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New Approaches to the Treatment of Breast Cancer

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  1. New Approaches to the Treatment of Breast Cancer Richard G. Pestell, MD, PhD Kimmel Cancer Center Jefferson University Hospitals INCTR 6th Annual meeting Chennai, India

  2. Unique Point in History www.cnn.com

  3. Overview • Epidemiology • Current therapies • Developing therapies • Genetic markers • Nanotechnology • LAG therapy

  4. Breast Cancer -Epidemiology • the most frequently diagnosed malignancy in women (>215,000 in 2004) • the second leading cause of cancer related deaths (>40,000 per year)

  5. Incidence by Year (Jemal et al. CA Cancer J Clin 2005. 55:10.)

  6. Mortality by Year (EBCTCG. Lancet 2005. 365:1687.)

  7. Incidence by Year

  8. Mortality by Year

  9. Epidemiology

  10. Reproductive Risk Factors • early menarche • late onset of menopause • prolonged use of exogenous estrogen • nulliparity • older age at first pregnancy • breast-feeding

  11. Non-Reproductive Risk Factors • advanced age • history of ADH, LCIS, or DCIS • history of invasive breast cancer • family history of breast cancer • regular alcohol intake • early exposure to ionizing radiation

  12. Genetic Risk Factors • BRCA1 or BRCA2 positivity • p53 mutations (Li-Fraumeni syndrome) • PTEN mutations (Cowden disease)

  13. Palpable Breast Masses CANCER (10%) fibrocystic changes (40%) fibroadenoma (7%) benign NOS (13%) no disease (30%)

  14. Screening Recommendations • routine screening mammogram • every one to two years • age >40 • age <50 and >70 controversial • 17% reduction in mortality (age 40-49) • 26% reduction in mortality (age 50-74)

  15. Prognostic/Predictive Factors • hormone receptor status • Her-2/neu status

  16. Endocrine Therapy • direct correlation between the response to endocrine therapy and hormone receptor status • no documented benefit for patients with truly hormone receptor negative disease

  17. Trastuzumab (Herceptin) • Her-2/neu overexpression in 20 to 25% of all invasive breast cancers • 15% overall response rate (monotherapy) • 30% absolute increase (36% to 62%) in overall response (with chemotherapy)

  18. Early Stage Breast Cancer • operable disease • disease confined to breast + axilla

  19. Early Stage Breast Cancer definitive surgery  adjuvant chemotherapy  adjuvant radiotherapy  adjuvant hormonal therapy

  20. Principles of Adjuvant Therapy • risk of recurrence and death from breast cancer with local therapy alone • 30% with node-negative disease • 75% with node-positive disease

  21. Principles of Adjuvant Therapy • endocrine therapy benefits only those with hormone receptor positive disease • chemotherapy benefits everyone

  22. ADJUVANT ENDOCRINE THERAPY

  23. Endocrine Therapy: Approaches • estrogen receptor modulators • pure anti-estrogens • ovarian ablation or suppression • sex steroids • aromatase inhibitors

  24. Classes of Hormonal Agents • sex steroids • estrogen receptor modulators • aromatase inhibitors • pure anti-estrogens • ovarian ablation or suppression

  25. Menopausal and Hormone Receptor Status 70 60 50 40 % of Patients Premenopausal 30 Postmenopausal 20 10 0 ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- Hormone Receptor Status (Beck, WW. Obstetrics and Gynecology. 1989.)

  26. Hormone Synthesis HYPOTHALAMUS PITUITARY GLAND FSH, LH ACTH Corticosteroids Prolactin OVARIES ADRENAL GLAND Growth Hormone Progesterone Androgens Estrogens Progesterone PERIPHERAL TISSUES Estrogens

  27. Estrogen Receptor Modulators • tamoxifen (Nolvadex) • toremifene (Farnesdon) • raloxifene (Evista)

  28. NONSELECTIVE AI’s aminoglutethimide SELECTIVE AI’s non-steroidal inhibitors anastrozole (Arimidex) letrozole (Femara) fadrozole vorozole steroidal inactivators exemestane (Aromasin) formestane Aromatase Inhibitors

  29. Aromatase Inhibitors: Mechanism of Action Cholesterol Cortisol Pregnenolone Testosterone Androstenedione Progesterone Aromatase InactivatorsandAromatase Inhibitors Aldosterone Estrone Estradiol

  30. Endocrine Therapy: Tamoxifen • no significant advantage to more than five years of therapy • proportional benefits at 10 years • 47% reduction in risk of recurrence • 26% reduction in risk of death (EBCTCG. Lancet 1998. 351:1451.)

  31. Postmenopausal Women: New Standards? • instead of tamoxifen • anastrozole • letrozole • in sequence with tamoxifen • anastrozole • letrozole • exemestane

  32. Premenopausal Women:New Standards? • ovarian functional suppression . . . • instead of chemotherapy • instead of tamoxifen • with tamoxifen • with an aromatase inhibitor

  33. ADJUVANT CHEMOTHERAPY

  34. Systemic Therapy: Overview • EBCTCG meta-analyses of the major randomized trials in adjuvant therapy • last published in 2005 (15 year data) • Adjuvant polychemotherapy • Reduction in recurrence 12%,death 10% (<50 yo) • Reduction in recurrence 4%,death 3% 50-69 yo) EBCTG Lancet 2005 365 1687-717

  35. Chemotherapy: Principles • combination chemotherapy is more effective than monotherapy • no significant advantage with more than six months of chemotherapy

  36. Chemotherapy: Principles • proportional reduction in risk was the same irrespective of nodal status • the greater the risk of recurrence or death, the greater the absolute benefit of therapy

  37. Chemotherapy: Benefits • Reduction in yearly death rate: absolute benefits in 10 year survival • Addition of anthracycline effect on death rate • 38% for women <50 years old • 20% for women 50-69 years old • women >70 years old -not represented (EBCTCG. Lancet 1998. 352:930.) EBCTG Lancet 2005 365 1687-717

  38. Anthracyclines • doxorubicin/cyclophosphamide (ACx4) • cyclophosphamide/MTX/5FU (CMFx6) • studies have demonstrated an incremental benefit to anthracycline-containing regimens, particularly with Her-2/neu positive breast cancers • 6 months anthracycline based polychemo- • reduced death rate 38% (<50 yo),20% (50-69 y)

  39. Taxanes • increasing evidence to support the role of taxanes in high-risk disease • AC  paclitaxel or docetaxel • docetaxel/doxorubicin/cyclophosphamide (TAC) • doxorubicin/docetaxel • Fluorouracil/epirubicin(100mg)/cyclophosphamide (FEC100) • TAC, FEC100,CEF- greatest reduction in death rate (EBCTCG) EBCTG Lancet 2005 365 1687-717

  40. ADJUVANT CHEMOTHERAPY:THE ROLE OF TRASTUZUMAB

  41. Trastuzumab: Joint Analysis • 50% patients < 50 years old • 11% node-negative (N9831) • 50% ER/PR positive • 40% T < 2 cm

  42. Trastuzumab: Joint Analysis ACTHH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH  H 1672 134 HR=0.48, 2P=3x10-12 DFS Years from Randomization

  43. Trastuzumab: Joint Analysis HR 0.67 (p = .015)

  44. Trastuzumab: HERA • 33% node-negative • 30% 1-3 node-positive • 50% ER/PR positive • 68% received anthracycline • 25% received anthracycline + taxane • 6% received CMF-like chemotherapy

  45. Trastuzumab: HERA 100 Trastuzumab 1 year 90 80 Observation 70 60 % 50 40 HR [95% CI] p value Events 2 y DFS % 30 127 85.8 0.54 [0.43,0.67] <0.0001 20 220 77.4 10 0 0 5 10 15 20 25 DFS Months from randomization 1694 1472 1067 629 303 102 Number at risk 1693 1428 994 580 280 87

  46. New Strategies • Molecular genetics - therapeutic stratification general/specific • target signal transduction • target cell proliferation and function • stimulate the native immune system • promote apoptosis • modulate drug resistance • block angiogenesis • block mechanism invasion / metastasis

  47. Molecular targets- cell cycle

  48. Molecular genetics in therapeutic stratification