Highly effective cancer drugs, such as doxorubicin and trastuzumab (Herceptin(R)) are used widely in the treatment of many cancers and have led to important survival gains. However, these agents carry a significant risk of cardiovascular (CV) morbidity and mortality in a growing cancer population of over 12.7 million individuals worldwide. Doxorubicin-induced cardiotoxicity occurs in 9% of treated patients at dosages of 250mg/m2, and carries a particularly poor prognosis once it ensues. The combination of doxorubicin and trastuzumab result in an increased incidence of cardiotoxicity of 18-34% and severe heart failure in 2-4%. The objective of this proposal is to develop multimarker risk prediction algorithms which comprehensively integrate key biologic, imaging, and clinical data to identify patients at increased risk for doxorubicin- and doxorubicin + trastuzumab-induced cardiotoxicity.
In Aim 1, we will determine if the level of or interval change in multiple biomarkers is associated with the risk of cardiotoxicity in participants from the Penn Cardiotoxicity of Cancer Therapy (CCT) cohort, an established longitudinal prospective cohort study of breast cancer patients undergoing treatment with doxorubicin or doxorubicin + trastuzumab.
In Aim 2, we will determine if baseline or early changes in sensitive echocardiographic measures of cardiac function and myocardial mechanics are associated with the risk of cardiotoxicity in this cohort. We will leverage this new knowledge and integrate these findings in Aim 3, and develop risk prediction algorithms to identify individual patients at increased risk for doxorubicin and doxorubicin + trastuzumab-induced cardiotoxicity. We will derive these scores in the Penn CCT cohort, and externally validate our findings in the Vanderbilt (VUMC) Doxorubicin cohort and Massachusetts General Hospital (MGH) Herceptin cohorts. All analyses, including our risk scores, will be stratified by treatment regimen (doxorubicin alone and doxorubicin + trastuzumab). Through this comprehensive proposal, we will define the utility of an integrated multimarker approach in predicting cancer therapy cardiotoxicity. By improving the CV risk stratification of individual patients, we will help ensure the safe delivery of highly effective and necessary cancer therapies;enable the early institution of cardioprotective strategies;prevent the interruption or discontinuation of cancer therapy;and reduce early and late CV and oncologic morbidity and mortality. This work will advance our biologic and physiologic understanding of this disease and accelerate the discovery of strategies to help prevent and treat cancer therapy cardiotoxicity.

Public Health Relevance

Cancer therapy with agents such as doxorubicin and trastuzumab are highly efficacious in the treatment of various malignancies. However, in certain patients, this treatment can result in significant adverse effects on the heart. The current methods for identifying those patients who will suffer from cardiac dysfunction are limited, and lack sensitivity and specificity. Our proposed multidisciplinary study, one of the first of its kin, will define the utility of a comprehensive multimarker approach that integrates biomarkers, imaging markers, and clinical variables, to robustly identify cancer patients at high risk for adverse cardiovascular outcomes. This work will improve the overall cardiovascular and oncologic health of a growing population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL118018-01A1
Application #
8629968
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$790,083
Indirect Cost
$260,508
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Kathleen W; Finkelman, Brian S; Gulati, Gaurav et al. (2018) Abnormalities in 3-Dimensional Left Ventricular Mechanics With Anthracycline Chemotherapy Are Associated With Systolic and Diastolic Dysfunction. JACC Cardiovasc Imaging 11:1059-1068
Catino, Anna B; Hubbard, Rebecca A; Chirinos, Julio A et al. (2018) Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma. Circ Heart Fail 11:e004408
Narayan, Hari K; Wei, Wei; Feng, Ziding et al. (2017) Cardiac mechanics and dysfunction with anthracyclines in the community: results from the PREDICT study. Open Heart 4:e000524
Beer, Lynn A; Ky, Bonnie; Barnhart, Kurt T et al. (2017) In-Depth, Reproducible Analysis of Human Plasma Using IgY 14 and SuperMix Immunodepletion. Methods Mol Biol 1619:81-101
Beer, Lynn A; Liu, Pengyuan; Ky, Bonnie et al. (2017) Efficient Quantitative Comparisons of Plasma Proteomes Using Label-Free Analysis with MaxQuant. Methods Mol Biol 1619:339-352
Narayan, Hari K; Finkelman, Brian; French, Benjamin et al. (2017) Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 Years of Follow-Up. Circulation 135:1397-1412
Finkelman, Brian S; Putt, Mary; Wang, Teresa et al. (2017) Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer. J Am Coll Cardiol 70:152-162
Liu, Pengyuan; Beer, Lynn A; Ky, Bonnie et al. (2017) Quantitative Comparisons of Large Numbers of Human Plasma Samples Using TMT10plex Labeling. Methods Mol Biol 1619:319-337
Armenian, Saro H; Lacchetti, Christina; Barac, Ana et al. (2017) Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 35:893-911
Narayan, Vivek; Keefe, Stephen; Haas, Naomi et al. (2017) Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res 23:3601-3609

Showing the most recent 10 out of 22 publications