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Current Situation of Breast Cancer Treatment in US

Current Situation of Breast Cancer Treatment in US. Stefan Glück MD PhD Professor of Medicine Clinical Director Braman Family Breast Cancer Institute UMSylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine.

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Current Situation of Breast Cancer Treatment in US

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  1. Current Situation of Breast Cancer Treatment in US Stefan Glück MD PhD Professor of Medicine Clinical Director Braman Family Breast Cancer Institute UMSylvester Comprehensive Cancer Center University of Miami, Miller School of Medicine

  2. Classical CMF Significantly Improves Survival vs No Adjuvant Treatment

  3. Available Regimens (Level I Evidence)

  4. AC x 4 + TAM if >50 yrs. NSABP B-18: Trial Design Operable Breast Cancer Stratification • Age • Clinical Tumor Size • Clinical Nodal Status Operation AC x 4 + TAM if >50 yrs. Operation Fisher et al. J Clin Oncol. 1998;16(8):2672-2685.

  5. NSABP B-18 Conclusions • Survival benefit was equivalent for pre-operative or post-operative therapy • pCR correlates with a significant increase in disease free survival (p=0.00005) and overall survival (p=0.0008) • Pre-operative chemotherapy increases the rate of breast conserving surgeries

  6. Primary Outcomes Mauri D et al. J Natl Cancer Inst 2005;97(3):188-94.

  7. NSABP B-27: Design Operable Breast Cancer Randomization AC X 4 Tam X 5 yrs AC X 4 Tam X 5 yrs AC X 4 Tam X 5 yrs Surgery Docetaxel X 4 Surgery Docetaxel X 4 Surgery I II III Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

  8. NSABP B-27: Pathologic Complete Responses in Breast 26.1%* 14.3%* 12.8%* Percentage ( % ) (n=764) (n=767) (n=775) *P < 0.001 for test of heterogeneity across groups Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

  9. NSABP B-27: Overall SurvivalpCR versus non-pCR Patients 100 90 80 % Surviving 70 Treatment N Deaths Non pCR 1899 396 pCR 409 31 HR=0.33 P<0.0001 60 50 40 0 1 2 3 4 5 Years after surgery Bear et al. Breast Cancer Res Treat. 2004;88(Suppl 1):S16. Abstract 26.

  10. ErbB Family of Tyrosine Kinase Receptors Extracellular Domain (Binds Ligand) • Family of evolutionarily conserved type I receptor tyrosine kinases • Four members: • ErbB-1 (EGFR/HER1) • ErbB-2 (HER2) • ErbB-3 (HER3) • ErbB-4 (HER4) TM Domain Cytoplasmic Domain (Kinase Activity)

  11. ErbB-2 or HER2 • Also known as HER2/neu • No known ligands • Activation thought to occur through heterodimerization with other ErbB family members • ErbB-2 is the preferred heterodimerization partner with other family members • Most resistant to intracellular degradation, slower to inactivate compared to other family members • ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival times

  12. Poorer Survival of Patients With HER2+ Primary Breast Cancer 1.0 N=220 (majority >1 cm); all patients received standard therapy 0.9 0.8 0.7 0.6 HER2– Proportion surviving 0.5 0.4 0.3 HER2+ 0.2 P<0.0001 0.1 0 0 2 4 6 8 10 12 14 16 Years Witton et al. J Pathol. 2003;200:290.

  13. Summary of Adjuvant Trastuzumab Trials NSABP B-31 HERA 52 wks 1 Yr 2 Yr 4 cycles Pax HD q 3 wk 4 cycles No therapy Trastuzumab Standard ChemoRx Dox/Cyc Trastuzumab 4 cycles Pax HD q 3 wk Trastuzumab BCIRG 006 NCCTG 9831 52 wks 12 wks 64 wks Docetaxel 4 cycles Trastuzumab Pax LD/wk Dox/Cyc Docetaxel Trastuzumab 4 cycles Docetaxel Dox/Cyc Trastuzumab Pax LD/wk Carboplatin Pax LD/wk Trastuzumab

  14. Combined Analysis: Overall Survival ACTH 94% 91% ACT 92% 87% N Deaths ACT 1679 92 ACTH 1672 62 HR=0.67, 2P=0.015 Years From Randomization B31/N9831

  15. Ras-GDP Ras-GDP RAF PAK Akt MER JNKK PKC S6K Abl Bad MAPK JNK Complexity of HERSignaling LPA, thrombin, ET, etc TGF(1) EGF(1) Epiregulin(1,4) -cellulin(1) HB-EGF(1,4) Amphi-regulin(1) NRG1(3,4)   NRG2(4)   NRG3(4) NRG4(4) Cytokines Ligands Input layer Receptor dimers Adaptors andenzymes Src Jak Cbl Shc Crk PLC Grb7 PI(3)K Vav Shp2 Grb2 Nck GAP Sos Rac Signal-processing layer Cascades Multiple pathway interactions (eg, ER) Jun Transcription factors Sp1 Myc Fos Elk Egr1 Stat Output layer Apoptosis Migration Growth Adhesion Differentiation Adapted from Yarden and Sliwkowski. Nat Rev Mol Cell Biol. 2001;2:127.

  16. Summary and Conclusion • There is increased clarity regarding adjuvant treatment of node-positive breast cancer • Use of an anthracycline and taxane is a standard if not THE standard • Adjuvant trastuzumab improves outcomes and became standard • Neoadjuvant treatment is the treatment of choice for patients with locally advanced breast cancer, and a resonable option for patients with operable breast cancer • Novel combinations hold promise for improving outcomes for women in high risk settings • Genomic data and DNA microarray analysis will gain increasing importance in clinical investigation as well as clinical management of breast cancer

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