Slide 56 -
THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC
GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. 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.
Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. 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 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
Early Breast Cancer Treatment Schema SURGERY Adjuvant
+/- Endocrine Tx Adjuvant
Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP
R breast lumpectomy, SLNB and axillary dissection 6 weeks ago
2.5 cm size
Tumour Grade II/III
ER 80%, PR 80%
Lymph nodes 3/12 involved
HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years?
Without any further treatment?
What is her risk of dying from breast cancer within 10 years?
Without any further treatment?
Chemotherapy for PreMP BC First generation protocols:
AC x 4
Second generation protocols:
Third generation protocols:
Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (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 MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF
AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3
G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 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. MA.5 Incidence Of CRA (ER+) 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 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 90 80 60 40 20 0 5 10+ 0
Node -ve: 14.9% SD 1.4: 2P<0.00001
Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen
(~5 y) Placebo Placebo Tamoxifen
(~5 y) Recurrence as First Event 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
biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth 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.
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. 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. ErbB Receptor Tyrosine Kinases
ErbB-1 (EGFR, HER-1)
ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or 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. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression
Gene amplification results in overexpression of normal receptors
Receptors spontaneously homodimerize
Drives tumour growth
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. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. 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. 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. 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
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. 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
Case No. 2 56 year old healthy postMP patient
Left lumpectomy and axillary dissection 4 weeks ago
2.5cm invasive ductal ca nos
0/12 LN involved
ER pos 90%, PR pos 90%
HER2neu overexpression neg 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
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 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
Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting 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 2005 20 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 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 Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group
AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION
FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials 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. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. 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 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 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 Patient Recommendations On AIs BMD performed at baseline and q12-18mos
If patient has had an osteoporotic #, add a bisphosphonate right away
If there is evidence of OP, add bisphosphonate right away
If there is osteopenia, evaluate other RFs and consider bisphosphonate
If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate
Case No. 2 Continues 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
SCC notes she is in rapid AFib and sends her to ER
Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management
Chemotherapy Related Cardiotoxocity Anthracyclines
Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone
Acute (during administration)
Early (Several days to mos following)
CHF with peak at 3 mos after last dose
Late (years to decades following)
CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity
Cumulative dose – strongest risk factor
Concomitant administration of other agents
Previous history of cardiac disease Conclusions
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
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