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  1. THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC

  2. No conflicts of interest

  3. Goal • To review current information on making an informed decision about adjuvant treatment of early stage breast cancer.

  4. Objectives • Case-based approach to evaluating the diagnosis and individualizing treatment. • Understand the rationale for treatment. • Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. • Review current standard chemotherapy protocols. • Interpret survival data. • Interpret morbidity data. • To review health issues after cancer treatment.

  5. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 105 UK 90 60 USA Annual death rateper 100,000 women 45 75 30 15 0 1950 1960 1970 1980 2000 1990 Year Reprinted with permission from Elsevier Science. Lancet 2000.

  6. Early Stage Breast Cancer • Many women are cured with surgery alone • Some women will have a systemic relapse • All systemic relapses lead to death • Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk

  7. Decision: Adjuvant Therapy • An agent that is active in the metastatic setting • Targets microscopic metastatic disease • Should be effective on minimal foci • Given “blind”: no information on the efficacy for the individual patient • Ideally should improve DFS and OS

  8. Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab

  9. Case No. 1 • 45-year-old female patient, healthy and preMP • R breast lumpectomy, SLNB and axillary dissection 6 weeks ago • Pathology • 2.5 cm size • Tumour Grade II/III • ER 80%, PR 80% • Lymph nodes 3/12 involved • HER 2 neu overexpression - positive

  10. Case No. 1 - Chemotherapy • What is her recurrence risk over 10 years? • Without any further treatment? • With chemotherapy? • What is her risk of dying from breast cancer within 10 years? • Without any further treatment? • With chemotherapy?

  11. Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF

  12. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003

  13. MA.21 Relapse-Free Survival: All Patients CEF EC-T P = 0.001 (stratified) AC-T 2 yr 4 yr 701701702 125101113 CEF EC/T AC/T 451441405

  14. MA.21 Results: RFS *Adjusted for Stratification

  15. Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% Percentage of patients (%) 29.6% None G1 G2 G3

  16. Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 82.4% 65.2% Percentage of patients (%) None G1 G2 G3

  17. Case No. 1 – Endocrine Therapy • After her 3rd cycle of CEF, the patient stops having menstrual periods. • Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. • At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women.

  18. MA.5 Incidence Of CRA (ER+)

  19. EBCTCG (meta-analysis) • Tamoxifen is an anti-estrogen • 37,000 women in 55 trials of tam vs nil • 70% had HR+ tumours, most PM • For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk

  20. Tamoxifen: Improvement in Disease-Free Survival Recurrence as First Event 100 Tamoxifen (~5 y) 87.4 90 79.2 Placebo 80 74.9 Tamoxifen (~5 y) Node -ve 70 75.6 64.3 Placebo 60 59.7 58.3 Node +ve 50 % Recurrence-free 40 44.5 30 Absolute Recurrence Reduction 20 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 10 0 0 5 10+ Years Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science.

  21. Aromatase Inhibitors • selectively block peripheral conversion of androstenedione to estrone • occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell • net result: inhibition of circulating estradiol in serum in PM women only • eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal • eg. Exemestane (Aromasin) – steroidal

  22. Antiestrogens Estrogen biosynthesis Inhibition of growth Aromatase inhibitors Inhibition ofEstrogen-Dependent Growth Estrogen biosynthesis Nucleus Cancer cell

  23. Case No. 1 - Trastuzumab • Upon completion of chemotherapy, MUGA scan reports EF 59%. • Her cancer was HER2neu overexpression + • Patient advised to consider Herceptin (trastuzumab) q3weeks for one year.

  24. ErbB2 (HER2/neu) Overexpression • ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene • ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers • Adverse prognostic factor • Confers resistance to some chemotherapy or hormone therapy • Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488.

  25. ErbB Receptor Tyrosine Kinase System • The ErbB system includes four growth factor receptors and their numerous ligands • Important in human growth and development • Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

  26. Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB Receptor Tyrosine Kinases ErbB-1 ErbB-2 ErbB-3 ErbB-4 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

  27. ErbB-2or HER-2/neu • Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize • Usually does not homodimerize • Heterodimerization with other ErbB receptors is necessary for activation Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. .

  28. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression • Gene amplification results in overexpression of normal receptors • Receptors spontaneously homodimerize • Drives tumour growth 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137.

  29. Rationale for Inhibiting ErbB Receptors • ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors • Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250.

  30. Monoclonal Antibodies • Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein • Mechanism of action: • Inhibit TK activation • Induce receptor endocytosis and degradation • Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173.

  31. Results of Adjuvant Trastuzumab Trials • NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% • Brief median followup of 1-2 years • SEs: hypersensitivity with first infusion CHF 5%

  32. Case No. 1 Continues • After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) • Patient advised to stop Herceptin • Even though patient is asymptomatic, referral is made to cardiologist • Medical management and close follow-up by cardiologist.

  33. Trastuzumab And Cardiotoxicity • erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) • In adult heart, erbB2 modifies cardiac response to stress • Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes

  34. Case No. 2 • 56 year old healthy postMP patient • Left lumpectomy and axillary dissection 4 weeks ago • Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg

  35. Case No. 2 - Chemotherapy • Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy • Risk of relapse at 10years is 35% • Chemo options are reviewed

  36. Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit

  37. Case No. 2 – Endocrine Therapy • Baseline MUGA EF 55% • AC administered q 3 weeks x 4 cycles without serious effects • After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years

  38. TAM ATAC R ANASTRO TEAM R BIG1-98 Early (Upfront) Adjuvant Trials Surgery 0-5 years ANASTRO + TAM TAM EXEM TAM LETRO R TAM LETRO LETRO TAM

  39. DFS: Reduction of Event Rate in the Adjuvant Setting Review: Mouridsen HT, January 2005 EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 20

  40. Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI

  41. ASCO Technology Assessment 2004 • Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen

  42. Total Cholesterol in BIG 1-98: Summary • Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group

  43. AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE

  44. Osteoporosis/Fractures Reported in Adjuvant AI Trials Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P A T AC 68 AN A T A M F r a c tu r e 11. 0 vs 7.7 < 0.00 0 1 BIG 1–98 26 L E T R O T A M F r a c tu r e 5.8 vs 4.1 N I IES 31 E X E M T A M F r a c tu r e 3.1 vs 2.3 0.0 8 O s te o por os i s 7.4 vs 5.7 0.0 5 AR N O 28 AN A T A M F r a c tu r e 2.4 vs 2.1 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e 3.6 vs 2.9 0.2 4 O s te o por os i s 5.8 vs 4.5 0.0 7 ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. Mouridsen 0305

  45. ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62.

  46. How Serious Is This Difference? • No placebo arm • What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years • ATAC Tam: 13.44 # per 1000 pt years • ATAC Arimidex: 21.55 # per 1000 pt years

  47. ATAC BMD Substudy • No bisphosphonates allowed • 2 years A => 4% loss in LS 3.2% loss in hip • 2 years Tam => 1.9% gain in LS 1.2% gain in hip • Considered small losses compared to the natural BMD loss that occurs in menopause • Benefits of the drug outweigh this risk

  48. Patient Recommendations On AIs • Stop smoking • Reduce caffeine and alcohol intake • Perform regular weight-bearing exercise • Supplement with Calcium 1500mg/d and vitamin D 800 IU/d • Never take estrogen • Raloxifene is contraindicated