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

THE CHOICES FOR THE CHOICES FOR BREAST CANCER BREAST CANCER

TREATMENTTREATMENTNadia Califaretti MD Nadia Califaretti MD

FRCPCFRCPC

Medical OncologistMedical Oncologist

GRRCCGRRCC

No conflicts of No conflicts of interestinterest

GoalGoal

To review current information on To review current information on making an informed decision making an informed decision about adjuvant treatment of about adjuvant treatment of early early stagestage breast cancer. breast cancer.

ObjectivesObjectives Case-based approach to evaluating the Case-based approach to evaluating the

diagnosis and individualizing treatment.diagnosis and individualizing treatment. Understand the rationale for treatment.Understand the rationale for treatment. Review the three main treatment options: Review the three main treatment options:

chemotherapy, endocrine therapy, trastuzumab.chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy Review current standard chemotherapy

protocols.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.

Mortality Rates in Patients Mortality Rates in Patients With Breast Cancer Aged With Breast Cancer Aged

50 to 69 Years50 to 69 Years

0

Year

105

90

75

60

45

30

15

1950 1960 1970 1980 1990 2000

An

nu

al d

eath

rat

ep

er

10

0,0

00

wo

men

UK

USA

Reprinted with permission from Elsevier Science. Lancet 2000.

Early Stage Breast Early Stage Breast CancerCancer

Many women are cured with surgery Many women are cured with surgery alonealone

Some women will have a systemic Some women will have a systemic relapse relapse

All systemic relapses lead to deathAll systemic relapses lead to death Medical oncologist’s role is to assess Medical oncologist’s role is to assess

the risk of relapse/death for an the risk of relapse/death for an individual woman and make individual woman and make recommendations on how to reduce recommendations on how to reduce this riskthis risk

Decision: Adjuvant Decision: Adjuvant TherapyTherapy

An agent that is active in the An agent that is active in the metastatic settingmetastatic setting

Targets microscopic metastatic Targets microscopic metastatic diseasedisease

Should be effective on minimal fociShould be effective on minimal foci Given “blind”: no information on the Given “blind”: no information on the

efficacy for the individual patientefficacy for the individual patient Ideally should improve DFS and OSIdeally should improve DFS and OS

Early Breast Cancer Early Breast Cancer Treatment SchemaTreatment Schema

SURGERY

AdjuvantChemotherapy

AdjuvantRadiation

+/- Endocrine Tx

AdjuvantTrastuzumab

Case No. 1Case No. 1

45-year-old female patient, healthy 45-year-old female patient, healthy and preMPand preMP

R breast lumpectomy, SLNB and R breast lumpectomy, SLNB and axillary dissection 6 weeks agoaxillary dissection 6 weeks ago

PathologyPathology 2.5 cm size2.5 cm size Tumour Grade II/III Tumour Grade II/III ER 80%, PR 80% ER 80%, PR 80% Lymph nodes 3/12 involvedLymph nodes 3/12 involved HER 2 neu overexpression - positiveHER 2 neu overexpression - positive

Case No. 1 - Case No. 1 - ChemotherapyChemotherapy

What is her recurrence risk over What is her recurrence risk over 10 years? 10 years? Without any further treatment? Without any further treatment? With chemotherapy?With chemotherapy?

What is her risk of dying from What is her risk of dying from breast cancer within 10 years? breast cancer within 10 years? Without any further treatment? Without any further treatment? With chemotherapy?With chemotherapy?

Chemotherapy for PreMP Chemotherapy for PreMP BCBC

First generation protocolsFirst generation protocols::AC x 4AC x 4

Second generation Second generation protocolsprotocols::

AC-Taxol, FEC-100 AC-Taxol, FEC-100

Third generation Third generation protocolsprotocols::

Dose dense AC-Taxol, CEFDose 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: MA.21 Relapse-Free Survival: All PatientsAll Patients

P = 0.001 (stratified)

CEFCEF

EC-TEC-T

AC-TAC-T

CEFEC/TAC/T

701701702

451441405

125101113

2 yr 4 yr

MA.21 Results: RFSMA.21 Results: RFS

** Adjusted for StratificationAdjusted for Stratification

TreatmentTreatment 3 year RFS3 year RFS**

CEFCEF 90.1 %90.1 %

ECEC/T/T 89.5 %89.5 %

AC/AC/TT 85.0 %85.0 %

Case No. 1: Recurrence Risk Case No. 1: Recurrence Risk (10 yr)(10 yr)

Benefit from ChemotherapyBenefit from Chemotherapy

0

10

20

30

40

50

60

70

57.6%

29.6%

Perc

en

tag

e o

f p

ati

en

ts

(%)

None G3G1 G2

Case No. 1: Case No. 1: Survival Benefit from Survival Benefit from

ChemotherapyChemotherapy(Alive in 10 years)(Alive in 10 years)

0

10

20

30

40

50

60

70

80

65.2%

82.4%

Perc

en

tag

e o

f p

ati

en

ts

(%)

None G1 G2 G3

Case No. 1 – Endocrine Case No. 1 – Endocrine TherapyTherapy

After her 3After her 3rdrd cycle of CEF, the patient cycle of CEF, the patient stops having menstrual periods.stops having menstrual periods.

Upon completion of CEF, she is Upon completion of CEF, she is offered Tamoxifen as endocrine offered Tamoxifen as endocrine therapy.therapy.

At the discussion of hormonal At the discussion of hormonal therapy she brings in her Google therapy she brings in her Google search for Femara (Letrozole), which search for Femara (Letrozole), which is superior to tamoxifen in postMP is superior to tamoxifen in postMP women.women.

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

SIX MOSSIX MOS CEFCEF CMFCMF

<<3939 62%62% 28%28%

40-4440-44 82%82% 68%68%

>>4545 82%82% 83%83%

TWELVE MOSTWELVE MOS

<<3939 47%47% 36%36%

40-4440-44 80%80% 76%76%

>>4545 89%89% 90%90%

EBCTCG (meta-analysisEBCTCG (meta-analysis))

Tamoxifen is an anti-estrogenTamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam For ER+ pre/postMP pts 5 years of tam

results inresults in

47%47% relative reduction in recurrence relative reduction in recurrence risk at 10y risk at 10y

26%26% relative reduction in mortality relative reduction in mortality riskrisk

47%47% reduction in contralateral ca risk reduction in contralateral ca risk

Tamoxifen: Improvement Tamoxifen: Improvement in Disease-Free Survivalin Disease-Free Survival

Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science.

Years

100

% R

ecu

rren

ce-f

ree

90

80

60

40

20

05 10+0

Node -ve: 14.9% SD 1.4: 2P<0.00001Node +ve: 15.2% SD 2.5: 2P<0.00001

Node -ve

Node +ve

87.4

79.274.9

75.6 64.3

59.758.3

44.5

70

50

30

10

Absolute Recurrence Reduction

Tamoxifen (~5 y)

Placebo

Placebo

Tamoxifen (~5 y)

Recurrence as First Event

Aromatase InhibitorsAromatase Inhibitors selectively block peripheral selectively block peripheral

conversion of androstenedione to conversion of androstenedione to estroneestrone

occurs in ovary, adipose tissue, skin, occurs in ovary, adipose tissue, skin, muscle, liver, cancer cellmuscle, liver, cancer cell

net result: inhibition of circulating net result: inhibition of circulating estradiol in serum estradiol in serum in PM women onlyin PM women only

eg: eg: anastrozole (Arimidex), letrozole anastrozole (Arimidex), letrozole (Femara)(Femara) – nonsteroidal – nonsteroidal

eg. eg. Exemestane (Aromasin)Exemestane (Aromasin) – – steroidalsteroidal

Estrogenbiosynthesis

Cancer cell

Nucleus

Inhibition ofInhibition ofEstrogen-Dependent GrowthEstrogen-Dependent Growth

Inhibition of growth

Estrogenbiosynthesis

Antiestrogens

Aromatase

inhibitors

Case No. 1 - Case No. 1 - TrastuzumabTrastuzumab

Upon completion of Upon completion of chemotherapy, MUGA scan chemotherapy, MUGA scan reports EF 59%.reports EF 59%.

Her cancer was HER2neu Her cancer was HER2neu overexpression +overexpression +

Patient advised to consider Patient advised to consider Herceptin (trastuzumab) Herceptin (trastuzumab) q3weeks for one year.q3weeks for one year.

ErbB2 (HER2/neu) ErbB2 (HER2/neu) OverexpressionOverexpression

ErbB2 is a human epidermal growth ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 factor receptor encoded by the ErbB2 genegene

ErbB2 is amplified in approximately ErbB2 is amplified in approximately 20% to 25% of metastatic breast 20% to 25% of metastatic breast cancerscancers

Adverse prognostic factorAdverse prognostic factor Confers resistance to some Confers resistance to some

chemotherapy or hormone therapychemotherapy or hormone therapy Confers aggressive form of disease Confers aggressive form of disease

with significantly shortened disease-with significantly shortened disease-free survival and overall survivalfree 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 ErbB Receptor Tyrosine Kinase SystemSystem

The ErbB system includes four The ErbB system includes four growth factor receptors and their growth factor receptors and their numerous ligands numerous ligands Important in human growth and Important in human growth and

developmentdevelopment Active in proliferating cells, Active in proliferating cells,

inactive in quiescent 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 ErbB Receptor Tyrosine KinasesKinases

Four receptors:Four receptors: ErbB-1 (EGFR, ErbB-1 (EGFR,

HER-1)HER-1) ErbB-2 ErbB-2

(HER-2/neu)(HER-2/neu) ErbB-3 (HER-3)ErbB-3 (HER-3) ErbB-4 (HER-4)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-2ErbB-2 or HER-2/neuor HER-2/neu Because of a unique Because of a unique

ECD conformation, ECD conformation, does not bind to does not bind to ligands, but is primed ligands, but is primed to dimerizeto dimerize

Usually does not Usually does not homodimerizehomodimerize

Heterodimerization Heterodimerization with other ErbB with other ErbB receptors is necessary receptors is necessary for activationfor activation

.Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

Common Mechanisms of ErbB Common Mechanisms of ErbB Activation in Tumors Activation in Tumors – – Receptor Receptor

OverexpressionOverexpression Gene amplification Gene amplification

results in results in overexpression of overexpression of normal receptors normal receptors

Receptors Receptors spontaneously spontaneously homodimerizehomodimerize

Drives tumour Drives tumour growthgrowth

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 Rationale for Inhibiting ErbB ReceptorsReceptors

ErbB receptor inhibition may suppress ErbB receptor inhibition may suppress cell growth, enhance cell death, and cell growth, enhance cell death, and improve response to other cancer improve response to other cancer therapy in some tumorstherapy in some tumors

Inhibiting ErbB receptors may more Inhibiting ErbB receptors may more selectively target cancer cells and selectively target cancer cells and spare normal cells, thereby reducing spare normal cells, thereby reducing unwanted side effects of therapyunwanted 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 AntibodiesMonoclonal Antibodies Trastuzumab is humanized Trastuzumab is humanized

monoclonal antibody monoclonal antibody against EC domain of the against EC domain of the HER-2 proteinHER-2 protein

Mechanism of action:Mechanism of action: Inhibit TK activationInhibit TK activation Induce receptor Induce receptor

endocytosis and endocytosis and degradationdegradation

Induce immune-Induce immune-mediated cytotoxicitymediated 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 Results of Adjuvant Trastuzumab TrialsTrastuzumab Trials

NEJM 2005: HERA Trial and NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a chemotherapy reduces the risk of a breast cancer recurrence by 50%breast cancer recurrence by 50%

Brief median followup of 1-2 yearsBrief median followup of 1-2 years SEs: hypersensitivity with first SEs: hypersensitivity with first

infusioninfusion

CHF 5%CHF 5%

Case No. 1 ContinuesCase No. 1 Continues

After 10 treatments of Herceptin, After 10 treatments of Herceptin, her MUGA reveals EF 45% her MUGA reveals EF 45% (baseline 59%)(baseline 59%)

Patient advised to stop HerceptinPatient advised to stop Herceptin Even though patient is Even though patient is

asymptomatic, referral is made to asymptomatic, referral is made to cardiologistcardiologist

Medical management and close Medical management and close follow-up by cardiologist.follow-up by cardiologist.

Trastuzumab And Trastuzumab And CardiotoxicityCardiotoxicity

erbB2 plays a critical role in the erbB2 plays a critical role in the developing embryonic heart (gene developing embryonic heart (gene deletion=mouse death)deletion=mouse death)

In adult heart, erbB2 modifies In adult heart, erbB2 modifies cardiac response to stresscardiac response to stress

Two-hit model: erbB2 deficient Two-hit model: erbB2 deficient heart is more susceptible to heart is more susceptible to cardiotoxic effects of other stressors cardiotoxic effects of other stressors (eg. Anthracycline chemo) (eg. Anthracycline chemo) increased loss of cardiac myocytesincreased loss of cardiac myocytes

Case No. 2Case No. 2 56 year old healthy postMP patient56 year old healthy postMP patient Left lumpectomy and axillary Left lumpectomy and axillary

dissection 4 weeks agodissection 4 weeks ago PathologyPathology 2.5cm invasive ductal ca nos2.5cm invasive ductal ca nos Grade II/IIIGrade II/III 0/12 LN involved0/12 LN involved ER pos 90%, PR pos 90%ER pos 90%, PR pos 90% HER2neu overexpression negHER2neu overexpression neg

Case No. 2 - Case No. 2 - ChemotherapyChemotherapy

Pt wants to be aggressive Pt wants to be aggressive with treatment, but is with treatment, but is frightened by the concept of frightened by the concept of chemotherapychemotherapy

Risk of relapse at 10years is Risk of relapse at 10years is 35%35%

Chemo options are reviewedChemo options are reviewed

Case No. 2 ContinuesCase No. 2 ContinuesFirst generation protocolsFirst generation protocols

AC 7% AC 7% benefitbenefit

Second generation protocolsSecond generation protocols

AC-Taxol, FEC-100 12% AC-Taxol, FEC-100 12% benefitbenefit

Third generation protocolsThird generation protocols

Dose dense AC-Taxol, FEC-D 16% benefitDose dense AC-Taxol, FEC-D 16% benefit

Case No. 2 – Endocrine Case No. 2 – Endocrine TherapyTherapy

Baseline MUGA EF 55%Baseline MUGA EF 55% AC administered q 3 weeks x AC administered q 3 weeks x

4 cycles without serious 4 cycles without serious effectseffects

After chemo completed she After chemo completed she starts adjuvant letrozole starts adjuvant letrozole 2.5mg po od for planned 5 2.5mg po od for planned 5 yearsyears

Early (Upfront) Adjuvant Early (Upfront) Adjuvant TrialsTrials

0-5 yearsSurgery

TAM

EXEM

ANASTRO + TAM

TAMANASTRO

LETROTAM

R

R

R

TAM

LETRO

LETRO

TAM

ATAC

TEAM

BIG1-98

DFS: Reduction of Event DFS: Reduction of Event Rate Rate

in the Adjuvant Settingin the Adjuvant SettingFollow-up Follow-up (mo)(mo)

Rel. Red. Rel. Red. %%

Abs. Red. Abs. Red. %%

EarlyEarly TAM 5 vs noneTAM 5 vs none 120120 4747 12 (5 yrs)12 (5 yrs)

EarlyEarly ANA 5 vs TAM 5ANA 5 vs TAM 5 6868 1313 3.3 (6 yrs)3.3 (6 yrs)

EarlyEarly LET 5 vs. TAM 5LET 5 vs. TAM 5 25.825.8 1919 2.6 (5 yrs)2.6 (5 yrs)

Early Early seq.seq.

TAM 2 TAM 2 EXE 3 vs EXE 3 vs TAM 5TAM 5 30.630.6 3232 4.7 (3 yrs) 4.7 (3 yrs)

Early Early seq.seq.

TAM 2 TAM 2 ANA 3 vs ANA 3 vs TAM 5TAM 5 2828 4040 3.1 (3 yrs)3.1 (3 yrs)

ExtendeExtendedd

LETRO 5 vs placeboLETRO 5 vs placebo 3030 4242 4.6 (4 yrs)4.6 (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 2005

2020

Relative Effect of AIs on Post MP Relative Effect of AIs on Post MP Recurrences at 5 YearsRecurrences at 5 Years

38% recurrences with no adjuvant treatment (EBCTCG)

47% risk reduction with Tamoxifen

Further 26% risk reduction

with AI

ASCO Technology Assessment 2004ASCO Technology Assessment 2004

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

Total Cholesterol in BIG 1-Total Cholesterol in BIG 1-98: Summary98: Summary

Serum cholesterol decreased by Serum cholesterol decreased by ~~ 12% in the tamoxifen group 12% in the tamoxifen group and was fairly stable in the and was fairly stable in the letrozole groupletrozole group

AIs and BoneAIs and Bone

NORMAL BONE OSTEOPOROTIC BONE

VERTEBRAL COMPRESSIONFRACTURE

Osteoporosis/Fractures Osteoporosis/Fractures Reported in Adjuvant AI Reported in Adjuvant AI

TrialsTrials

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.

ATAC

BIG 1–98

68

26

ANA

LETRO

TAM

TAM

Fracture

Fracture

11.0 vs 7.7

5.8 vs 4.1

<0.0001

NI

IES

ARNO

31

28

EXEM

ANA

TAM

TAM

FractureOsteoporosis

Fracture

3.1 vs 2.37.4 vs 5.7

2.4 vs 2.1

0.080.05

NI

MA-17 28 LETRO Placebo FractureOsteoporosis

3.6 vs 2.95.8 vs 4.5

0.240.07

Mouridsen 0305

Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P

ATAC: Bone Fracture Adverse ATAC: Bone Fracture Adverse Events at Treatment Events at Treatment Completion AnalysisCompletion Analysis

Anastrozole Anastrozole % of patients% of patients

n=3092n=3092

TamoxifTamoxifenen

% of % of patientspatients

n=3094n=3094

p-valuep-value

Joint DisordersJoint Disorders 35.6 (27.8)35.6 (27.8) 29.5 29.5 (21.2)(21.2) <0.0001<0.0001

All FracturesAll Fractures

- - spinespine

- hip- hip

- wrist- wrist

11.0 (5.8) 11.0 (5.8)

1.51.5

1.21.2

2.32.3

7.7 (3.7)7.7 (3.7)

0.90.9

1.01.0

2.02.0

<0.0001<0.0001

0.030.03

0.50.5

0.40.4

(Bisphosphonate (Bisphosphonate usage)usage) 9.69.6 6.46.4

ATAC Trialists’ Group. SABCS 2004. ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62.Lancet 2005; 365: 60-62.

How Serious Is This How Serious Is This Difference?Difference?

No placebo arm No placebo arm What fracture rate might normally What fracture rate might normally

be observed in a similarly aged be observed in a similarly aged population?population?

12-25 # per 1000 patient years12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt ATAC Tam: 13.44 # per 1000 pt

yearsyears ATAC Arimidex: 21.55 # per 1000 ATAC Arimidex: 21.55 # per 1000

pt yearspt years

ATAC BMD SubstudyATAC BMD Substudy No bisphosphonates allowedNo bisphosphonates allowed 2 years A => 4% loss in LS2 years A => 4% loss in LS 3.2% loss in hip3.2% loss in hip 2 years Tam => 1.9% gain in LS2 years Tam => 1.9% gain in LS 1.2% gain in hip1.2% gain in hip Considered small losses compared to Considered small losses compared to

the natural BMD loss that occurs in the natural BMD loss that occurs in menopausemenopause

Benefits of the drug outweigh this Benefits of the drug outweigh this risk risk

Patient Recommendations Patient Recommendations On AIsOn AIs

Stop smokingStop smoking Reduce caffeine and alcohol intakeReduce caffeine and alcohol intake Perform regular weight-bearing Perform regular weight-bearing

exerciseexercise Supplement with Calcium 1500mg/d Supplement with Calcium 1500mg/d

and vitamin D 800 IU/dand vitamin D 800 IU/d Never take estrogenNever take estrogen Raloxifene is contraindicatedRaloxifene is contraindicated

Patient Recommendations Patient Recommendations On AIsOn AIs

BMD performed at baseline and q12-BMD performed at baseline and q12-18mos18mos

If patient has had an osteoporotic #, If patient has had an osteoporotic #, add a bisphosphonate right awayadd a bisphosphonate right away

If there is evidence of OP, add If there is evidence of OP, add bisphosphonate right awaybisphosphonate right away

If there is osteopenia, evaluate other If there is osteopenia, evaluate other RFs and consider bisphosphonateRFs and consider bisphosphonate

If follow-up BMD loss >3% LS or >5% If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonateFN, add a bisphosphonate

Case No. 2 ContinuesCase No. 2 Continues

4 years later she reports profound 4 years later she reports profound fatigue x 2 mosfatigue x 2 mos

Drops in to office to see her SCC, Drops in to office to see her SCC, complaining of fatigue, wants to set up complaining of fatigue, wants to set up an appointment with oncologistan appointment with oncologist

SCC notes she is in rapid AFib and SCC notes she is in rapid AFib and sends her to ERsends her to ER

Cardiologist diagnoses her with Cardiologist diagnoses her with anthracycline-induced cardiomyopathy anthracycline-induced cardiomyopathy requiring medical managementrequiring medical management

Chemotherapy RelatedChemotherapy Related CardiotoxocityCardiotoxocity

AnthracyclinesAnthracyclines Daunorubicin, Daunorubicin, doxorubicindoxorubicin, idarubicin, , idarubicin,

epirubicinepirubicin, and mitoxantrone, and mitoxantrone Toxicity effectsToxicity effects

Acute (during administration)Acute (during administration) Arrhythmias, pericarditis-myocarditisArrhythmias, pericarditis-myocarditis

Early (Several days to mos following)Early (Several days to mos following) CHF with peak at 3 mos after last doseCHF with peak at 3 mos after last dose

Late (years to decades following)Late (years to decades following) CHF may develop up to 10-12 yrs after last CHF may develop up to 10-12 yrs after last

anthracycline doseanthracycline dose

Cardiac Toxicity – Cardiac Toxicity – AnthracyclinesAnthracyclines

Risk factors for the development Risk factors for the development of anthracycline cardiac toxicityof anthracycline cardiac toxicity Cumulative dose – strongest risk Cumulative dose – strongest risk

factorfactor AgeAge Prior irradiationPrior irradiation Concomitant administration of Concomitant administration of

other agentsother agents Previous history of cardiac diseasePrevious history of cardiac disease

ConclusionsConclusions Key advances in the management of breast cancer Key advances in the management of breast cancer

have been made in the last few yearshave been made in the last few years Adjuvant treatment is individualized to possibly Adjuvant treatment is individualized to possibly

include chemotherapy, hormone therapy and include chemotherapy, hormone therapy and trastuzumabtrastuzumab

New treatments are intensive and may result in long-New treatments are intensive and may result in long-term health concernsterm health concerns

Evidence-based, informative discussion to review Evidence-based, informative discussion to review risks and benefits for each patient is of critical risks and benefits for each patient is of critical importanceimportance

Thank you for Thank you for your attentionyour attention