agentciplatincarboplatin etoposide (oral)vinblastin Optional agentciplatincarboplatin etoposide (oral)vinblastin sequential useendocrine therapy sequential useendocrine therapy Systemic disease Bevacizumabhumanized monoclonal antibody against the bascular endothelial growth factor Bevacizumabhumanized monoclonal antibody against the bascular endothelial growth factor Ixabepiloneepothilone B analogue (2A)capacitabine (2B) Ixabepiloneepothilone B analogue (2A)capacitabine (2B) Targeting the Cancer Environment: Angiogenesis Inhibition BLOOD VESSEL CELL VEGFReceptor VEGF Bevacizumab (Avastin) Anti-VEGF Antibody: binds to VEGF and blocks tumor blood vessel growth CANCER CELL Other VEGF/VEGFR inhibitors: sunitinibsorafenib Eligibility: -No prior treatment for mets -HER-2 negative RANDOMIRANDOMIZEZERANDOMIRANDOMIZEZE weekly paclitaxel + bevacizumab weekly paclitaxel + bevacizumab weekly paclitaxel E2100: Paclitaxel (Taxol) +/- Bevacizumab (Avastin) in Advanced Breast Cancer PI: K. Miller Addition of Bevacizumab (Avastin) and Trastuzumab (Herceptin) to Paclitaxel (Taxol) Slamon D et al, NEJM 2001 Miller KD et al, San Antonio 2005, abstract 3 Months PFS Paclitaxel + bevacizumab Paclitaxel Paclitaxel + trastuzumab Paclitaxel Months Paclitaxel +/- Trastuzumab 3.0 months 6.9 months 11.4 months 6.11 months Paclitaxel +/- Bevacizumab (E2100) Progression-free survival HER-2 Negative HER-2 Positive Paclitaxel (Taxol) +/- Bevacizumab (Avastin) in Metastatic Breast Cancer (E2100 Study) Chemo alone Chemo + Bevacizumab % 16% 38% monthsmonthsmonthsmonths Classes of Cancer Chemotherapy Drugs: Anti- Tubulins Anti-Tubulins (plant alkaloids): block cell division during mitosis (mitotic spindle interference) Anti-Tubulins (plant alkaloids): block cell division during mitosis (mitotic spindle interference) Vinca alkaloids: vinorelbine (Navelbine) Vinca alkaloids: vinorelbine (Navelbine) Taxanes: paclitaxel (Taxol), docetaxel (Taxotere) Taxanes: paclitaxel (Taxol), docetaxel (Taxotere) Epothilones Epothilones A New Anti-Tubulin Class (Epothilones) Phase III Trial of Capecitabine (Xeloda) +/- Ixabepilone in Patients with Metastatic Breast Cancer Vahdat L et al, ASCO 2007, abstract # 1006 Patients: 752 metastatic breast cancer patients s/p anthracycline and resistant to taxanes Patients: 752 metastatic breast cancer patients s/p anthracycline and resistant to taxanes Treatment: Treatment: Capecitabine 1250 mg BID (14/21) vs Capecitabine 1000 mg BID (14/21) + Ixabepilone 40 mg/m2 q3 weeks Phase III Trial of Capecitabine (Xeloda) +/- Ixabepilone in Patients with Metastatic Breast Cancer Vahdat L et al, ASCO 2007, abstract # 1006 Results:CC + I Results:CC + I OR14%35% p< PFS4.2 mo5.8 mo p< week PFS55%71% p< Toxicity (grade 3, 4) Toxicity (grade 3, 4) Neuropathy0%23% Hand/foot17%18% Fatigue3%9% Neutropenia 11%68% FDA has granted ixabepilone priority review status Systemic disease HER2 targeted therapy HER2 (+)trastuzumab mono- or combination, shift to lapatinib + capacitabine if failure to herceptin, taxane and anthracycline HER2 (+)trastuzumab mono- or combination, shift to lapatinib + capacitabine if failure to herceptin, taxane and anthracycline Trastuzumab: no suggestion with anthracycline ( 27% of cardiac dysfunction) Trastuzumab: no suggestion with anthracycline ( 27% of cardiac dysfunction) __ _____ __ ________ __ _____ __ ________ The HER Family of Receptors HER1 EGFR HER2 HER3 HER4 Tumor Cell Trastuzumab (Herceptin)Trastuzumab (Herceptin) Pertuzumab (Omnitarg)Pertuzumab (Omnitarg) LapatinibLapatinib Erlotinib (Tarceva)Erlotinib (Tarceva) Gefitinib (Iressa)Gefitinib (Iressa) Cetuximab (Erbitux)Cetuximab (Erbitux) Drugs Targeting HER-2 in Breast Cancer HER-2 nucleus cancer cell cell division Trastuzumab (Herceptin) Anti-HER-2 Antibody (IV) HER-2 Oncogene: overexpressed in 20-25% of breast cancers Lapatinib (Tykerb) Dual HER-1/HER-2 (oral) Tyrosine Kinase Inhibitor A Promising New HER-2 Targeted Drug Lapatinib (Tykerb) kinase Cell division/tumor growth signalling Tumor Cell HER-1 (EGFR) HER-2 lapatinib Specificity for both HER-1 (EGFR) and HER-2 receptorsSpecificity for both HER-1 (EGFR) and HER-2 receptors Binds inside the cancer cell, to the enzyme portion of HER-2/HER-1Binds inside the cancer cell, to the enzyme portion of HER-2/HER-1 OralOral Crosses blood-brain barrierCrosses blood-brain barrier Trastuzumab (Herceptin) binds here Chemotherapy +/- Trastuzumab (Herceptin) in Metastatic Breast Cancer Slamon D et al, N Eng J Med 2001 ORR P