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

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Presentation on theme: "THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC."— Presentation transcript:

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

5 Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year Annual death rate per 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000.

6 Early Stage Breast Cancer Many women are cured with surgery alone Many women are cured with surgery alone Some women will have a systemic relapse Some women will have a systemic relapse All systemic relapses lead to death 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 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 An agent that is active in the metastatic setting Targets microscopic metastatic disease Targets microscopic metastatic disease Should be effective on minimal foci Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Ideally should improve DFS and OS

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

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

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

12 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

13 Citron, M. L. et al. J Clin Oncol; 21: (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. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol

14 MA.21 Relapse-Free Survival: All Patients P = (stratified) CEF EC-T AC-T CEF EC/T AC/T yr4 yr

15 MA.21 Results: RFS * Adjusted for Stratification Treatment 3 year RFS * CEF 90.1 % EC/T 89.5 % AC/T 85.0 %

16 Case No. 1: Recurrence Risk (10 yr) Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) NoneG3G1G2

17 Case No. 1: Survival Benefit from Chemotherapy (Alive in 10 years) 65.2% 82.4% Percentage of patients (%) NoneG1G2G3

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

19 MA.5 Incidence Of CRA (ER+) SIX MOS CEFCMF <39 62%28% %68% >45 82%83% TWELVE MOS <39 47%36% %76% >45 89%90%

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

21 Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998, with permission from Elsevier Science. Years 100 % Recurrence-free Node -ve: 14.9% SD 1.4: 2P< Node +ve: 15.2% SD 2.5: 2P< Node -ve Node +ve Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Tamoxifen (~5 y) Recurrence as First Event

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

23 Estrogen biosynthesis Cancer cell Nucleus Inhibition of Estrogen-Dependent Growth Inhibition of growth Estrogen biosynthesis Antiestrogens Aromatase inhibitors

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

25 ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene 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 ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival 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:

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

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

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

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

30 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 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 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): Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S Nicholson R, et al. Endocr Relat Cancer. 2001b;8: Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2: Woodburn J. Pharmacol Ther. 1999;82:

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

32 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% 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 Brief median followup of 1-2 years SEs: hypersensitivity with first infusion SEs: hypersensitivity with first infusion CHF 5% CHF 5%

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

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

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

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

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

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

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

41 DFS: Reduction of Event Rate in the Adjuvant Setting Follow-up (mo) Rel. Red. % Rel. Red. % Abs. Red. % Abs. Red. % Early TAM 5 vs none (5 yrs) Early ANA 5 vs TAM (6 yrs) Early LET 5 vs. TAM (5 yrs) Early seq. TAM 2  EXE 3 vs TAM (3 yrs) Early seq. TAM 2  ANA 3 vs TAM (3 yrs) Extended LETRO 5 vs placebo (4 yrs) 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 Review: Mouridsen HT, January

42 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

43 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 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen

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

45 AIs and Bone NORMAL BONEOSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE

46 Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. 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. ATAC BIG 1– ANA LETRO TAM TAM Fracture Frac re 11.0 vs vs4.1 < NI IES ARNO EXEM ANA TAM TAM Fracture Osteoporosis Fracture 3.1 vs vs vs NI MA-1728LETROPlaceboFracture Osteoporosis 3.6 vs vs Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P

47 ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis Anastrozole % of patients n=3092Tamoxifen n=3094p-value Joint Disorders 35.6 (27.8) 29.5 (21.2) < All Fractures - spine - spine - hip - hip - wrist - wrist 11.0 (5.8) (3.7) < (Bisphosphonate usage) (Bisphosphonate usage) ATAC Trialists’ Group. SABCS Lancet 2005; 365:

48 How Serious Is This Difference? No placebo arm No placebo arm What fracture rate might normally be observed in a similarly aged population? What fracture rate might normally be observed in a similarly aged population? # per 1000 patient years # per 1000 patient years ATAC Tam: # per 1000 pt years ATAC Tam: # per 1000 pt years ATAC Arimidex: # per 1000 pt years ATAC Arimidex: # per 1000 pt years

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

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

51 Patient Recommendations On AIs BMD performed at baseline and q12-18mos BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate

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53 Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline- induced cardiomyopathy requiring medical management Cardiologist diagnoses her with anthracycline- induced cardiomyopathy requiring medical management

54 Chemotherapy Related Cardiotoxocity Anthracyclines Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Toxicity effects Acute (during administration) Acute (during administration) Arrhythmias, pericarditis-myocarditis Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) Early (Several days to mos following) CHF with peak at 3 mos after last dose CHF with peak at 3 mos after last dose Late (years to decades following) Late (years to decades following) CHF may develop up to yrs after last anthracycline dose CHF may develop up to yrs after last anthracycline dose

55 Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Cumulative dose – strongest risk factor Age Age Prior irradiation Prior irradiation Concomitant administration of other agents Concomitant administration of other agents Previous history of cardiac disease Previous history of cardiac disease

56 Conclusions Key advances in the management of breast cancer have been made in the last few years Key advances in the management of breast cancer have been made in the last few years Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab New treatments are intensive and may result in long-term health concerns New treatments are intensive and may result in long-term health concerns Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance

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59 Thank you for your attention


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