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