Cardiac Sequelae of Common Breast Cancer Treatments Health/Health... · affect CV system1 •...

Ana Barac, MD, PhD, FACC

Associate Professor of Medicine, Georgetown University

Director, Cardio-Oncology Program, MedStar Heart and Vascular Institute

Cardiac Sequelae of Common Breast Cancer

Treatments

Charleston, Cardio-Oncology Symposium, November 2019

Disclosures: Not Relevant for This Presentation

• Cardiology PI for SAFE-HEaRt, investigator-initiated study

supported by Genentech (non-financial)

• Bristol Myers Squibb (honoraria)

• CTI Biopharma (DSMB)

Objectives

• Recognize complexity of cardiovascular risks in

patients with breast cancer and cancer survivors

• Incorporate cardiology and oncology professional

society guideline recommendations into clinical practice

• Identify role of cardiac imaging in CV management of

breast cancer patient during cancer treatment continuum

✓ CV Disease and Cancer = Two Leading

Causes of Death Worldwide

Cardio-Oncology = Intersection between Cancer and CV Disease

www.cdc.gov

Cardiovascular Needs of Patients with Cancer

and Cancer Survivors - in 2019

• Exponential growth of novel cancer treatments with potential to

affect CV system1

• Rapidly growing population of cancer survivors with high

burden of CV risk factors2

• New knowledge about synergism between CV risk, cancer and

cancer treatment risk3

• Gap in knowledge about CV evaluation and treatment4

1 Moslehi J NEJM 2016; 375:14572 Armenian SH et al. JCO 2016; 34:11223 Shelburne N et al. JNCI 2014; 106:94 Barac A et al. JACC 2015; 65:2739

JASE 2014:27:911 JCO 2017: 35:893

~ 2011 No Guidelines

AnnOnc 2012: supp 7

EHJ 2016: 37:2768

~ 2019 Too Many Guidelines

•52 y.o. postmenopausal African American woman

•Invasive left breast ductal carcinoma: 3.2 cm, 4/10

lymph nodes+, ER-/PR-, HER2-, Stage III

•Oncology treatment

–Surgery: Lumpectomy and sentinel lymph node biopsy

–Adjuvant systemic chemotherapy

•ddAC-T = doxorubicin (240 mg/m2), cyclophosphamide, paclitaxel

•or non-anthracycline regimen

–Radiation

Case: Patient with Breast Cancer

52 yo African American woman with high-risk TNBC

•Hypertension; non-smoker

•Physical exam: BP 150/90 mmHg

•BMI 36

•No JVD, normal S1 and S2, no murmurs, no edema

•Asymptomatic at lower levels of physical activity

•ECG NSR, HR 89 bpm

•LDL 148, HDL 38, TG 168, HgbA1c 6.2

Referred for Cardiology Visit

Echo

Normal LV size and function

LVEF 62%, GLS -24%LVEF 62%, GLS -24%

Adverse CV Effects of Breast Cancer Treatment

Systemic chemotherapy and Targeted Biologic Therapy

• Anthracyclines - HF/Cardiomyopathy

• HER2 targeted therapy - HF/Cardiomyopathy

• All systemic chemotherapy - Decreased VO2– Alkylating agents - cyclophosphamide, carboplatinum

– Anti-microtubule agents - paclitaxel, docetaxel

• CKD 4/6 inhibitor (ribociclib) – Prolonged QT

Radiation - CAD, HF with preserved EF

Aromatase inhibitors – Hyperlipidemia, CVD

ASCO Guideline on Cardiac Dysfunction

Development Methodology

• a systematic literature review by

ASCO guidelines staff

• an expert panel provides critical

review and evidence interpretation

to inform guideline

recommendations

• final guideline approval by ASCO

CPGC

JCO 2017: 35:893

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Clinical Question # 1: Who is At Risk for Cardiac Dysfunction?

Armenian S. JCO 2017: 35:893

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Armenian S. JCO 2017: 35:893

Clinical Question # 1: Who is At Risk for Cardiac Dysfunction?

ALL OTHER CANCER THERAPIES

No Determination of Risk

Cancer/Cancer Treatment

Host Interaction

CV Risk factors and CV disease

Cancer treatment-related CV toxicities

HEART FAILUREStage A - D

VALVULARDISEASE

Therapeutic chest radiation

CORONARY ARTERY DISEASE

PERIPHERAL ARTERIAL EVENTS

HYPERTENSION

ATRIAL FIBRILLATION Ibrutinib

(Anthracyclines, HER2-agents)VSPIs, Proteasome inhibitors, Immune checkpoint inhibitors

Therapeutic chest radiation, AIs, CVRFs

VSPIs: Sunitinib, sorafenib, bevacizumab, lenvatinib

TKIs: Ponatinib, Nilotinib

DVT AND THROMBOSIS

CARDIACAMYLOIDOSIS

Multiple myeloma

CANCER SURVIVORSHIP

Thalidomide,Lenalidomide, Pomalidomide

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Clinical Question # 2: Preventive Strategies PRIOR to Tx

Armenian S. JCO 2017: 35:893

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

The ABC Trials: Anthracycline Still Needed in

High-Risk Breast Cancer

Blum et al . JCO 2017

Stage II-IIIStage I-Triple negative (size > 1 cm)

-ER/PR+ (size > 1 cm high rec score)

Blum JL et al. JCO 2017; 35(23):2647

Thanks to Dr. Chau Dang

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline

Clinical Question # 3: Preventive Strategies DURING Tx

PRADA MANTICORE CECCY

Study Population (N=130)

– All epirubicin, 22% trastuzumab

Study design

– 2x2, metoprolol and candesartan

Primary Outcome

– Changes in LVEF by CMR at 10-64 weeks

Results

– Attenuation of LVEF decline with candesartan (order of 2-3%)

Study Population (N=94)

• All trastuzumab, 12-33% anthracycline

Study design

• 1:1:1 bisoprolol, perindopril, placebo

Primary Outcome

• Changes in LVEDVi by CMR at 1 year _ NEG

Results

• 2nd : Attenuation of LVEF decline with bisoprolol (~4%)

Gulati G. EHJ. 2016 Pituskin E. JCO 2017

Study Population (N=200)

• All doxorubicin

• Study design

• 1:1 carvedilol and placebo

• Echo

• Primary Outcome

• Reduction in Echo LVEF>10% at 6months

• Results

• No significant difference in LVEF decline (13.5% vs 14.5%)

Avila MS. JACC 2018

Primary Prevention Trials In Patients with Early Stage Breast Cancer

Primary Prevention Trials In Patients with Breast Cancer

Lynce F, Blaes, A, Barac A. JACC June 2019

Primary Prevention of Cancer Treatment Related Cardiac Dysfunction

from Mann D Circ 1999;100:999

Gaps in evidence•Evidence on the effect of early preventive measures to reduce type I cardiotoxicity is inconclusive.•The most appropriate strategy to improve risk stratification and prevent CVD in patients treated for cancer needs to be tested prospectively.

Eur Heart J. 2016 Aug 1; 37(29): 2315–2381.

Clinical Question # 4: Preferred Surveillance/Monitoring Approaches DURINGtreatment in Patients at risk for Cardiac Dysfunction

How Often to Image?

What if LVEF decreases?

Baseline Echo

LBBB, LVEF 41% (biplane Simpsons)

Case: Ms MB

• 70 yo w with hypertension, hyperlipidemia, and glucose intolerance

• Diagnosed with Stage II, ER/PR positive, HER2-positive right

breast cancer

• Medications: HCTZ, metoprolol, atorvastatin, ibuprofen

• Exam: BP 121/69 mmHg, HR 88 bpm, BMI 36, 1+ bilateral pretibial

edema

• Labs: creatinine 0.77, potassium 3.9, HgbA1c 6.1, NT-proBNP 54

• Planned Cancer Treatment

– Surgery/ adjuvant TCH/ radiation/ hormonal therapy

Baseline ECG

Safety Recommendations for Anthracycline and HER2-

targeted Therapeutics-related Cardiotoxicity

• FDA for trastuzumab

– Baseline normal LVEF

– Frequent LVEF assessments

– ≥ 16% absolute decrease in LVEF from pre-treatment values OR

LVEF below institutional limits of normal and ≥ 10% in LVEF

decrease

• ASE/EACVI Expert Consensus (Plana JC et al. JASE 2014; 27:911

– CTRCD = a decrease in the LVEF of >10 percentage

points, to a value <53%

Prevention and Monitoring of Cardiac Dysfunction In Survivors of Adult Cancers: ASCO Clinical Practice

Guideline Plana JC et al. JASE 2014, 27: 911-939

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy (ASE/ EACVI)

On treatment LVEF

Plana JC et al. JASE 2014; 27:911

URGENT NEED: A joint cardio-oncology pathway for collaborative treatment approach

Baseline LVEF

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy (ASE/ EACVI)

A pilot study evaluating the cardiac SAFEty of HER2

targeted therapy

in patients with HER2 positive breast cancer and reduced

left ventricular function

• Investigator-initiated, funded by Genentech, Inc.

• IND for trastuzumab, pertuzumab and TDM-1

• Sites: MWHC, MGUH/LCCC, MSKCCC

• Chair (PI): Sandra Swain, Cardiology Co-Chair: Ana Barac, MGUH PI:

Filipa Lynce, MSKCCC: Chau Dang/Anthony Yu

• Rationale: Retrospective data suggest that trastuzumab may be

safe in patients with asymptomatic drop in LVEF (if on optimized

cardiac therapy)

ClinicalTrials.gov Identifier:

NCT01904903

Eligibility criteria

▪HER2+ breast cancer stage I-IV

▪LVEF 40% and < 50%

▪Tx with trastuzumab, trastuzumab + pertuzumab or T-DM1

▪No HF in last 12 months nor current HF

▪No concomitant use of anthracyclines in the last 50 days

SAFE HEaRt: Design

SAFE HEaRt: Study Flow

• Cardiology assessment and

ECHO

• 6 weeks & q 3 months

• Independent Core Lab

• Internal Cardiac Review Panel

• DSMB

12 months

SAFE HEaRt: Cardiac Medication Titration

35

58%42%

Treatment intent

Curative

Palliative

48%45%

7%

HER2 therapy received

Trastuzumab

Pertuzumabandtrastuzumab

TDM1

55%45%

Previous anthracyclines

Yes

No

SAFE HEaRt: Patient Characteristics

SAFE HEaRt Results : Primary

Endpoint

Breast Cancer Res Treat. 2019 Jun;175(3):595-603

SAFE HEaRt Results : Primary

Endpoint

Breast Cancer Res Treat.2019 Jun;175(3):595-603

SAFE HEaRt Results : Changes in

LVEF

Clinical Question # 5: Preferred Surveillance/MonitoringApproaches AFTER treatment in Patients at risk for Cardiac Dysfunction

Armenian S. JCO 2017: 35:893

5.1 Careful History and Physical Exam: If clinical signs or symptoms: ECHO (Cardiac MRI /MUGA, Serum cardiac biomarkers)

5.2 In asymptomatic individuals an Echo may be considered 6-12 months post treatment (CMR/MUGA)

5.3 Referral to cardiologist if asymptomatic LV dysfunction

5.4 No recommendation re duration and frequency of imaging in patients at risk who are asymptomatic and without evidence of dysfunction on Echo

5.5 Clinicians should regularly evaluate and manage CV risk factors

Lessons from Cardiac Imaging

LVEF

Cancer Treatment

Cancer Treatment

Oncology Questions:• Will it Improve Outcomes?

• Can it lead to Potential Harm?

• Compromise Cancer Treatment?

• Feasibility and Cost?

• Is it Justified in many patients?

LVEF Used to Assure Cardiac Safety➢ Accuracy of LVEF

➢ Other measures of CVD Risk

➢ Early Detection of Subclinical Cardiac Injury (Risk Stratification)

➢ Interventions

Kenigsberg B, Barac A. JACC Heart Failure. 2018;6:87

Historical Perspective: Cardiology and Oncology Professional

Society Statements

Campia U, Moslehi J et al. Circulation 2019; 139:e579Mehta LS, Watson KE et al. Circulation 2018;137:e30

Shared and Separate Risk Factors Between CVD and Breast Cancer

Circulation 2018;137:e30

Risk Factors for Development of CVD/Breast Cancer

Circulation 2018;137:e30

Cardiometabolic Risk Factors and Survival after Breast Cancer in the Women's Health Initiative

Simon MS et al. Cancer 2018:124(8):1798

Mortality: Breast Ca, n=619, 28% CVD, n=459, 21% Other causes, n=506, 23%

N= 8641 women with early BC, 11.3 years, Total Deaths= 2181

High WC

Diabetes

High cholesterol

High BP

Breast Ca CVD Other CauseUnadjusted Mortality HR:

# CM abnormalities

Simon MS et al. Cancer 2018:124(8):1798

Cardiometabolic Risk Factors and Survival after Breast Cancer in the Women's Health Initiative

Chlebowski RT et al. JAMA Onc 2018:4(10):e1812

Chlebowski RT et al. JAMA Onc 2018:4(10):e1812

DESIGN• 1764 postmenopausal women in WHI

dietary intervention trial, dg of breast cancer

• Median 11.5 years of follow-up• 516 deaths: 37% breast cancer, 20% other

cancer, 18% CVD

RESULTS:• Improved 10 year survival in low-fat vs

standard diet (82% vs 78%, HR 0.78, %95 CI 0.65-0.94, p=0.01)

• Less breast cancer-specific death, death from other cancers and CVD death

Circulation, Feb

2019

DATA GAP

Gilchrist S, Barac A et al. Circulation 2019; 139:00

Conclusions

➢Growing unmet needs for CV Care of Breast Cancer Patients

➢Current guidelines focused on changes in LVEF with anthracycline and HER2 targeted therapy

➢Opportunities for Partnership

➢ Improved Definitions and Measurement of CVD risk

➢New Risk Stratification Approaches that include cancer treatment continuum

➢CV Intervention trials embedded in Oncology care

➢ Inclusion of CV and Oncology outcomes

Thank You!

Ana.Barac@medstar.net

@AnaBaracCardio

Thank you

Ana.Barac@medstar.net

Zamorano JL. 2016 ESC CPG Position Paper. EHJ 2016

Plana JC et al. JASE 2014, 27: 911-939

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy (ASE/ EACVI)

59

LiveCourse

COURSE DIRECTORSAna Barac, MD, PhD, FACC

Bonnie Ky, MD, MSCE, FACC

JANUARY 25 – 27, 2019 The Ritz-Carlton

Washington, DCFor more

information

and to register visit

ACC.org/CVOncology

Advancing the Cardiovascular Care of the

OncologyPatient

ACC Cardio-Oncology SectionASCO-ACC Taskforce

2011 2017 201920162013 201820152014

LCCC Research Grant: CV function in BRCA carriers

GHUCCTS- KL2 award

SAFE-HEaRt study: investigator-initiated multicenter trial

Cardio-oncology clinics at MWHC and MGUH

NIH/NHLBI/NCI

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