Alvarez-Cardona, Jose A

Fisch, Michael J

Lenihan, Daniel J

Mitchell, Joshua D

Zaha, Vlad G

Zhang, Kathleen W

English

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker 2020-Current year OA Pubs Open Access Publications 12-1-2020 Cardiac biomarkers during cancer therapy: Practical applications for cardio-oncology Jose A Alvarez-Cardona Washington University School of Medicine in St. Louis Kathleen W Zhang Washington University School of Medicine in St. Louis Joshua D Mitchell Washington University School of Medicine in St. Louis Vlad G Zaha University of Texas Southwestern Michael J Fisch University of Texas MD Anderson Cancer Center See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/oa_4  Part of the Medicine and Health Sciences Commons Please let us know how this document benefits you. Recommended Citation Alvarez-Cardona, Jose A; Zhang, Kathleen W; Mitchell, Joshua D; Zaha, Vlad G; Fisch, Michael J; and Lenihan, Daniel J, "Cardiac biomarkers during cancer therapy: Practical applications for cardio-oncology." JACC: CardioOncology. 2, 5. 791 - 794. (2020). https://digitalcommons.wustl.edu/oa_4/1123 This Open Access Publication is brought to you for free and open access by the Open Access Publications at Digital Commons@Becker. It has been accepted for inclusion in 2020-Current year OA Pubs by an authorized administrator of Digital Commons@Becker. For more information, please contact vanam@wustl.edu. Authors Jose A Alvarez-Cardona, Kathleen W Zhang, Joshua D Mitchell, Vlad G Zaha, Michael J Fisch, and Daniel J Lenihan This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/oa_4/1123 HOW TOCardiac Biomarkers DuringCancer TherapyPractical Applications for Cardio-OncologyJose A. Alvarez-Cardona, MD,a Kathleen W. Zhang, MD,a Joshua D. Mitchell, MD,a Vlad G. Zaha, MD, PHD,bMichael J. Fisch, MD,c Daniel J. Lenihan, MDaC ombined modality approaches to cancertreatment have dramatically improved clin-ical outcomes. At the same time, there hasbeen increased attention to acute, chronic, and lateeffects of treatment, including the management ofcardiac disease in patients with cancer (1). It is recog-nized that there are limited sensitivity and specificityof traditional cardiovascular (CV) testing, such aselectrocardiography (ECG) and transthoracic echocar-diography (TTE), for early detection of myocardialinjury. Therefore, there is a compelling need toimprove risk prediction and to detect subclinical dis-ease at a potentially reversible stage to allow imple-mentation of cardioprotective strategies andimprove outcomes (2). Cardiac blood-based bio-markers continue to be explored to improve thedetection and long-term monitoring of subclinicalcardiotoxicity.In order for a biomarker to be useful, it should beaccurate, be easy to measure, and provide importantinformation relative to treatment outcome. A prog-nostic biomarker forecasts the likely course of a dis-ease irrespective of treatment, whereas a predictivebiomarker forecasts the likely response to a specifictreatment (3). It is important to understand the clinicalimplications of an abnormal cardiac biomarker andhow this information can inform treatment decisions.Figure 1 shows 4 different profiles (I, II, III, and IV)in which traditional cardiac biomarkers, natriureticpeptides (N-terminal pro–B-type natriuretic peptide[NT-proBNP] or B-type natriuretic peptide [BNP]) andtroponins, can help identify the development of a CVadverse event during cancer therapy. In general, anelevated natriuretic peptide (NP) level represents he-modynamic congestion, whereas an abnormaltroponin is amarker ofmyocardial injury. Although thespecific CV conditions a patient may experience withcontemporary cancer therapy are broad (Figure 1),cardiac biomarkers can indicate ongoing stress andinjury. The following cases illustrate how cardiac bio-markers may be used to guide clinical decision-makingin cardio-oncology.CASE 1: PREDICTION AND DETECTIONOF CARDIOTOXICITYA 73-year-old woman with stage IVB diffuse largeB-cell lymphoma was scheduled for 6 cycles of rit-uximab, cyclophosphamide, doxorubicin (anticipatedcumulative dose 280 mg/m2), vincristine, prednisone,and CC-122 (an experimental pleiotropic pathwaymodifier that is an immune modulatory therapy), and4 cycles of intrathecal methotrexate. Pre-chemotherapy evaluation showed a left ventricular(LV) ejection fraction (LVEF) of 53%, global longitu-dinal strain (GLS) 15.5% (normal <18% to 22%),and grade I diastolic dysfunction on TTE, NT-proBNPelevation at 864 pg/ml (normal <300 pg/ml), andISSN 2666-0873 https://doi.org/10.1016/j.jaccao.2020.08.014From the aCardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis,Missouri, USA; bDivision of Cardiology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center andAdvanced Imaging Research Center, University of Texas Southwestern, Dallas, Texas, USA; and the cDepartment of GeneralOncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Daniela Cardinale, MD, served as the GuestAssociate Editor for this paper. Anju Nohria, MD, served as Guest Editor-in-Chief for this paper.The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,visit the Author Center.Manuscript received May 22, 2020; revised manuscript received August 19, 2020, accepted August 21, 2020.J A C C : C A R D I O O N C O L O G Y VO L . 2 , N O . 5 , 2 0 2 0ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A NC O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .undetectable troponin I (Figure 1) (profile II).Her total cholesterol was 250 mg/dl and low-density lipoprotein was 133 mg/dl, and chestcomputed tomography revealed substantialcoronary calcifications. Her age, hyperlipid-emia, anticipated high-dose exposure toanthracyclines (>250 mg/m2), coronarycalcification, and underlying heart failure(HF) with preserved ejection fraction(HFpEF) placed her at high risk for car-diotoxicity. Carvedilol, rosuvastatin, andaspirin 81 mg were initiated before andcontinued through chemotherapy (1,4).Furosemide was prescribed for evidence ofvolume overload and HF. At 3 months, LVEFremained unchanged, but NT-proBNPincreased to 2,963 pg/ml, and troponin I hadbecome minimally elevated at 0.05 ng/ml(normal <0.03 ng/ml) indicating congestionand potential injury, prompting adjustmentof furosemide and carvedilol dosing. Uponcompletion of 6 months of chemotherapy, theLVEF decreased to 45% (GLS not obtained),NT-proBNP had improved to 795 pg/ml, buttroponin I was persistently elevated (0.22 to 0.25 ng/ml) on serial assessment (profile IV), with an un-changed ECG. Lisinopril was added to optimize CVtherapy. The differential diagnosis included myocar-dial ischemia, anthracycline-related cardiotoxicity,and CC-122–related myocarditis, and a cardiac mag-netic resonance imaging (cMRI) was performedshowing a mildly depressed LVEF (43%) with lategadolinium enhancement (LGE) in the right coronaryartery territory suggestive of prior myocardial infarc-tion. Subsequent left heart catheterization showedmild, nonobstructive multivessel coronary artery dis-ease and elevated LV end-diastolic pressure at18mmHg. The combination of a elevated troponin andLGE on cMRI is consistent with myocardial injury,probably related to anthracycline chemotherapyespecially in the absence of significant coronary arterydisease. It is currently unknown whether there areimportant CV effects of CC-122. Twelve months afterinitiating anthracycline-based chemotherapy andwithoptimal cardioprotective therapy, her LVEF normal-ized (67%), but GLS did not (11.9%). NT-proBNPremained modestly elevated at 440 pg/ml andtroponin was undetectable (profile II).This case illustrates how cardiac biomarkers mayhelp with CV risk stratification before and during car-diotoxic cancer therapy (4). Although this patient’sLVEF fully recovered at 1-year post-chemotherapy,medical optimization is an essential priority to allowthe most effective cancer therapy to occur. Given thebiomarker elevation in this case, cardioprotectivetherapy and heightened surveillance for progressivecardiac dysfunction are recommended (1).LEARNING POINTS Elevated pre-chemotherapy cardiac biomarkerscan detect underlying myocardial injury and stress,and help with risk stratification and medical opti-mization before and during cancer therapy (5). NPs and troponin may detect congestion and injuryduring and after anthracycline-based cardiotoxiccancer therapy, independent of detectable changesin LVEF (6).CASE 2: DETECTION AND MONITORINGOF IMMUNOTHERAPY-RELATED CARDIOTOXICITYA 48-year-old African-American woman with stage IVlung adenocarcinoma was initially treated over a 4-year period with right lower lobe wedge resectionfollowed by sequential carboplatin/pemetrexed andradiation therapy. She was ultimately switched toatezolizumab, a programmed cell death 1 receptor(PD-L1) inhibitor, due to suboptimal treatmentresponse. Cardiac testing was not obtained beforeinitiation on immunotherapy. Approximately2 months later, she developed dyspnea and edema.TTE showed severe global hypokinesis with LVEF28%, GLS 5%, normal right ventricular size andfunction, and a small-to-moderate pericardial effu-sion without tamponade physiology. Biomarkertesting included troponin I of 0.35 ng/ml, NT-proBNP3,863 pg/ml, and high-sensitivity C-reactive protein(hsCRP) 55.2 mg/dl (normal <3 mg/dl) (Figure 1)(profile IV). The ECG was unrevealing. A cMRI was notfeasible, so an endomyocardial biopsy (EMBx) wasperformed showing focal, mild cardiomyocyte dam-age with mild lymphoplasmacytic inflammationconsistent with myocarditis (Figure 1). Atezolizumabwas permanently discontinued, and she was treatedwith methylprednisolone 1 g intravenously daily for 3doses, followed by a slow taper of prednisone. In lightof her depressed LVEF, she was started on carvediloland sacubitril-valsartan. One month later, troponin Iwas undetectable, and NT-proBNP and hsCRP bothdecreased to 574 pg/ml and 17.7 mg/dl, respectively.cMRI at this time showed a persistently reduced LVEFat 21% and no evidence of LGE. The patient continuedon guideline-directed HF therapy including spi-ronolactone as well as prednisone with resolution ofher HF symptoms. On a 6-month follow-up TTE, LVEFhad increased to 37% and GLS improved to 8.5%.Immunotherapy-related adverse events, includingmyocarditis, are uncommon, but potentially serious.ABBR EV I A T I ON SAND ACRONYMSBNP = B-type natriureticpeptidecMRI = cardiac magneticresonance imagingCV = cardiovascularECG = electrocardiographyEMBx = endomyocardial biopsyGLS = global longitudinalstrainHF = heart failureHFpEF = heart failure withpreserved ejection fractionLGE = late gadoliniumenhancementLV = left ventricularLVEF = left ventricular ejectionfractionNP = natriuretic peptideNT-proBNP = N-terminal pro–B-type natriuretic peptideTTE = transthoracicechocardiographyAlvarez-Cardona et al. J A C C : C A R D I O O N C O L O G Y , V O L . 2 , N O . 5 , 2 0 2 0Cardiac Biomarkers During Cancer Therapy D E C E M B E R 2 0 2 0 : 7 9 1 – 4792Although establishing the diagnosis of myocarditisfrequently requires EMBx, cardiac biomarkers areusually elevated due to ongoing myocardial injuryand may be supportive of the diagnosis. AchievingNT-proBNP <1,000 pg/ml on HF therapy has previ-ously been associated with subsequent improve-ments in LVEF and more substantial reductions in LVvolumes in patients with systolic HF (7). In theabsence of permanent myocardial damage or ongoingexposure to cardiotoxic therapies, this patient’simproved biomarker response to optimal HF treat-ment correlated with improved symptoms and animproved LVEF.LEARNING POINTS Troponin and NPs have potential utility for thediagnosis of immunotherapy-related adverseevents. NT-proBNP response to HF therapy has beenshown to be prognostic of cardiac recovery.CASE 3: PROGNOSIS IN THE TREATMENTOF CARDIOMYOPATHYA 65-year-old man was diagnosed with HFpEF af-ter presenting with worsening lower extremityedema and dyspnea. His NT-proBNP (1,060 pg/ml)and troponin I (0.22 ng/ml) levels were bothelevated, and his ECG demonstrated low QRSvoltages and a pseudoinfarct pattern (Figure 1)(profile IV). cMRI showed mild LVEF depression(47%), diffuse biventricular wall thickening, bia-trial enlargement, and extensive subendocardialand transmural LGE. Serum lambda free lightchain level was 8.0 mg/dl, kappa free light chain0.64 was mg/dl, and the kappa/lambda ratio wasFIGURE 1 Practical Strategy for Using Cardiac Biomarkers in Cardio-OncologyBiomarker profiling can help identify patients with cardiotoxicity during cancer therapy (left). If abnormal, there is a broad differential diagnosis considered (right)determined by the type of cancer therapy received. CV ¼ cardiovascular; ECG ¼ electrocardiogram; LV ¼ left ventricular; NP ¼ natriuretic peptide.J A C C : C A R D I O O N C O L O G Y , V O L . 2 , N O . 5 , 2 0 2 0 Alvarez-Cardona et al.D E C E M B E R 2 0 2 0 : 7 9 1 – 4 Cardiac Biomarkers During Cancer Therapy79312.5. Bone marrow biopsy showed 20% lambda-restricted plasma cells, and an EMBx confirmedthe diagnosis of AL cardiac amyloidosis. He wastreated with 4 cycles of cyclophosphamide, borte-zomib, and dexamethasone. Upon completion oftherapy, NT-proBNP rose to 1,295 pg/ml and thendecreased to 656 pg/ml 1 year later, whereastroponin T remained minimally elevated between0.02 and 0.03 ng/ml (normal <0.01 ng/ml) (profileIV). Serum kappa and lambda free light chainlevels normalized after chemotherapy. He remainson spironolactone and torsemide with stable NewYork Heart Association functional class II HFsymptoms and relative hypotension since theoriginal diagnosis of cardiac amyloidosis. Nofurther chemotherapy is planned.Cardiac biomarkers, specifically NT-proBNP andtroponin T, have been incorporated into the prog-nostic staging system for AL amyloidosis since 2012(8). Abnormal values in a patient with HFpEF andother suggestive clinical or cardiac imaging findingsshould prompt evaluation for cardiac amyloidosis(Figure 1). Although a complete hematologicresponse can be achieved with standard myelomatreatment, cardiac involvement may progress asevidenced by persistent cardiac biomarker elevation(9,10). In our experience, the decision to continuetreatment for AL amyloidosis is based primarily onhematologic response. In this situation, we recom-mend periodic assessment of cardiac biomarkers,careful assessment and management of volumeoverload, and close collaboration with hematology/oncology to discuss the benefit of pursuingadditional myeloma treatment as well as consider-ation for advanced HF therapies, including trans-plantation, in patients with progressive HF.LEARNING POINTS NT-proBNP and troponin T have diagnostic andprognostic utility in AL cardiac amyloidosis. The prognostic significance of persistent cardiacbiomarker elevation in the setting of completehematologic response to AL therapy requiresfurther investigation.CONCLUSIONSIn summary, the use of cardiac biomarkers as a toolfor monitoring during cancer therapy has expandedgreatly in recent years; however, there continues tobe a need to establish the firm threshold for anabnormal value and the requisite action that shouldresult from early detection of cardiac damage orstress.AUTHOR DISCLOSURESAll authors have reported that they have no relationships relevant tothe contents of this paper to disclose.ADDRESS FOR CORRESPONDENCE: Dr. Daniel JLenihan, Cardio-Oncology Center of Excellence, Car-diovascular Division, Washington University in St.Louis, 660 South Euclid Avenue, Campus Box 8086, St.Louis, Missouri 63110. E-mail: djlenihan@wustl.edu.Twitter: @ICOSociety, @kzhangmd, @joshmitchellmd,@vgzmd, @fischmd.RE F E RENCE S1. Curigliano G, Lenihan D, Fradley M, et al. Man-agement of cardiac disease in cancer patientsthroughout oncological treatment: ESMOconsensus recommendations. Ann Oncol 2020;31:171–90.2. Cardinale D, Colombo A, Sandri MT, et al. Pre-vention of high-dose chemotherapy-induced car-diotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–81.3. Buyse M, Sargent DJ, Grothey A, Matheson A,de Gramont A. Biomarkers and surrogate endpoints–the challenge of statistical validation. NatRev Clin Oncol 2010;7:309–17.4. Armenian SH, Lacchetti C, Barac A, et al. Pre-vention and monitoring of cardiac dysfunction insurvivors of adult cancers: American Society ofClinical Oncology Clinical Practice Guideline. J ClinOncol 2017;35:893–911.5. Cornell RF, Ky B, Weiss BM, et al. Prospectivestudy of cardiac events during proteasome inhib-itor therapy for relapsed multiple myeloma. J ClinOncol 2019;37:1946–55.6. Lenihan DJ, Stevens PL, Massey M, et al. Theutility of point-of-care biomarkers to detect car-diotoxicity during anthracycline chemotherapy: afeasibility study. J Cardiac Fail 2016;22:433–8.7. Daubert MA, Adams K, Yow E, et al. NT-proBNPgoal achievement is associated with significantreverse remodeling and improved clinical outcomesin HFrEF. J Am Coll Cardiol HF 2019;7:158–68.8. Kumar S, Dispenzieri A, Lacy MQ, et al. Revisedprognostic staging system for light chainamyloidosis incorporating cardiac biomarkers andserum free light chain measurements. J Clin Oncol2012;30:989–95.9. Zhang KW, Mitchell J, Alvarez-Cardona J, et al.Plasma hepatocyte growth factor for diagnosisand prognosis in light chain and transthyretincardiac amyloidosis. J Am Coll Cardiol CardioOnc2020;2:56–66.10. Palladini G, Dispenzieri A, Gertz MA, et al. Newcriteria for response to treatment in immunoglobulinlight chain amyloidosis based on free light chainmeasurement and cardiac biomarkers: impact onsurvival outcomes. J Clin Oncol 2012;30:4541–9.KEY WORDS amyloidosis, anthracyclines,biomarkers, cardiotoxicity, chemotherapy,detectionAlvarez-Cardona et al. J A C C : C A R D I O O N C O L O G Y , V O L . 2 , N O . 5 , 2 0 2 0Cardiac Biomarkers During Cancer Therapy D E C E M B E R 2 0 2 0 : 7 9 1 – 4794

Cardiac biomarkers during cancer therapy: Practical applications for cardio-oncology

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Cardiac biomarkers during cancer therapy: Practical applications for cardio-oncology

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